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CORK Bibliography: Prenatal Drug Exposure

69 citations. January 2009 to present

Prepared: September 2009

Altink ME; Slaats-Willemse DIE; Rommelse NNJ; Buschgens CJM; Fliers EA; Arias-Vasquez A et al. Effects of maternal and paternal smoking on attentional control in children with and without ADHD. European Child and Adolescent Psychiatry 18(8): 465-475, 2009. (56 refs.)

Maternal smoking during pregnancy is a risk factor for attention-deficit/hyperactivity disorder (ADHD), but data on its adverse effects on cognitive functioning are sparse and inconsistent. Since the effect of maternal smoking during pregnancy may be due to correlated genetic risk factors rather than being a pure environmental effect, we examined the effect of prenatal exposure to smoking on attentional control, taking into account the effects of both maternal and paternal smoking, and examined whether these effects were genetically mediated by parental genotypes. We further examined whether the effect of prenatal exposure to smoking on attentional control interacted with genotypes of the child. Participants were 79 children with ADHD, ascertained for the International Multi-centre ADHD Gene project (IMAGE), and 105 normal controls. Attentional control was assessed by a visual continuous performance task. Three genetic risk factors for ADHD (DRD4 7-repeat allele of the exon 3 variable number of tandem repeats (VNTR), DAT1 10/10 genotype of the VNTR located in the 3' untranslated region, and the DAT1 6/6 genotype of the intron 8 VNTR) were included in the analyses. Paternal smoking had a negative effect on attentional control in children with ADHD and this effect appeared to be mediated by genetic risk factors. The prenatal smoking effect did not interact with genotypes of the child. Maternal smoking had no main effect on attentional control, which may be due to lower smoking rates. This study suggests that the effects of paternal smoking on attentional control in children with ADHD should be considered a proxy for ADHD and/or smoking risk genes. Future studies should examine if the results can be generalized to other cognitive domains.

Andersen MR; Simonsen U; Uldbjerg N; Aalkjaer C; Stender S. Smoking cessation early in pregnancy and birth weight, length, head circumference, and endothelial nitric oxide synthase activity in umbilical and chorionic vessels: An observational study of healthy Ssngleton pregnancies. Circulation 119(6): 857-864, 2009. (41 refs.)

Background-Reduced production of the vasodilator nitric oxide (NO) in fetal vessels in pregnant smokers may lower the blood flow to the fetus and result in lower birth weight, length, and head circumference. The present study measured endothelial NO synthase (eNOS) activity in fetal umbilical and chorionic vessels from nonsmokers, smokers, and ex-smokers and related the findings to the fetal outcome. Methods and Results-Of 266 healthy, singleton pregnancies, 182 women were nonsmokers, 43 were smokers, and 41 stopped smoking early in pregnancy. eNOS activity and concentration were quantified in endothelial cells of the fetal vessels. Cotinine, lipid profiles, estradiol, L-arginine, and dimethylarginines that may affect NO production were determined in maternal and fetal blood. Serum cotinine verified self-reported smoking. Newborns of smokers had a lower weight (P <= 0.001) and a smaller head circumference (P <= 0.041) and were shorter (P <= 0.001) than newborns of nonsmokers and ex-smokers. eNOS activity in umbilical veins of smokers was 36% lower (P<0.001), eNOS concentration was 47% lower (P<0.001), and the fetal plasma level of high-density lipoprotein was 18% lower (P<0.001) than those of nonsmokers, whereas the same levels were found in umbilical veins from ex-smokers and nonsmokers. The same patterns in eNOS activity and concentration were found in umbilical arteries and chorionic vessels. Fetal plasma levels of estradiol, L-arginine, dimethylarginines, total cholesterol, and triglycerides were similar for nonsmokers, smokers, and ex-smokers. Conclusions-The findings suggest that maternal smoking reduces eNOS activity in the fetal vascular bed, contributing to retarded fetal growth caused by the reduction of vasodilatory capacity, and suggest that smoking cessation early in pregnancy prevents these effects in newborns.

Bagner DM; Sheinkopf SJ; Miller-Loncar C; LaGasse LL; Lester BM; Liu J et al. The effect of parenting stress on child behavior problems in high-risk children with prenatal drug exposure. Child Psychiatry & Human Development 40(1): 73-84, 2009. (31 refs.)

Objective: To examine the relationship between early parenting stress and later child behavior in a high-risk sample and measure the effect of drug exposure on the relationship between parenting stress and child behavior. Methods: A subset of child-caregiver dyads (n = 607) were selected from the Maternal Lifestyle Study (MLS), which is a large sample of children (n = 1,388) with prenatal cocaine exposure and a comparison sample unexposed to cocaine. Of the 607 dyads, 221 were prenatally exposed to cocaine and 386 were unexposed to cocaine. Selection was based on the presence of a stable caregiver at 4 and 36 months with no evidence of change in caregiver between those time points. Results: Parenting stress at 4 months significantly predicted child externalizing behavior at 36 months. These relations were unaffected by cocaine exposure suggesting the relationship between parenting stress and behavioral outcome exists for high-risk children regardless of drug exposure history. Conclusions: These results extend the findings of the relationship between parenting stress and child behavior to a sample of high-risk children with prenatal drug exposure. Implications for outcome and treatment are discussed.

Bakstad B; Sarfi M; Welle-Strand GK; Ravndal E. Opioid maintenance treatment during pregnancy: Occurrence and severity of neonatal abstinence syndrome. European Addiction Research 15(3): 128-134, 2009. (38 refs.)

Background: Opioid maintenance treatment (OMT) is widely used to treat pregnant women with a history of opioid dependence. This study investigated whether maternal methadone/buprenorphine dose and nicotine use in pregnancy affects the occurrence and duration of neonatal abstinence syndrome (NAS) in the infant. Methods: Forty-one pregnant women from OMT programmes in Norway who gave birth between January 2005 and January 2007 were enrolled in a national prospective study. Thirty-eight women (81% of the population) were interviewed in the last trimester of pregnancy and 3 months after delivery. Data from the European Addiction Severity Index and a questionnaire measuring enrolled birth information were compared with medical records and urine analyses. Results: Treatment requiring NAS occurred in 58% of the methadone-exposed and in 67% of the buprenorphine-exposed infants. There was no significant relationship between a maternal dose of methadone or buprenorphine in pregnancy and NAS treatment duration for the infant. The mean number of cigarettes consumed correlated significantly with NAS treatment duration for the methadone group. Birth weight for the methadone group was approximately 200 g above international findings despite high doses during pregnancy. Conclusions: Maternal methadone/buprenorphine dose predicted neither the occurrence nor the need for NAS treatment for the infant.

Bergin C; McCollough P. Attachment in substance-exposed toddlers: The role of caregiving and exposure. Infant Mental Health Journal 30(4): 407-423, 2009. (80 refs.)

Prenatal substance exposure is linked to adverse outcomes in children. Some adverse outcomes may result from insecure attachment and low-quality caregiving rather than from substance exposure. Little is known about the caregiving of poly substance-using mothers. To address this, low-income mothers (n = 41) with their substance-ex posed 12-month-olds were compared with a nonexposed group case-matched for other risk factors. Maternal sensitivity and involvement were analyzed from 2 hr of videotaped interaction. Attachment was assessed using the Attachment Q-Set. Attachment security and quality of caregiving were quite low for both groups, with no significant differences. In addition, regression analyses revealed that quality of caregiving predicted attachment, but amount of alcohol and cocaine exposure did not. These results suggest that among toddlers with social risk, substance exposure may not predict insecure attachment. Previous research linking attachment to exposure may be better explained by low-quality caregiving. Implications are that substance-exposed children, and nonexposed children with comparable social risk, are likely to need intervention to enhance maternal sensitivity and involvement to improve psychiatric outcomes.

Biederman J; Monuteaux MC; Faraone SV; Mick E. Parsing the associations between prenatal exposure to nicotine and offspring psychopathology in a nonreferred sample. Journal of Adolescent Health 45(2): 142-148, 2009. (35 refs.)

Purpose: Several studies have suggested an association between maternal smoking during pregnancy and both attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) in the offspring of women who smoke during pregnancy. However, it is unclear whether one or both of the documented links are spurious, given the considerable comorbidity between these disorders. The main aim of this study was to disentangle the association between maternal smoking during pregnancy with psychopathological outcomes, adjusting for possible confounders. Methods: Two large, identically designed, longitudinal, case-control family studies of male and female probands with and without ADHD were combined. We used data from the nonreferred siblings of the probands from both studies (n = 536). All subjects were blindly assessed with structured diagnostic interviews. Logistic regression analysis was used to determine the adjusted effect of exposure to maternal smoking during pregnancy. Results: Among all siblings, maternal smoking during pregnancy was significantly associated with ADHD, independent of CD and other covariates. In contrast, maternal smoking during pregnancy was a risk factor for CD only in siblings of control probands, after adjusting for covariates. Conclusions: These results support the hypothesis that maternal smoking during pregnancy is a risk factor for both ADHD and CD, independently of each other. However, the risk for CD appears to be conditional on family risk status.

Bisgaard H; Loland L; Holst KK; Pipper CB. Prenatal determinants of neonatal lung function in high-risk newborns. Journal of Allergy and Clinical Immunology 123(3): 651-657, 2009. (43 refs.)

Background: Neonatal lung function is suspected to be associated with wheezy disorders, but little is known about risk factors for the early lung function. Objectives: To study prenatal determinants of neonatal lung function. Methods: This is a clinical, prospective birth cohort study of 411 newborns, the Copenhagen Prospective Study on Asthma in Childhood, in a single-center research clinic dedicated solely to this longitudinal birth cohort study. Lung function was determined at I month of age by infant spirometry (the raised volume rapid thoraco-abdominal compression technique) and bronchial responsiveness to methacholine by transcutaneous oxygen measurements. Risk factor analyses included anthropometrics; demographics; socioeconomic factors; parental atopic history; previous deliveries; exposures during the third trimester to the mother's smoking, alcohol, and medicines; third trimester pregnancy complications including mother's asthma status; and mode of delivery. Results: Lung function was determined in 404 neonates, age 6 weeks. Neonates with body mass index in the upper quartile had 14% lower baseline forced expiratory volume at 0.5 second, and neonates of mothers smoking during the third trimester had 7% lower baseline forced expiratory volume at 0.5 second. Sex or parental atopic disease did not affect the neonatal lung function and bronchial responsiveness. Maternal intake of paracetamol during the third trimester was associated with doubling of the bronchial responsiveness in the neonates, but the statistical significance may have been driven by outliers. Bronchial responsiveness exhibited a parabola development with tripling of bronchial responsiveness reaching the nadir at 3 months of age, but this needs replication in a study with repetitive measurements within individuals. Conclusion: High body mass index in newborns and mothers smoking is associated with reduced neonatal lung function. This suggests that the association between body proportion and wheezing disorders may be a result of shared genes or prenatal nutrition.

Bouwstra H; Dijk-Stigter GR; Grooten HMJ; Janssen-Plas FEM; Koopmans AJ; Mulder CD et al. Prevalence of abnormal general movements in three-month-old infants. Early Human Development 85(6): 399-403, 2009. (32 refs.)

Background: The quality of general movements (GMs) is a sensitive tool to measure neurodevelopmental condition in early infancy. No information is available on prevalence rates of abnormal GMs in the general population. Objective: To assess the prevalence of abnormal GMs in the general population of three-month-old infants and to evaluate the association of abnormal GM quality with medical and social risk factors. Method: We recruited 535 infants in six well baby clinics in The Netherlands. GMs were video-taped at the corrected age of 2 to 4 months. GM-quality was assessed by two persons unaware of the infant's history. GM-quality was classified as normal optimal (NO), normal suboptimal (SO), mildly abnormal (MA) and definitely abnormal (DA). Only the last category implies clinically relevant dysfunction. Social, perinatal and postnatal characteristics were collected and their association with DA and abnormal (DA + MA) GMs were evaluated by means of univariate and logistic regression analyses. Results: GM-quality Could be assessed reliably in 455 infants (85%). Seventeen infants (3.7%) showed DA GMs and 113 (25%) MA GMs. DA GMs were associated with preterm birth and smoking during pregnancy; abnormal (DA + MA) GMs with preterm birth, a relatively low level of paternal profession and urban living conditions. These factors explained between 3% and 7% of variance. Conclusion: The study indicates that the prevalence of definitely abnormal GMs in the general population is 3.7% and that of mildly abnormal GMs 25%. The clinically relevant definitely abnormal GMs were associated with preterm birth and smoking during pregnancy.

Braun JM; Daniels JL; Kalkbrenner A; Zimmerman J; Nicholas JS. The effect of maternal smoking during pregnancy on intellectual disabilities among 8-year-old children. Paediatric and Perinatal Epidemiology 23(5): 482-491, 2009. (34 refs.)

Prenatal tobacco smoke exposure has been implicated as a risk factor for cognitive deficits in children. The purpose of this study is to examine the association between prenatal tobacco smoke exposure and diagnosis of intellectual disabilities (ID) among 8-year-old children living in Arkansas, Georgia, North Carolina and Utah. In 2002 and 2004, 965 ID case children were identified through a surveillance network and compared with the population of children born in the surveillance region during the same period (n = 104 607). Prenatal tobacco smoke exposure was determined from birth certificates. We estimated the effect of prenatal tobacco smoke exposure (none, < 10, 10-19 and >= 20 cigarettes per day) on ID using logistic regression. Generally, the risk of ID was mildly elevated among children whose mothers smoked >= 20 cigarettes per day during pregnancy [RR 1.34; 95% (confidence interval) CI 0.96, 1.87] after adjustment for maternal education, maternal race, maternal age, marital status, child sex, birth year and study site. However, the effect of exposure to >= 20 cigarettes per day significantly differed for males [RR 1.77, 95% CI 1.20, 2.62] compared with females [RR 0.81, 95% CI 0.44, 1.50]. Supplemental analyses reveal substantial confounding of this relationship by socio-economic indicators. A differential effect of tobacco smoke exposure on the risk of ID is suggested for males and females and deserves further investigation; however, the interpretation is tempered by the potential for residual confounding.

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.

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.

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.

Cloak CC; Ernst T; Fujii L; Hedemark B; Chang L. Lower diffusion in white matter of children with prenatal methamphetamine exposure. Neurology 72(24): 2068-2075, 2009. (27 refs.)

Background: Methamphetamine use is a common problem among women of childbearing age, leading to an increasing number of children with prenatal methamphetamine exposure. Whether microstructural brain changes associated with prenatal methamphetamine exposure can be detected with diffusion tensor imaging (DTI) is unknown. Method: Twelve-direction DTI was performed in 29 methamphetamine-exposed and 37 unexposed children ages 3-4 years on a 3-T MRI scanner. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were determined in the corpus callosum (genu and splenium) and bilaterally in the frontal and parietal white matter (WM), basal ganglia (caudate, putamen, globus pallidus), and thalamus. Results: Children with prenatal methamphetamine exposure had lower ADC in the frontal (right: -2.1%, p = 0.04; left: -2.0%, p = 0.09) and parietal WM (right: -3.9%, p = 0.002; left: -3.3%, p = 0.02) compared to unexposed children. The methamphetamine- exposed children also showed a trend for higher FA in the left frontal WM (-4.9%, p = 0.06) compared to the unexposed children. Conclusion: Since less myelination and higher dendritic or spine density have been reported in animals exposed to methamphetamine, lower diffusion in our children may reflect more compact axons or greater dendritic or spine density associated with prenatal methamphetamine exposure. These findings suggest alterations in white matter maturation in these children exposed to methamphetamine in utero.

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.

Dahshan A. Prenatal exposure to methamphetamine presenting as neonatal cholestasis. Journal of Clinical Gastroenterology 43(1): 88-90, 2009. (22 refs.)

Introduction: Methamphetamine has been recognized as a common cause of acute toxic hepatitis in adults with clinical and histologic features indistinguishable front acute viral hepatitis. Clinical presentation of methamphetamine hepatotoxicity ranges front mild acute hepatitis With prompt recovery to fulminant hepatic failure. The pathophysiology of this hepatotoxicity is not well elucidated Prenatal exposure to methamphetamine has been linked to intrauterine growth retardation and variety of withdrawal symptoms. Neonatal cholestasis is rare but serious problem that indicates hepatobiliary dysfunction and has several categories of etiologies. These include infectious, metabolic, endocrine, toxic, structural, familial, and autoimmune disorders. Cholestatic hepatitis is a recognized complication of exposure to some drugs including carbamazepine and trimethoprim-sulfamethoxazole. Case: A 35-week preterm, appropriate for gestational age, white girl was born to a 39-year-old mother who had no prenatal care. The mother's urine drug screen revealed methamphetamine. The baby passed pale meconium and her subsequent stools were hypopigmented. A detailed work up was done and was unremarkable except for hepatobiliary scintigraphy, with no activity noted in the small bowel on delayed imaging. An operative cholangiogram and liver biopsy were performed. The cholangiogram revealed patent title ducts. Liver biopsy was consistent with acute viral or toxic hepatitis. Gradual drop of bilirubin was noted. With negative extensive work LIP for other etiolog. known hepatotoxicity of methamphetamine, early onset of cholestasis that improved without specific therapy it is strongly suspected that prenatal exposure to methamphetamine is the most likely culprit in this patient. Discussion: This is the first recorded case of neonatal cholestasis related to prenatal exposure to methamphetamine. Methamphetamine is considered the fastest-growing illicit drug in United States. Hence, prenatal exposure to methamphetamine is expected to rise. Healthcare providers should become aware of the possibility of methamphetamine effect on the fetal liver. Raising awareness of the expectant mothers through the healthcare profession may reduce the risk of this condition.

Downing C; Balderrama-Durbin C; Hayes J; Johnson TE; Gilliam D. No effect of prenatal alcohol exposure on activity in three inbred strains of mice. Alcohol and Alcoholism 44(1): 25-33, 2009. (85 refs.)

Aims: Prenatal exposure to alcohol can have adverse effects on the developing fetus. Two of the hallmarks of children exposed to alcohol prenatally are attention deficits and hyperactivity. While hyperactivity has been observed in rats following prenatal ethanol exposure, few studies have examined these effects in mice. The present study investigated the effects of prenatal ethanol exposure on activity in mice from three inbred strains: C57BL/6 (B6), Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS). Methods: On Days 7 through 18 of gestation, mice were intragastrically intubated twice daily with either 3.0 g/kg ethanol (E) or an isocaloric amount of maltose-dextrin (MD); non-intubated control (NIC) litters were also generated. Offspring activity was monitored at 30, 60, 90 and 150 days of age. Results: While results showed no effects of prenatal ethanol exposure on any measures of activity, we did observe differences in baseline activity among the strains. ISS mice were more active than B6 and ILS for all activity measures except stereotypy; B6 mice had higher measures of stereotypy than ILS and ISS. Younger mice were more active than older mice. The only sex effects were on measures of stereotypy, where males had higher scores. Conclusions: Mice are an excellent organism to study genetic influences on many phenotypes. However, our study and others have shown few effects of prenatal ethanol exposure on behavior in mice. It appears as if the prenatal period in mice, corresponding to organogenesis, is not a sensitive period for producing behavioral deficits following ethanol exposure. It is likely that the first 2 weeks postnatally, corresponding to the brain growth spurt, are more sensitive for producing behavioral effects.

Dryden C; Young D; Hepburn M; Mactier H. Maternal methadone use in pregnancy: Factors associated with the development of neonatal abstinence syndrome and implications for healthcare resources. BJOG: An International Journal of Obstetrics and Gynaecology 116(5): 665-671, 2009. (43 refs.)

The objectives of this study were to investigate factors associated with the development of neonatal abstinence syndrome (NAS) and to assess the implications for healthcare resources of infants born to drug-misusing women. Retrospective cohort study from 1 January 2004 to 31 December 2006. Inner-city maternity hospital providing dedicated multidisciplinary care to drug-misusing women. Four hundred and fifty singleton pregnancies of drug-misusing women prescribed substitute methadone in pregnancy. Case note review. Development of NAS and duration of infant hospital stay. 45.5% of infants developed NAS requiring pharmacological treatment. The odds ratio of the infant developing NAS was independently related to prescribed maternal methadone dose rather than associated polydrug misuse. Breastfeeding was associated with reduced odds of requiring treatment for NAS (OR 0.55, 95% CI 0.34-0.88). Preterm birth did not influence the odds of the infant receiving treatment for NAS. 48.4% infants were admitted to the neonatal unit (NNU) 40% of these primarily for treatment of NAS. The median total hospital stay for all infants was 10 days (interquartile range 7-17 days). Infants born to methadone-prescribed drug-misusing mothers represented 2.9% of hospital births, but used 18.2% of NNU cot days. Higher maternal methadone dose is associated with a higher incidence of NAS. Pregnant drug-misusing women should be encouraged and supported to breastfeed. Their infants are extremely vulnerable and draw heavily on healthcare resources.

Dwyer JB; McQuown SC; Leslie FM. The dynamic effects of nicotine on the developing brain. (review). Pharmacology & Therapeutics 122(2): 125-139, 2009

Nicotinic acetylcholine receptors (nAChRs) regulate critical aspects of brain maturation during the prenatal, early postnatal, and adolescent periods. During these developmental windows, nAChRs are often transiently upregulated or change subunit composition in those neural structures that are undergoing major phases of differentiation and synaptogenesis, and are sensitive to environmental stimuli. Nicotine exposure, most often via tobacco smoke, but increasingly via nicotine replacement therapy, has been shown to have unique effects on the developing human brain. Consistent with a dynamic developmental role for acetylcholine, exogenous nicotine produces effects that are unique to the period of exposure and that impact the developing structures regulated by acetylcholine at that time. Here we present a review of the evidence, available from both the clinical literature and preclinical animal models, which suggests that the diverse effects of nicotine exposure are best evaluated in the context of regional and temporal expression patterns of nAChRs during sensitive maturational periods, and disruption of the normal developmental influences of acetylcholine. We present evidence that nicotine interferes with catecholamine and brainstem autonomic nuclei development during the prenatal period of the rodent (equivalent to first and second trimester of the human), alters the neocortex, hippocampus, and cerebellum during the early postnatal period (third trimester of the human), and influences limbic system and late monoamine maturation during adolescence.

Fenercioglu AK; Tamer I; Karatekin G; Nuhogiu A. Impaired postnatal growth of infants prenatally exposed to cigarette smoking. Tohoku Journal of Experimental Medicine 218(3): 221-228, 2009. (15 refs.)

Most of the previous studies have shown a significant inverse relationship between smoking during pregnancy and weight, height and head circumference of infants at birth, but there is limited literature that assesses the head circumference measures of infants of smoker mothers in postnatal follow-up. The aim of this study was to assess the effects of maternal smoking and passive smoking during pregnancy on postnatal anthropometric measures of infants. Infants were divided into 3 groups: infants of smokers (n = 48), passive smokers (n = 57) and nonsmokers (n = 54), and were evaluated for their weight, height and head circumference at birth, 3 months and 6 months of age. Infants of smokers showed significant weight and head circumference deficits at birth compared to nonsmokers' infants (p < 0.05 and p < 0.001, respectively). At 6 months of age, infants of smokers continued to show significant deficits in all 3 measures compared to nonsmokers' infants (p < 0.001 for each), and infants of passive smokers showed only marginal decreases. Moreover, the weight and height growth velocities of the smokers' infants remained deficient, whereas their growth velocity of the head circumferences increased from birth up to 6 months and reached the growth velocity of the nonsmokers' infants. Infants of passive smokers showed a complete catch-up growth at 6 months. This study indicates that smoking during pregnancy results in serious deficits in infants' growth even after birth. Therefore, it is essential to inform smoker women before pregnancy the possible growth retardation of infants.

Gaither KH; Huber LRB; Thompson ME; Huet-Hudson YM. Does the use of nicotine replacement therapy during pregnancy affect pregnancy outcomes? Maternal and Child Health Journal 13(4): 497-504, 2009. (27 refs.)

Objectives: Although nicotine replacement therapies (NRT) may assist with smoking cessation, little is known about the safety of NRT use during pregnancy. Our purpose was two-fold: to determine characteristics of women prescribed or recommended NRT during pregnancy and to investigate whether NRT prescription/recommendation was associated with adverse pregnancy outcomes using data from the 2004 Pregnancy Risk Assessment Monitoring System. Methods: Smoking and NRT referral was self-reported by 5,716 women. Information on pregnancy outcomes was obtained from birth certificates. Multivariate logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results Smokers < 35 years of age and of Hispanic, Non-Hispanic Black, and Asian/Pacific Islander race/ethnicity were less likely to be prescribed or recommended NRT during pregnancy. After adjustment for age, marital status, education, and race/ethnicity, women recommended NRT had twice the risk of low birthweight as compared to nonsmokers (OR = 1.95, 95% CI: 1.10, 3.46) while smokers had 1.31 times the risk of low birthweight (95% CI: 0.92, 1.87). Results for preterm birth were similar after adjustment for the same confounding variables (NRT: OR = 2.04, 95% CI: 1.14, 3.63 and smoking: OR = 1.09, 95% CI: 0.74, 1.61). Conclusions: Risks of low birthweight and preterm birth were highest for women prescribed or recommended NRT. These findings may be related to frequency of maternal smoking. While heavier smokers may be more likely to be recommended NRT, they also may have the most difficulty with cessation. Greater efforts should be made to ensure that these women do successfully cease smoking.

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.

Gray TR; Kelly T; LaGasse LL; Smith LM; Derauf C; Haning W et al. Novel biomarkers of prenatal methamphetamine exposure in human meconium. Therapeutic Drug Monitoring 31(1): 70-75, 2009. (40 refs.)

Meconium analysis can detect fetal exposure to drugs taken by the mother during pregnancy. Methamphetamine (MAMP) and amphetamine (AMP) have previously been observed in meconium of MAMP-exposed neonates; the presence of other metabolites has not been investigated. Detection of such analytes may lead to more sensitive identification and thus improved medical treatment of affected infants. Forty-three MAMP-positive meconium specimens were analyzed for newly identified MAMP biomarkers, p-hydroxymethamphetamine, p-hydroxyamphetamine, and norephedrine. Due to MAMP adulteration in illicit ecstasy and to simultaneously monitor 3,4-methylenedioxymethamphetaniine and MAMP prenatal exposure, 3,4-methylenedioxymethamphetamine, its metabolites, and related sympathomimetic amines were assayed. MAMP AM-P, and unconjugated p-hydroxyrnethamphetamine were the most prevalent and abundant analytes present in meconium; however, unconjugated p-hydroxyamphetarnine and norephedrine also were identified. It is possible that one of these additional analytes could be important for predicting toxicity or maternal or neonatal outcome measures in fetuses exposed to MAMP at specific gestational ages or with different metabolic capabilities. Although these new biomarkers were present in lower concentrations than MAMP and AMP in the meconium of previously confirmed specimens, additional research will determine if inclusion of these analytes can increase identification of MAMP-exposed neonates. Novel methamphetamine biomarker concentrations were characterized in meconium of infants exposed in utero to MAMP

Grazuleviciene R; Danileviciute A; Nadisauskiene R; Vencloviene J. Maternal smoking, GSTM1 and GSTT1 polymorphism and susceptibility to adverse pregnancy outcomes. International Journal of Environmental Research and Public Health 6(3): 1282-1297, 2009. (40 refs.)

The objective of the study was to investigate the association between maternal smoking, GSTM1, GSTT1 polymorphism, low birth weight (LBW, < 2,500 g) and intrauterine growth restriction (IUGR, < 2,500 g and gestation >= 37 weeks) risk. Within a prospective cohort study in Kaunas (Lithuania), a nested case-control study on LBW and IUGR occurrence among 646 women with genotyping of GSTT1 and GSTM1 polymorphisms who delivered live singletons was conducted. Multivariate logistic regression analysis was used to study the association of maternal smoking and polymorphism in two genes metabolizing xenobiotics. Without consideration of genotype, light-smoking (mean 4.8 cigarettes/day) during pregnancy was associated with a small increase in LBW risk, adjusted OR 1.21; 95% CI 0.44 - 3.31. The corresponding odds for IUGR risk was 1.57; 95% CI 0.45 - 5.55. The findings suggested the greater LBW risk among light-smoking mothers with the GSTM1-null genotype (OR 1.91; 95% CI 0.43 - 8.47) compared to those with GSTM1-present genotype (OR 1.11; 95% CI 0.26 - 4.47). When both GSTM1 and GSTT1 genotypes were considered, the synergistic effect was found among smoking mothers: GSTT1-present and GSTM1-null genotype OR for LBW was 3.31; 95% CI 0.60-18.4 and that for IUGR was 2.47; 95% CI 0.31 - 13.1. However there was no statistically significant interaction between maternal smoking, GSTT1-present and GSTM1-null genotypes for LBW (OR 1.45; 95% CI 0.22 - 10.1, p = 0.66) and for IUGR (OR 1.10; 95% CI 0.10 - 12.6, p = 0.93). The results of this study suggested that smoking, even at a low-level, ought to be considered a potential risk factor for adverse birth outcomes and that genetic polymorphism may contribute to individual variation in tobacco smoke response.

Jackson IT; Kelly C; Bello-Rojas G. Palatal fistulae resulting from cocaine abuse. Annals of Plastic Surgery 62(1): 67-69, 2009. (13 refs.)

Cocaine fistulae require repair with well-vascularized material. In the technique used this is accomplished by closure of the nasal layer by delayed palatal flaps and the oral layer with a tongue flap. Three cases are presented.

Jahanfar S; Sharifah H. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome. (review). Cochrane Database of Systemic Reviews 2009(2): article CD006965, 2009. (33 refs.)

Background: Maternal caffeine consumption during pregnancy may have adverse effects on fetal, neonatal and maternal outcomes. Objectives This review investigates the effects of restricting caffeine intake by mothers on fetal, neonatal and pregnancy outcomes. Search strategy: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register ( December 2008), scanned bibliographies of published studies and corresponded with investigators. Selection criteria: Randomised controlled trials including quasi-randomised controlled trials (RCTs) investigating the effect of caffeine and/ or supplementary caffeine versus restricted caffeine intake or placebo on pregnancy outcome. Data collection and analysis: The two review authors independently assessed trial quality and extracted data. Main results: One study met the inclusion criteria. Caffeinated instant coffee ( 568 women) was compared with decaffeinated instant coffee ( 629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight or length of gestation. Authors' conclusions: There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome. PLAIN LANGUAGE SUMMARY: Caffeine is a stimulant found in tea, coffee, cola, chocolate and some over-the-counter medicines. Conflicting results found in the literature make it difficult for health professionals to advise pregnant women about avoiding caffeine during pregnancy. Clearance of caffeine from the mother's blood slows down during pregnancy. Some authors of observational studies have concluded that caffeine intake is harmful to the fetus, causing growth restriction, reduced birthweight, preterm birth or stillbirth. The newborn could also have withdrawal symptoms if the mother has a high intake of caffeine ( more than eight cups of coffee per day). Only one controlled study was identified. The study was based in Denmark. Women less than 20 weeks pregnant were randomly assigned to drinking caffeinated instant coffee ( 568 women after exclusions) or decaffeinated instant coffee ( 629 women). Drinking three cups of coffee a day in early pregnancy had no effect on birthweight, preterm births or growth restriction. Sufficient evidence is not available from randomised controlled trials to support any benefits from avoiding caffeine during pregnancy.

Jansen PW; Tiemeier H; Looman CWN; Jaddoe VWV; Hofman A; Moll HA et al. Explaining educational inequalities in birthweight: the Generation R Study. Paediatric and Perinatal Epidemiology 23(3): 216-228, 2009. (54 refs.)

Although low socio-economic status has consistently been associated with lower birth-weight, little is known about the factors whereby socio-economic disadvantage influences birthweight. We therefore examined explanatory mechanisms that may underlie the association between the educational level of pregnant women, as an indicator of socio-economic status, and birthweight. The study was embedded within a population-based cohort study in the Netherlands. Information on maternal education, offspring's birthweight and several determinants of birthweight was available for 3546 pregnant women of Dutch origin. Infants of the lowest educated women had a statistically significantly lower birthweight than infants of the highest educated women [difference adjusted for gender and gestational age: -123 g (95% CI -167, -79)]. Parity, age of the pregnant women, hypertension, parental height and parental birthweight, marital status, pregnancy planning, financial concerns, number of people in household, weight gain and smoking habits individually explained part of the differences in birthweight, while adjustment for working hours and body mass index resulted in increases in birthweight differences between the educational levels. After full adjustment, the difference in birthweight between lowest and highest education was reduced by 66%. Our study confirmed remarkable educational inequalities in birthweight, a large part of which was explained by pregnancy characteristics, anthropometrics, the psychosocial and material situation, and lifestyle-related factors. Altering smoking habits may be an option to reduce educational differences in birthweight, as many lower-educated women tend to continue smoking during pregnancy. In order to tackle inequalities in birthweight, it is important that interventions are accessible for pregnant women in lower socioeconomic strata.

Jansson LM; Dipietro JA; Velez M; Elko A; Knauer H; Kivlighan KT. Maternal methadone dosing schedule and fetal neurobehaviour. Journal of Maternal-Fetal & Neonatal Medicine 22(1): 29-35, 2009. (23 refs.)

Objective. Daily methadone maintenance is the standard of care for opiate dependency during pregnancy. Previous research has indicated that single-dose maternal methadone administration significantly suppresses fetal neurobehaviours. The purpose of this study was to determine if split-dosing would have less impact on fetal neurobehaviour than single-dose administration. Methods. Forty methadone-maintained women were evaluated at peak and trough maternal methadone levels on single- and split-dosing schedules. Monitoring sessions occurred at 36- and 37-weeks gestation in a counterbalanced study design. Fetal measures included heart rate, variability, accelerations, motor activity and fetal movement-heart rate coupling (FM-FHR). Maternal measures included heart period, variability, skin conductance, respiration and vagal tone. Repeated measure analysis of variance was used to evaluate within-subject changes between split- and single-dosing regimens. Results. All fetal neurobehavioural parameters were suppressed by maternal methadone administration, regardless of dosing regimen. Fetal parameters at peak were significantly lower during single versus split methadone administration. FM-FHR coupling was less suppressed from trough to peak during split-dosing versus single-dosing. Maternal physiologic parameters were generally unaffected by dosing condition. Conclusion. Split-dosed fetuses displayed less neurobehavioural suppression from trough to peak maternal methadone levels as compared with single-dosed fetuses. Split-dosing may be beneficial for methadone-maintained pregnant women.

Johansen AMW; Wilcox AJ; Lie RT; Andersen LF; Drevon CA. Maternal consumption of coffee and caffeine-containing beverages and oral clefts: A population-based case-control study in Norway. American Journal of Epidemiology 169(10): 1216-1222, 2009. (23 refs.)

A large, population-based case-control study of facial clefts was carried out in Norway between 1996 and 2001. The study included 573 cases-025EF377 with cleft lip with or without cleft palate and 196 with cleft palate only-025EFand 763 randomly selected controls. Maternal consumption of coffee and other caffeine-containing beverages in early pregnancy was recorded shortly after birth. Compared with that for no coffee consumption, the adjusted odds ratios for cleft lip with or without cleft palate were 1.39 (95% confidence interval: 1.01, 1.92) for less than 3 cups a day and 1.59 (95% confidence interval: 1.05, 2.39) for 3 cups or more. Coffee consumption was not associated with risk of cleft palate only (for >= 3 cups vs. none, adjusted odds ratio = 0.96, 95% confidence interval: 0.55, 1.67). Tea consumption was associated with a reduced odds ratio of both cleft lip with or without cleft palate and cleft palate only. There was little evidence of an association between caffeine exposure and clefts when all sources of caffeine were considered. Adjustment for known confounding factors in general had minor effects on risk estimates. Still, the authors could not rule out the possibility of uncontrolled confounding by factors associated with the habit of drinking coffee.

Johansson ALV; Dickman PW; Kramer MS; Cnattingius S. Maternal smoking and infant mortality: Does quitting smoking reduce the risk of infant death? Epidemiology 20(4): 590-597, 2009. (20 refs.)

Background: Maternal smoking has repeatedly been associated with increased infant mortality rates. No study has investigated whether smoking cessation influences the risk of infant death. This study estimates infant mortality after the second pregnancy in relation to smoking behavior in both the first and the second pregnancy. Methods: We used the Swedish Medical Birth Register to identify women who delivered their first and second singleton infants during 1983-2002. Maternal smoking during the 2 pregnancies was categorized into (1) never smoker, (2) quitter, (3) starter, and (4) persistent smoker. In the second pregnancy, 555,046 live births (of at least 22 completed gestational weeks) were followed for infant death within 1 year. Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Compared with infants born to never smokers, the HR (95% CI) of infant mortality in the second pregnancy was 2.0 (1.7-2.4) among infants born to persistently heavy smokers, whereas among women who stopped smoking in the second pregnancy, the HRs were 1.4 (1.0-2.0) among those who had been heavy smokers in the first pregnancy, and 1.0 (0.8-1.2) among those who had been light smokers. The association of smoking during pregnancy with infant mortality was modified by infant's age, and was strongest at 4-15 weeks after birth. The smoking effect on neonatal mortality, but not postneonatal mortality, was mediated by gestational age. Conclusions: Smoking cessation reduced the risk of infant death. The smoking-related risk of neonatal mortality appears to be mediated by smoking effects on gestational age, a factor that only partly explains the association between smoking and postneonatal mortality.

Kable JA; Coles CD; Lynch ME; Carroll J. The impact of maternal smoking on fast auditory brainstem responses. Neurotoxicology and Teratology 31(4): 216-224, 2009. (91 refs.)

Deficits in auditory processing have been posited as one of the underlying neurodevelopmental consequences of maternal smoking during pregnancy that leads to later language and reading deficits. Fast auditory brainstem responses were used to assess differences in the sensory processing of auditory stimuli among infants with varying degrees of prenatal cigarette exposure. Maternal report of consumption of cigarettes and blood samples were collected in the hospital to assess exposure levels and participants were then seen at 6-months. To participate in the study, all infants had to pass the newborn hearing exam or a clinically administered ABR and have no known health problems. After controlling for participant age, maternal smoking during pregnancy was negatively related to latency of auditory brainstem responses. Of several potential covariates, only perinatal complications and maternal alcohol use were also related to latency of the ABR responses and maternal smoking level accounted for significant unique variance after controlling for these factors. These results suggest that the relationship between maternal smoking may lead to disruption in the sensory encoding of auditory stimuli.

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.

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.

Lim S; Prasad MR; Samuels P; Gardner DK; Cordero L. High-dose methadone in pregnant women and its effect on duration of neonatal abstinence syndrome. American Journal of Obstetrics and Gynecology 200(1): Article Number: 70.e1, 2009. (18 refs.)

OBJECTIVE: The purpose of this study was to examine high-dose methadone in pregnant women and its effect on the duration of neonatal abstinence syndrome. STUDY DESIGN: This was a retrospective chart review of 68 neonates and their mothers who received methadone therapy during pregnancy. The last dosage of maternal methadone just before delivery and the length of treatment for neonatal abstinence syndrome were examined with an analysis of variance model. RESULTS: When the data were analyzed for methadone dosages as a continuous variable, each 1-mg increase in the last maternal methadone dosage before delivery was associated with an additional 0.18 days of infant treatment for neonatal abstinence syndrome (P < .001; 95% CI, 0.112-0.255). In other words, every increase of 5.5 mg of methadone in the mother was associated statistically with 1 additional day of neonatal abstinence syndrome treatment for the infant. Gestational age at delivery and birthweight were not statistically significant. CONCLUSION: Higher doses of maternal methadone were associated with an increase in diagnosis and longer duration of neonatal abstinence syndrome.

Lu LH; Johnson A; O'Hare ED; Bookheimer SY; Smith LM; O'Connor MJ et al. Effects of prenatal methamphetamine exposure on verbal memory revealed with functional magnetic resonance imaging. Journal of Developmental and Behavioral Pediatrics 30(3): 185-192, 2009. (30 refs.)

Objective: Efforts to understand specific effects of prenatal methamphetamine (MA) exposure on cognitive processing are hampered by high rates of concomitant alcohol use during pregnancy. We examined whether neurocognitive systems differed among children with differing prenatal teratogenic exposures when they engaged in a verbal memory task. Patients and Methods: Participants (7-15 years) engaged in a verbal paired associate learning task while undergoing functional magnetic resonance imaging. The MA group included 14 children with prenatal MA exposure, 12 of whom had concomitant alcohol exposure. They were compared with 9 children with prenatal alcohol but not MA exposure (alcohol-exposed only) and 20 unexposed controls. Groups did not differ in age, gender, or socioeconomic status. Participants' IQ and verbal learning performance were measured using standardized instruments. Results: The MA group activated more diffuse brain regions, including bilateral medial temporal structures known to be important for memory, than both the alcohol-exposed only and the CON groups. These group differences remained after IQ was covaried. More activation in medial temporal structures by the MA group compared with the alcohol-exposed only group cannot be explained by performance differences because both groups performed at similar levels on the verbal memory task. Conclusions: More diffuse activation in the MA group during verbal memory may reflect recruitment of compensatory systems to support a weak verbal memory network. Differences in activation patterns between the MA and alcohol-exposed only groups suggest that prenatal MA exposure influences the development of the verbal memory system above and beyond effects of prenatal alcohol exposure.

Malanga CJ. Still no time for complacency: Developmental effects of prenatal methamphetamine exposure. (editorial). Neurology 72(24): 2062-2063, 2009. (10 refs.)

Marin SJ; Keith L; Merrell M; McMillin GA. Comparison of drugs of abuse detection in meconium by EMIT (R) II and ELISA. Journal of Analytical Toxicology 33(3): 148-154, 2009. (20 refs.)

The results of meconium specimens and fortified samples screened for drugs of abuse by both enzyme multiplied immunoassay technique (EMIT(r) II) and enzyme-linked immunosorbent assay (ELISA) methods were compared. The sample preparation for the ELISA screen was a simple buffer extraction versus a lengthy and more laborious sample preparation procedure for the EMIT II screen. The ELISA method was automated using a TECAN Genesis. The EMIT II analysis was automated with an Olympus AU400e. The opioid screen was calibrated with hydromorphone and the benzodiazepine screen was calibrated with clonazepam to maximize detection for these analytes. Previously validated gas chromatography-mass spectrometry (GC-MS), two-dimensional GC-MS, or liquid chromatography-tandem MS methods were used for confirmation. Results from the two techniques compared well. Agreement of the ELISA assay was greater than 90% when compared to EMIT II for all drug classes except barbiturates and benzodiazepines. ELISA appears to be more sensitive than EMIT II for the detection of amphetamines, methadone, propoxyphene, and cocaine. ELISA compared well to EMIT II for cannabinoids, opioids, and PCP. Specificity of the ELISA assay was slightly better for PCP and opioids. EMIT II appears to be more sensitive for the detection of barbiturates and benzodiazepines. The ELISA method reduced turnaround time by 50% compared to the EMIT II method.

Min MYO; Singer LT; Kirchner HL; Minnes S; Short E; Hussain Z et al. Cognitive development and low-level lead exposure in poly-drug exposed children. Neurotoxicology and Teratology 31(4): 225-231, 2009. (67 refs.)

The impact of early postnatal lead exposure measured at age 4 on children's IQ and academic achievement at and 11 years of age was examined. The sample consisted of 278 inner-city, primarily African American children who were polydrug exposed prenatally. Regression analyses indicated a linear effect of lead exposure on outcomes and no moderating effects of polydrug exposure. An IQ loss of about 4.1-5.4 Full Scale IQ points was estimated for each 10 mu g/dL increase in blood lead level at ages 4, 9, and 11 years as a function of blood lead level at age 4. Decrements in scores on tests of non-verbal reasoning were consistently associated with higher lead levels at age 4, while verbal decrements became apparent only at age 11. Lower reading summary scores at 9 and 11 years were consistently associated with higher lead exposure, while decrements in mathematics were not apparent until 11 years. Subgroup analyses on children with blood lead levels <10 mu g/dL showed detrimental lead effects even at the 5 mu g/dL level, providing additional evidence of adverse effects occurring at blood lead levels below the current 10 mu g/dL public health blood lead action level.

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.

Morales E; Sunyer J; Julvez J; Castro-Giner F; Estivill et al. GSTM1 polymorphisms modify the effect of maternal smoking during pregnancy on cognitive functioning in preschoolers. International Journal of Epidemiology 38(3): 690-697, 2009. (45 refs.)

Background Maternal smoking during pregnancy is associated with cognitive deficits in children. Parental factors are proposed as an explanatory. We studied the influence of GSTM1 and GSTT1 polymorphisms on the cognition effects induced by active maternal smoking during pregnancy. Methods Children (n = 384) from a prospective population-based birth cohort were assessed at 4 years. The McCarthy Scales of Children's Abilities (MCSA) was administrated. Maternal smoking was measured by questionnaire. Genotyping was conducted for null alleles from GSTM1 and GSTT1. Multivariable linear regression models were used to examine the association between active maternal smoking during pregnancy and MCSA outcomes by GSTM1 and GSTT1 genotypes. Results Maternal smoking during pregnancy (reporting, yes) was inversely associated with global cognitive score among children having null allele for GSTM1 (beta = 4.73, 95% CI -9.45 to -0.02); but not among children with present allele (beta = 1.04, 95% CI -7.88 to 5.81) ( P for interaction 0.089). The interaction remained after adjusting by post-natal maternal smoking (P = 0.081). The effect was stronger for perceptual-performance (beta = -3.68, 95% CI -8.39 to 1.03; P for interaction 0.087), quantitative (beta = 7.00, 95% CI -17.39 to 3.39; P for interaction 0.048), verbal (beta = 3.63, 95% CI -8.43 to 1.17; P for interaction 0.264) and executive function (beta = -4.87, 95% CI -9.55 to -0.20; P for interaction 0.127). No interaction was found for GSTT1. Conclusions GSTM1 deficiency increases the adverse effects of active maternal smoking during pregnancy on cognition in preschoolers, suggesting a biological interaction between child metabolic genes and tobacco smoke components in detoxification process during foetal neurodevelopment.

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

Obel C; Linnet KM; Henriksen TB; Rodriguez A; Jarvelin MR; Kotimaa A et al. Smoking during pregnancy and hyperactivity-inattention in the offspring-comparing results from three Nordic cohorts. International Journal of Epidemiology 38(3): 698-705, 2009. (32 refs.)

Background: Prenatal exposure to smoking has been associated with Attention Deficit Hyperactivity Disorder (ADHD) in a number of epidemiological studies. However, mothers with the ADHD phenotype may 'treat' their problem by smoking and therefore be more likely to smoke even in a society where smoking is not acceptable. This will cause genetic confounding if ADHD has a heritable component, especially in populations with low prevalence rates of smoking since this reason for smoking is expected to be proportionally more frequent in a population with few 'normal' smokers. We compared the association in cohorts with different smoking frequencies. Methods A total of 20 936 women with singleton pregnancies were identified within three population-based pregnancy cohorts in Northern Finland (1985-1986) and in Denmark (1984-1987 and 1989-1991). We collected self-reported data on their pre-pregnancy and pregnancy smoking habits and followed the children to school age where teachers and parents rated hyperactivity and inattention symptoms. Results: Children, whose mothers smoked during pregnancy, had an increased prevalence of a high hyperactivity-inattention score compared with children of nonsmokers in each of the cohorts after adjustment for confounders but we found no statistical significant difference between the associations across the cohorts. Conclusion: The estimated association was not strongest in the population with the fewest smokers which does not support the hypothesis that the association is entirely due to genetic confounding.

O'Callaghan FV; Al Mamun A; O'Callaghan M; Alati R; Najman JM; Williams GM et al. Maternal smoking during pregnancy predicts nicotine disorder (dependence or withdrawal) in young adults: A birth cohort study. Australian And New Zealand Journal of Public Health 33(4): 371-377, 2009. (44 refs.)

Objective: To investigate whether maternal smoking during pregnancy predicts offspring nicotine disorder (dependence or withdrawal) at 21 years. Method: Participants comprised a prospective birth cohort involving 7,223 singleton children whose mothers were enrolled between 1981 and 1983 at the first antenatal visit to the Mater Mothers' Hospital, Brisbane, Queensland. The present sub-cohort consisted of 2,571 youth who completed the Composite International Diagnostic Interview-computerised version (CIDI-Auto) that assesses nicotine dependence and withdrawal according to DSM-IV diagnostic criteria at the 21-year follow-up. Results: 12.8% of offspring met criteria for nicotine dependence and 8.5% met criteria for withdrawal. 16.6% met criteria for either dependence or withdrawal. Smoking during pregnancy resulted in offspring being more likely to have dependence or withdrawal at 21 years than offspring of mothers who never smoked (age adjusted odds ratio 1.53 (95% CI: 1.19-1.96). Conclusions: Findings emphasise the long-term adverse effects of maternal smoking during pregnancy, including nicotine dependence in young adult offspring. Implications: Public health approaches should strengthen arguments for mothers to cease smoking during pregnancy in view of the long-term health implications for offspring, and reinforce measures to help smokers among pregnant women and women of childbearing age to stop.

O'Donnell M; Nassar N; Leonard H; Hagan R; Mathews R; Patterson Y et al. Increasing prevalence of neonatal withdrawal syndrome: Population study of maternal factors and child protection involvement. Pediatrics 123(4): E614-E621, 2009. (28 refs.)

OBJECTIVES. Illicit drug use during pregnancy is an important public health issue, with adverse effects on the newborn and implications for subsequent parenting. The aim of this study was to measure the birth prevalence of neonatal withdrawal syndrome over time, associated maternal characteristics and child protection involvement. METHODS. This is a retrospective cohort study that used linked health and child protection databases for all live births in Western Australia from 1980 to 2005. Maternal characteristics and mental health- and assault-related medical history were assessed by using logistic regression models. RESULTS. The birth prevalence of neonatal withdrawal syndrome increased from 0.97 to a high of 42.2 per 10 000 live births, plateauing after 2002. Mothers with a previous mental health admission, low skill level, Aboriginal status or who smoked during pregnancy were significantly more likely to have an infant with neonatal withdrawal syndrome. These infants were at greater risk for having a substantiated child maltreatment allegation and entering foster care. Increased risk for maltreatment was associated with mothers who were aged <30 years, were from socially disadvantaged backgrounds, Aboriginal status, and had a mental health- or assault-related admission. CONCLUSIONS. There has been a marked increase in neonatal withdrawal syndrome in the past 25 years. Specific maternal characteristics identified should facilitate planning for early identification and intervention for these women. Findings demonstrate an important pathway into child maltreatment and highlight the need for well-supported programs for women who use illicit drugs during pregnancy as well as the support after birth. Pediatrics 2009; 123: e614-e621

O'Reilly EJ; Chen HL; Gardener H; Gao X; Schwarzschild MA; Ascherio A. Smoking and Parkinson's Disease: Using parental smoking as a proxy to explore causality. American Journal of Epidemiology 169(6): 678-682, 2009. (18 refs.)

In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated with a lower risk of Parkinson's disease, but whether this association is causal remains controversial. Alternatively, an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that determine smoking behavior and the future risk of Parkinson's disease. If so, parental smoking, commonly established before the birth of the first child, would be unlikely to be related to Parkinson's disease risk. The authors assessed the association between Parkinson's disease and parental smoking during childhood in the Nurses' Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and 18 years of follow-up, respectively, 455 newly diagnosed Parkinson's disease cases were documented among those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson's disease was 0.73 (95% confidence interval: 0.53, 1.00; P-trend = 0.04) comparing participants who reported that both parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not materially change the results. If the inverse association between smoking and Parkinson's disease were due to confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking would predict Parkinson's disease.

Paul IM; Lehman EB; Widome R. Maternal tobacco use and shorter newborn nursery stays. American Journal of Preventive Medicine 37(2, Supplement S): S172-S178, 2009. (35 refs.)

Objective: Nationally, 10%-15% of women report smoking during the last 3 months of pregnancy. Because the joint Commission on Accreditation of Healthcare Organizations (now the joint Commission) requires all U.S. hospitals to be smoke-free, and because tobacco is addictive, the maternal desire to smoke after childbirth could lead to requests for early hospital discharge for mothers and newborns. The authors hypothesized that maternal tobacco use would be associated with shorter newborn nursery hospital stays. Methods: Birth records from 405,622 singleton, "well" newborns, >= 35 weeks gestation born from 1998 to 2002 in Pennsylvania were merged with perinatal hospital record data and analyzed from 2006 to 2008. Perinatal data from 67,145 mothers self-reporting as having smoked cigarettes on the Certificate of Live Birth and data on their infants were compared 1:2 with data from mothers reporting to he nonsmokers and their infants via chi-square tests with odds ratios, 2-sample t-tests, and multiple linear regression. Results: In Pennsylvania, 16.6% of mothers smoked cigarettes during pregnancy. Tobacco-using mothers were more likely to be insured by Medicaid, unmarried, adolescent, not college educated, and have late inset of prenatal care. Their newborns were more likely to be low birth weight and be born at 35-36 weeks gestation. Nonetheless, these newborns had a significantly shorter mean length of stay (48.9 hours vs 52.4 hours; p<0.001), even after adjusting for confounders. A significant inverse relationship existed between number of cigarettes smoked per day by mothers and nursery length of stay for newborns. Conclusions: Hospital smoking bans send a strong public health message regarding the risks of tobacco and protect patients and staff from secondhand smoke exposure. However, the association between maternal tobacco use and shorter newborn hospital stays may demonstrate an unintended consequence for the vulnerable population of newborns whose mothers smoke. This association should be considered during prenatal counseling, where smoking cessation can be emphasized, and at the time of mother and infant discharge. These findings are particularly important given the health and socioeconomic disparities between smoking mother-infant pairs and their nonsmoking counterparts.

Paz MS; Smith LM; LaGasse LL; Derauf C; Grant P; Shah R et al. Maternal depression and neurobehavior in newborns prenatally exposed to methamphetamine. Neurotoxicology and Teratology 31(3): 177-182, 2009. (60 refs.)

Background: The effects of maternal depression on neonatal neurodevelopment in MA exposed neonates have not been well characterized. Objective: To determine the neurobehavioral effects of maternal depressive symptoms on neonates exposed and not exposed to methamphetamine (MA) using the NICU Network Neurobehavioral Scale (NNNS). Design: The purpose of the IDEAL study is to determine the effects of prenatal MA exposure on child outcome. IDEAL screened 13,808 subjects, 1632 were eligible and consented and 176 mothers were enrolled. Only biological mothers with Custody of their child at the one-month visit (n = 50 MA; n = 86 comparison) had the Addiction Severity Index (ASI) administered. The NNNS was administered to the neonate by an examiner blinded to MA exposure within the first five days of life. General Linear Models tested the effects of maternal depression and prenatal MA exposure on NNNS outcomes, with and without covariates. Significance was accepted at p<.05. Results: After adjusting for covariates, regardless of exposure status, maternal depressive symptoms were associated with lower handling and arousal scores, elevated physiological stress scores and an increased incidence of hypotonicity. When adjusting for covariates, MA exposure was associated with lower arousal and higher lethargy scores. Conclusions: Maternal depressive symptoms are associated with neurodevelopmental patterns of decreased arousal and increased stress. Prenatal MA exposure combined with maternal depression was not associated with any additional neonatal neurodevelopmental differences.

Pickett KE; Rathouz PJ; Dukic V; Kasza K; Niessner M; Wright RJ et al. The complex enterprise of modelling prenatal exposure to cigarettes: What is 'enough'? Paediatric and Perinatal Epidemiology 23(2): 160-170, 2009. (29 refs.)

While there is a burgeoning body of research linking smoking during pregnancy to problem behaviour in offspring, a major criticism of this work has been the crude measurement of exposure in these studies (e.g. retrospective, self-reported only) that could lead to biased estimates. To address this issue, we used a pregnancy cohort with repeated prospective measures of exposure as well as biological assays to generate estimates of exposure patterns using a range of modelling techniques. In this paper we report on the analytical approaches we have developed, including patterns of exposure over time and best-estimate approaches that combine self-report and cotinine measures, and compare their predictive value in relation to different dimensions of fetal growth as a first step towards examining the utility of greater precision of exposure measurement. Surprisingly, in this sample the more complex assessments of exposure, including biological measures, generally did not perform better than simple indicators of exposure based on repeated self-report measures, with one exception: a combined self-report cotinine 'best estimate' of third trimester exposure was uniquely associated with lower brain : body ratio. Further study is needed using more sophisticated cotinine assays and testing prediction of a range of outcomes to ascertain whether these findings represent true differences or are specific to the sample, methods and outcomes used. Such research will inform the development of guidelines for adequate exposure characterisation in developmental studies.

Polakowski LL; Akinbami LJ; Mendola P. Prenatal smoking cessation and the risk of delivering preterm and small-for-gestational-age newborns. Obstetrics and Gynecology 114(2, Part I): 318-325, 2009. (37 refs.)

OBJECTIVE: To examine the association between prenatal smoking cessation and delivery of a preterm or small-for-gestational-age (SGA) newborn in a large U.S. subpopulation using the revised (2003) birth certificate, which now assesses maternal smoking status by trimester. METHODS: We analyzed a cohort of U.S.-resident, singleton births in the 11 states that used the revised birth certificate in 2005 (n=915,441). Self-reported maternal smoking status was categorized as "never smoked," "quit in the first trimester," "quit in the second trimester," and "smoked throughout" pregnancy (referent). Multinomial logistic regression was used to estimate adjusted odds ratios (aORs) for three outcomes (preterm non-SGA, term SGA, or preterm SGA newborns) by maternal smoking status. Analyses stratified by maternal age were also conducted. RESULTS: Compared with women who smoked throughout pregnancy, first-trimester quitters reduced their odds of delivering a preterm non-SGA newborn by 31% (aOR 0.69, 95% confidence interval [CI] 0.65-0.74), a term SGA newborn by 55% (aOR 0.45, 95% CI 0.42-0.48), and a preterm SGA newborn by 53% (aOR 0.47, 95% Cl 0.40-0.55), similar to nonsmokers. Second-trimester quitters also reduced their odds of delivering preterm non-SGA and term SGA newborns but to a lesser magnitude. When comparing first-trimester quitters with smokers in each age group, older mothers had generally lower odds of these outcomes than younger mothers. CONCLUSION: Pregnant smokers who quit in the first trimester lowered their risk of delivering preterm and SGA newborns to a level similar to that of pregnant nonsmokers, and this benefit appeared to increase with maternal age. These findings reinforce current clinical guidance to encourage smoking cessation among pregnant smokers and serve as an additional incentive to quit.

Rogers JM. Tobacco and pregnancy. Reproductive Toxicology 28(2, Special Issue): 152-160, 2009. (127 refs.)

This paper will review the epidemiology of the impact of cigarette smoking and other forms of tobacco exposure on human development. Sources of exposure described include cigarettes and other forms of smoked tobacco, secondhand (environmental) tobacco smoke, several forms of smokeless tobacco, and nicotine from nicotine replacement therapy. Exposure is immense and worldwide, most of it due to smoking, but in some parts of the world and in some populations, smoking is exceeded by smokeless tobacco use. Nicotine and carbon monoxide exposure are of large concern, but cigarette smoke contains over 4000 chemical constituents and additives including known carcinogens, toxic heavy metals, and many chemicals untested for developmental toxicity. The impact of tobacco on human development will be reviewed. Fertility, conception, survival of the conceptus, most phases and aspects of development studied to date, as well as postnatal survival and health are adversely impacted by maternal tobacco use or exposure. Effects in surviving offspring are probably life-long, and are still being elucidated. It is hoped that this review will serve to keep a focus on the critical and continuing problem of tobacco use impacting human development.

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.

Roza SJ; Verhulst FC; Jaddoe VWV; Steegers EAP; Mackenbach JP; Hofman A et al. Maternal smoking during pregnancy and child behaviour problems: the Generation R Study. International Journal of Epidemiology 38(3): 680-689, 2009. (35 refs.)

Background: Several studies showed that maternal smoking in pregnancy is related to behavioural and emotional disorders in the offspring. It is unclear whether this is a causal association, or can be explained by other smoking-related vulnerability factors for child behavioural problems. Methods: Within a population-based birth cohort, both mothers and fathers reported on their smoking habits at several time-points during pregnancy. Behavioural problems were measured with the Child Behavior Checklist in 4680 children at the age of 18 months. Results: With adjustment for age and gender only, children of mothers who continued smoking during pregnancy had higher risk of Total Problems [odds ratio (OR) 1.59, 95% confidence interval (CI): 1.21-2.08] and Externalizing problems (OR 1.45, 95% CI: 1.15-1.84), compared with children of mothers who never smoked. Smoking by father when mother did not smoke, was also related to a higher risk of behavioural problems. The statistical association of parental smoking with behavioural problems was strongly confounded by parental characteristics, chiefly socioeconomic status and parental psychopathology; adjustment for these factors accounted entirely for the effect of both maternal and paternal smoking on child behavioural problems. Conclusions: Maternal smoking during pregnancy, as well as paternal smoking, occurs in the context of other factors that place the child at increased developmental risk, but may not be causally related to the child's behaviour. It is essential to include sufficient information on parental psychiatric symptoms in studies exploring the association between pre-natal cigarette smoke exposure and behavioural disorders.

Schnoll SH. Reflections of an academic clinical researcher on the past 40 years of addiction development. Journal of Drug Issues 39(1): 21-28, 2009. (10 refs.)

This paper reflects on three areas of addiction: prescription drug abuse, perinatal addiction, and the clinical fields of addiction medicine and addiction psychiatry. The concerns about the abuse and misuse of prescription drugs date back over a century with numerous laws passed to address these problems. Despite these laws, there has been increasing concern over the past decade about the increases in the nonmedical use and abuse of prescription drugs. This begs the question of whether the passing of laws addressing the supply side of the problem is the correct approach. Abuse of licit and illicit drugs by pregnant women creates concern because of the effects of drugs and alcohol on the fetus and future development of the child. Most of the studies have addressed newborn development without adequate studies of the effects of the drugs and withdrawal on pregnancy and the fetus. In addition, studies of long-term effects on the development of the child are needed. The only way to adequately address these important clinical issues will be to have well-trained clinicians and clinical investigators in addiction medicine and addiction psychiatry.

Scott JR. Effects of restricted caffeine intake by mother on fetal, neonatal, and pregnancy outcome. (editorial). Obstetrics and Gynecology 114(1): 161-162 [article CD006965], 2009. (5 refs.)

BACKGROUND: Maternal caffeine consumption during pregnancy may have adverse effects on fetal, neonatal and maternal outcomes. OBJECTIVES: This review investigates the effects of restricting caffeine intake by mothers on fetal, neonatal and pregnancy outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Child birth Group's Trials Register (December 2008), scanned bibliographies of published studies and corresponded with investigators. SELECTION CRITERIA: Randomized controlled trials including quasi-randomized controlled trials (RCTs) investigating the effect of caffeine and/or supplementary caffeine versus restricted caffeine intake or placebo on pregnancy outcome. DATA COLLECTION AND ANALYSIS: The two review authors independently assessed trial quality and extracted data. MAIN RESULTS: One study met the inclusion criteria. Caffeinated instant coffee (568 women) was compared with decaffeinated instant coffee (629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight or length of gestation. AUTHORS' CONCLUSION: There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome.

Shakleya DM; Huestis MA. Simultaneous quantification of nicotine, opioids, cocaine, and metabolites in human fetal postmortem brain by liquid chromatography tandem mass spectrometry. Analytical and Bioanalytical Chemistry 393(8): 1957-1965, 2009. (42 refs.)

A validated method for simultaneous LCMSMS quantification of nicotine, cocaine, 6-acetylmorphine (6AM), codeine, and metabolites in 100 mg fetal human brain was developed and validated. After homogenization and solid-phase extraction, analytes were resolved on a Hydro-RP analytical column with gradient elution. Empirically determined linearity was from 5-5,000 pg/mg for cocaine and benzoylecgonine (BE), 25-5,000 pg/mg for cotinine, ecgonine methyl ester (EME) and 6AM, 50-5000 pg/mg for trans-3-hydroxycotinine (OH-cotinine) and codeine, and 250-5,000 pg/mg for nicotine. Potential endogenous and exogenous interferences were resolved. Intra- and inter-assay analytical recoveries were a parts per thousand yen92%, intra- and inter-day and total assay imprecision were a parts per thousand currency sign14% RSD and extraction efficiencies were a parts per thousand yen67.2% with a parts per thousand currency sign83% matrix effect. Method applicability was demonstrated with a postmortem fetal brain containing 40 pg/mg cotinine, 65 pg/mg OH-cotinine, 13 pg/mg cocaine, 34 pg/mg EME, and 525 pg/mg BE. This validated method is useful for determination of nicotine, opioid, and cocaine biomarkers in brain.

Shaw GM; Carmichael SL; Vollset SE; Yang W; Finnell RH; Blom H et al. Mid-pregnancy cotinine and risks of orofacial clefts and neural tube defects. Journal of Pediatrics 154(1): 17-19, 2009. (24 refs.)

Objective: Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs. Study design: From a repository of > 180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery, outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies. and randomly selected 469 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL. and any exposure was defined as >= 2 ng/mL. Results: We observed odds ratios of 2.1 (95% Cl, 1.0-4.4) for clefts and 0.4 (95% Cl, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% Cl. 1.1-5.3) and 0.6 (95% Cl, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% Cl. 0.9-11.9) and 1.7 (95% Cl, 0.7-4.2). respectively. Conclusion: Smoking exposures, as measured with cotinine levels during mid-pregnancy were associated with increased risks of clefts and possibly reduced risks of NTDs.

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.

Shields B; Hill A; Bilous M; Knight B; Hattersley AT; Bilous RW et al. Cigarette smoking during pregnancy is associated with alterations in maternal and fetal thyroid function. Journal of Clinical Endocrinology and Metabolism 94(2): 570-574, 2009. (21 refs.)

Context: Studies in the general population have shown lower serum TSH levels in smokers as compared with nonsmokers. Aim: Our aim was to examine whether smoking is associated with changes in thyroid function of pregnant women and their fetus. Subjects and Methods: We examined the relationship between smoking and thyroid function (serum TSH, free T-4, and free T-3) in two independent cohorts of pregnant women without a history of thyroid disorder or an overt biochemical thyroid dysfunction: 1) first-trimester cohort (median gestation 9 wk) (n = 1428) and 2) third-trimester cohort (gestation 28 wk) (n = 927). We also analyzed the relationship between maternal smoking and thyroid hormone levels in cord serum of 618 full-term babies born to the women in the third-trimester cohort. Results: In smokers compared with nonsmokers, median serum TSH was lower (first-trimester cohort: 1.02 vs. 1.17 mlU/liter, P = 0.001; third-trimester cohort: 1.72 vs. 1.90 mlU/liter, P = 0.037), and median serum FT3 was higher (first-trimester cohort: 5.1 vs. 4.9 pmol/liter, P < 0.0001; third-trimester cohort: 4.4 vs. 4.1 pmol/liter, P = 0.0001). In both cohorts, serum FT4 in smokers and nonsmokers were similar. The prevalence of anti-thyroperoxidase antibodies was also similar in smokers and nonsmokers in both cohorts. Cord serum TSH of babies born to smokers was lower than of those born to nonsmokers (6.7 vs. 8.1 mlU/liter, P = 0.009). Conclusions: Cigarette smoking is associated with changes in maternal thyroid function throughout the pregnancy and in fetal thyroid function as measured in cord blood samples.

Singh AK; Gupta S; Jiang Y; Younus M; Ramzan M. In vitro neurogenesis from neural progenitor cells isolated from the hippocampus region of the brain of adult rats exposed to ethanol during early development through their alcohol-drinking mothers. (review). Alcohol and Alcoholism 44(2): 185-198, 2009. (102 refs.)

Aims: This study was aimed to determine whether ethanol exposure during early development altered neurogenesis in the brain of adult rats. Methods: Pregnant rats were given either ethanol-mixed or mannose-mixed (for control) rodent liquid diet ad libitum. Ethanol drinking continued during pregnancy and nursing. After weaning, the pups (AC(o): pups from control mothers, AE(o): pups from ethanol exposed mothers) received normal diet and water ad libitum for 11 weeks. Then the rats were anesthetized, their brains were collected and the hippocampal samples were processed for isolation of neural progenitor cells (NPCs). AC(o) NPCs and AE(o) NPCs were sequentially grown in media containing different growth factors that induced proliferation and differentiation. Results and Conclusions: Neuronal maturation was significantly delayed in ethanol-exposed rats. AC(o) NPCs, up to day 7 of culture, exhibited high beta-catenin-probe binding, an increase in Ca2+ when exposed to gamma-amino butyric acid (GABA) and lack of response to glutamate (Glu) exposure. beta-Catenin-probe binding and the stimulatory effects of GABA declined thereafter. AC(o) NPCs, at culture day 29, exhibited high beta-catenin-probe binding, lack of response to GABA and elevated Glu-induced increase in Ca2+i. Cultures of AE(o) NPCs showed an amplified stimulatory effects of GABA, attenuated stimulatory effects of Glu and attenuated the delayed (culture day 29) increase in the expression of Wnt proteins and beta-catenin-probe binding. This suggests a significant alteration in neurogenesis and synapse formation in adult rats exposed to ethanol at early development through their alcohol-drinking mothers.

Stroud LR; Paster RL; Papandonatos GD; Niaura R; Salisbury AL; Battle C et al. Maternal smoking during pregnancy and newborn neurobehavior: Effects at 10 to 27 Days. Journal of Pediatrics 154(1): 10-16, 2009. (36 refs.)

Objective: To examine effects of maternal smoking during pregnancy on newborn neurobehavior at 10 to 27 days. Study design Participants were 56 healthy infants (28 smoking-exposed. 28 unexposed) matched on maternal social class., age, and alcohol use. Maternal smoking during pregnancy was determined by maternal interview and maternal saliva cotinine. Postnatal smoke exposure was quantified by infant saliva cotinine. Infant neurobehavior was assessed through the NICU Network Neurobehavioral Scale. Results: Smoking-exposed infants showed greater need for handling and worse self-regulation (P < .05) and trended toward greater excitability and arousal (P < .10) relative to matched, unexposed infants (all moderate effect sizes). In contrast to prior studies of days 0 to 5, no effects of smoking-exposure on signs of stress/abstinence or muscle tone emerged. In stratified, adjusted analyses, only effects on need for handling remained significant (P < .05, large effect size). Conclusions Effects of maternal smoking during pregnancy at 10 to 27 days lire subtle and consistent with increased need for external intervention and poorer self-regulation. Along with parenting deficits, these effects may represent early precursors for long-term adverse outcomes from maternal smoking during pregnancy. That signs of abstinence shown in prior studies of 0- to 5-day-old newborns did not emerge in older newborns provides further evidence for the possibility of it withdrawal process in exposed infants.

Stroud LR; Paster RL; Goodwin MS; Shenassa E; Buka S; Niaura R et al. Maternal smoking during pregnancy and neonatal behavior: A large-scale community study. Pediatrics 123(5): e842-e848, 2009. (46 refs.)

OBJECTIVE. To investigate the influence of prospectively measured smoking during pregnancy on aspects of neonatal behavior in a large community sample. METHODS. Participants were mothers and infants from the Providence, Rhode Island, cohort of the National Collaborative Perinatal Project enrolled between 1960 and 1966. Mothers with pregnancy/medical complications and infants with medical complications and/or born premature or of low birth weight were excluded. The final sample included 962 mother-infant pairs, 23% of whom were black. Maternal smoking was measured prospectively at each prenatal visit. Neonatal behavior was assessed by using the Graham-Rosenblith Behavioral Examination of the Neonate. Items from the examination were reduced to 3 subscales: irritability, muscle tone, and response to respiratory challenge. RESULTS. Sixty-two percent of the sample reported smoking during pregnancy, with 24% of smokers reporting smoking 1 pack per day or more. We found a significant influence of maternal smoking exposure (none, moderate/less than 1 pack per day, heavy/1 pack per day or more) on irritability and muscle tone in the neonate, with exposed infants showing greater irritability and hypertonicity. Effects remained significant after controlling for significant covariates: maternal socioeconomic status, age, and race and infant birth weight and age. Posthoc tests suggested particular effects of heavy smoking on increased infant irritability and both moderate and heavy smoking exposure on increased muscle tone. CONCLUSIONS. In a large community sample, exposure to maternal smoking was associated with increased irritability and hypertonicity in neonates. Exposure to maternal smoking did not influence neonatal response to respiratory challenge. This study is the largest-scale investigation to date of the effects of maternal smoking (heavy and moderate) on examiner-assessed neonatal behavior. Given the associations between both maternal smoking and infant irritability and later behavioral dysregulation, results have important implications for early identification and intervention with at-risk offspring.

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.

Thiriez G; Bouhaddi M; Mourot L; Nobili F; Fortrat JO; Menget A et al. Heart rate variability in preterm infants and maternal smoking during pregnancy. Clinical Autonomic Research 19(3): 149-156, 2009. (39 refs.)

Tobacco smoke exposure increases the risk of premature birth and of dying of sudden infant death syndrome (SIDS). Prematurity significantly increases the risk of dying of SIDS, but mechanisms underlying this epidemiological finding are unclear. The cumulated effect of both prematurity and prenatal exposure to nicotine on autonomic heart rate control has not been studied. Using coarse-graining spectral analysis, we compared heart rate variability (HRV) indices of preterm newborns at 33-34 weeks post-conceptional age from smoking (n = 19) and non-smoking (n = 21) mothers. Assessment of tobacco exposure relied on maternal reports and newborns cotinine analysis. We observed how indicators of HRV depended on gestational age at birth. At 33-34 weeks postconceptional age, the newborns from smoking mothers had lower HRV low frequency power normalised to the total spectral power (LF/TP) than the control group (median values: 8% vs. 15% respectively, p < 0.02). In the non-smoking group, RR-interval values and total HRV power were correlated with gestational age at birth, with a shorter RR and a lower total HRV power in lesser gestational ages (rho = 0.67, p = 0.03, rho = 0.71, p = 0.003 respectively). This correlation was not observed for RR values in the group with smoking mothers.

van Gelder MMHJ; Reefhuis J; Caton AR; Werler MM; Druschel CM; Roeleveld N. Maternal periconceptional iIlicit drug use and the risk of congenital malformations. Epidemiology 20(1): 60-66, 2009. (35 refs.)

Background: In 2004, the Survey on Drug Use and Health showed that 5% of American women reported use of an illicit drug during pregnancy. The results of studies determining the association between periconceptional illicit drug use and birth defects have been inconsistent. Methods: We analyzed data from the National Birth Defects Prevention Study, a case-control study of major birth defects, and assessed all birth defects categories in which there were at least 250 interviewed case mothers. We included 10,241 infants with major congenital malformations (case infants) and 4,967 infants without major congenital malformations (control infants) born between 1997 and 2003 for whom there was a completed maternal interview with detailed information on prenatal illicit drug use and potential confounders. We used multivariable logistic regression to estimate the associations between cannabis, cocaine, and stimulant use in the month before pregnancy or during the first trimester (periconceptional period) and the occurrence of selected birth defects. Results: In the periconceptional period, 5% of the 15,208 mothers reported any use of illicit drugs. We did not find associations between illicit drug use and most of the 20 eligible categories of congenital malformations. Periconceptional cannabis use seemed to be associated with an increased risk of anencephaly (adjusted odds ratio = 1.7; 95% confidence interval = 0.9-3.4), whereas cocaine use in the periconceptional period was associated with the risk of cleft palate (2.5; 1.1-5.4). Conclusions: There were very few suggestions of positive associations between periconceptional illicit drug use and the 20 birth defects categories.

Varvarigou AA; Asimakopoulou A; Beratis NG. Impact of maternal smoking on birth size: Effect of parity and sex dimorphism. Neonatology 95(1): 61-67, 2009. (30 refs.)

Background: Maternal smoking during pregnancy causes a delay of intrauterine growth. Objective: To examine the effect of maternal smoking during pregnancy on fetal growth in relationship to maternal parity, age and number of cigarettes smoked/day, and offspring's gender. Subjects: We studied 2,108 term newborns (1,102 male, 1,006 female) delivered at the General University Hospital of Patras from 1994 to 2004. The 1,443 were born to mothers who did not smoke and 665 to mothers who smoked during pregnancy. Methods: Birth weight, length and head circumference were measured prospectively in all newborns. Also, maternal smoking status and number of cigarettes smoked per day, age, and parity were recorded. For the analysis, t test, one-way ANOVA, Mann-Whitney U test, Spearman rank correlation, and factorial MANOVA with covariates were used. Results: With increasing parity, in the neonates of nonsmoking mothers there was a gradual increase of growth, whereas in neonates of smoking mothers there was a gradual decrease of growth. This effect was more pronounced in males. A significant negative main effect on growth resulted from the interaction of smoking with parity (p = 0.013), and with gender and parity (p = 0.001). There was a significant negative correlation between number of cigarettes smoked per day and growth, the strength of which increased with parity, mainly in males. Conclusion: Maternal smoking during pregnancy causes a delay in fetal growth, which is greater in male offspring, an effect that is enhanced with parity but is independent of maternal age.

Whitbeck LB; Crawford DM. Gestational risks and psychiatric disorders among indigenous adolescents. Community Mental Health Journal 45(1): 62-72, 2009. (69 refs.)

This study reports on the effects maternal prenatal binge drinking, cigarette smoking, drug use, and pregnancy and birth complications on meeting criteria for psychiatric disorders at ages 10-12 and 13-15 years among 546 Indigenous adolescents from a single culture in the northern Midwest and Canada. Adolescent DSM-IV psychiatric disorders were assessed with the Diagnostic Interview Schedule for Children-Revised (DISC-R). Results indicate that maternal behaviors when pregnant have significant effects on adolescent psychiatric disorders even when controlling for age and gender of adolescent, family per capita income, living in a single mother household, and adolescent reports of mother's positive parenting.

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.

Winklbaur B; Baewert A; Jagsch R; Rohrmeister K; Metz V; Jachmann CA et al. Association between prenatal tobacco exposure and outcome of neonates born to opioid-maintained mothers. European Addiction Research 15(3): 150-156, 2009. (35 refs.)

Background: Prenatal nicotine exposure is associated with increased neonatal mortality, low birth weight, and smaller head circumference. Opioid-dependent pregnant women show a particularly high prevalence of tobacco smoking and are at greater risk for additional adverse events. However, little is known about the impact of tobacco smoking on opioid-maintained pregnant women and neonatal outcomes. Patients and Methods: This study examined the effect of cigarette smoking on 139 opioid-maintained pregnant women and their neonates. Forty-five percent of the participants were maintained on slow-release oral morphine (SROM), 39% received methadone maintenance, and 16% received buprenorphine. Participants were divided into two groups: (1) women who reported a low cigarette consumption of <= 10 cigarettes/day (56.8%) and (2) those reporting heavy consumption of >= 20 cigarettes/day (43.2%). Neonatal outcome measures were assessed, and a standardized Finnegan score was applied to determine the neonatal abstinence syndrome (NAS). Results: Fifty-two percent of the newborns did not require treatment for NAS (54% of neonates born to methadone-maintained mothers, 30% born to SROM-maintained mothers, and 95% born to buprenorphine-maintained mothers; p < 0.001). Heavy cigarette consumption was associated with significantly lower neonatal birth weight (p < 0.001), smaller birth length (p = 0.017) as well as with the severity of NAS (p = 0.03). With regard to concomitant consumption of opioids (p = 0.54), cocaine (p = 0.25), amphetamines (p = 0.90) or benzodiazepines (p = 0.09), no significant differences between heavy or low nicotine consumption were noted. Conclusion: Heavy tobacco smoking in opioid-maintained pregnant women is associated with adverse medical and developmental consequences for the newborn. Future treatment programs for this target group should focus on an individualized approach to opioid maintenance therapy in addition to offering specially tailored counseling for smoking cessation.

Youngentob SL; Glendinning JI. Fetal ethanol exposure increases ethanol intake by making it smell and taste better. Proceedings of the National Academy of Sciences 106(13): 5359-5364, 2009

Human epidemiologic studies reveal that fetal ethanol exposure is highly predictive of adolescent ethanol avidity and abuse. Little is known about how fetal exposure produces these effects. It is hypothesized that fetal ethanol exposure results in stimulus-induced chemosensory plasticity. Here, we asked whether gestational ethanol exposure increases postnatal ethanol avidity in rats by altering its taste and odor. Experimental rats were exposed to ethanol in utero via the dam's diet, whereas control rats were either pair-fed an iso-caloric diet or given food ad libitum. We found that fetal ethanol exposure increased the taste-mediated acceptability of both ethanol and quinine hydrochloride (bitter), but not sucrose (sweet). Importantly, a significant proportion of the increased ethanol acceptability could be attributed directly to the attenuated aversion to ethanol's quinine-like taste quality. Fetal ethanol exposure also enhanced ethanol intake and the behavioral response to ethanol odor. Notably, the elevated intake of ethanol was also causally linked to the enhanced odor response. Our results demonstrate that fetal exposure specifically increases ethanol avidity by, in part, making it taste and smell better. More generally, they establish an epigenetic chemosensory mechanism by which maternal patterns of drug use can be transferred to offspring. Given that many licit (e.g., tobacco products) and illicit (e.g., marijuana) drugs have noteworthy chemosensory components, our findings have broad implications for the relationship between maternal patterns of drug use, child development, and postnatal vulnerability.

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.