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Background: Exposure to tobacco and cannabis during developmental periods of enhanced vulnerability (e.g., in utero and early childhood) may have long-lasting effects on child health. One potential mechanism underlying these associations is the alteration of inflammatory pathways. Using data from a longitudinal study of mother/child dyads, we examined the adjusted and combined associations of prenatal and postnatal tobacco and cannabis exposure with inflammation in early childhood. Furthermore, we explored the relations between different measures of exposure, partly reflecting differences in timing, dose, and level of fetal exposure (e.g., self-report vs. biomarker), and inflammation. Finally, we explored child sex as a moderator of prenatal and postnatal tobacco and cannabis exposure and inflammation., Method: Women were recruited from a local hospital during their first prenatal appointment. Repeated assessments were conducted at each trimester, at birth, and when children were 2, 9, 16, 24, 36, and 60 months old (N = 215; 112 female children). To evaluate associations with different measurement approaches, prenatal tobacco and cannabis exposure were assessed using: 1) continuous dose-response variables of maternal self-reported tobacco and cannabis use during each trimester to assess associations with timing and severity of exposure, 2) categorization of children into exposure groups based on drugs and metabolites present in infant meconium reflecting later pregnancy fetal exposure, and 3) categorization into exposure groups using a combination of maternal self-report data and biomarker data derived from maternal saliva samples and infant meconium taking advantage of multiple methods of assessment to examine group differences. Postnatal exposure to tobacco (assessed using child salivary cotinine) and cannabis (assessed using maternal self-reported average joints smoked per day) was measured at each infancy/early childhood assessment. Adjusted pre- and postnatal exposure associations with child inflammation were assessed by including both measures as predictor variables in linear regression models predicting child salivary C-reactive protein (CRP) concentrations at 60 months. Interactions between pre- and postnatal exposure variables were then modeled to investigate the combined relations between pre- and postnatal substance exposure with child salivary CRP concentrations at 60 months., Results: Adjusting for postnatal exposure variables, there was a significant interaction between the average daily cigarettes and the average daily cannabis joints smoked during the third trimester predicting salivary CRP concentrations in early childhood. At high tobacco exposure, the effect of cannabis on CRP concentrations was negligible, whereas at low tobacco exposure, the effect of cannabis exposure on CRP concentrations was positive. Adjusting for postnatal tobacco and cannabis exposure, children for whom meconium data indicated co-exposure to tobacco and cannabis showed approximately 43% lower CRP concentrations at age 60 months compared to children with no exposure. However, when mother/child dyads were categorized based on a combination of maternal self-report data and biomarker data from saliva samples and infant meconium, there were no differences in salivary CRP concentrations at age 60 months across the three groups (no prenatal exposure, prenatal tobacco exposure only, prenatal co-exposure to tobacco and cannabis), controlling for postnatal associations. Regardless of the measurement method used to assess prenatal exposures in adjusted analyses, prenatal tobacco exposure alone did not predict CRP concentrations in early childhood, nor did postnatal tobacco exposure. Among boys, postnatal cannabis exposure was associated with higher concentrations of CRP at age 60 months, controlling for prenatal exposure relations. There were no significant combined associations of pre- and postnatal exposure with CRP concentrations., Conclusion: This study expands upon known relations between prenatal and postnatal substance exposure and immunological outcomes in early childhood, underscoring the importance of assessing cannabis exposure during gestation and early life in combination with tobacco exposure., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2022. Published by Elsevier Inc.)

Aim: A key aim of the Adolescent Brain Cognitive Development℠ (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting can obscure accurate drug use characterization. Hair toxicology provides objective historical substance use data but is rarely used in studies of youth. Here, we compare objective hair toxicology results with self-reported substance use in high-risk youth., Methods: A literature-based substance use risk algorithm prioritized 696 ABCD Study® hair samples from 677 participants for analysis at baseline, and 1 and 2-year follow-ups (spanning ages 9-13). Chi-square and t-tests assessed differences between participants' demographics, positive and negative hair tests, risk-for-use algorithm scores, and self-reported substance use., Results: Hair testing confirmed that 17% of at-risk 9-13 year-olds hair samples had evidence of past 3-month use of one (n = 97), two (n = 14), three (n = 2), or four (n = 2) drug classes. After considering prescribed medication and self-reported substance use, 10% had a positive test indicating substance use that was not reported. Participants with any positive hair result reported less sipping of alcohol (p < 0.001) and scored higher on the risk-for-use algorithm (p < 0.001) than those with negative toxicology results., Conclusions: 10% of hair samples from at-risk 9-13 year-olds tested positive for at least one unreported substance, suggesting underreporting in high-risk youth when participating in a research study. As hair testing prioritized youth with risk characteristics, the overall extent of underreporting will be calculated in future studies. Nonetheless, hair toxicology was key to characterizing substance use in high-risk youth., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although tobacco (TOB) and marijuana (MJ) are often co-used in pregnancy, little is known regarding the joint impact of MJ + TOB on offspring development, including the developing neuroendocrine stress system. Further, despite evidence for sex-specific impacts of prenatal exposures in preclinical models, the sex-specific impact of prenatal MJ + TOB exposure on offspring neuroendocrine regulation in humans is also unknown. In the current study, overall and sex-specific influences of MJ + TOB co-use on offspring cortisol regulation were investigated over the first postnatal month. 111 mother-infant pairs from a low-income, racially and ethnically diverse sample participated. Based on Timeline Followback data with biochemical verification, three groups were identified: (1) prenatal MJ + TOB, (2) TOB only, and (3) controls. Baseline cortisol and cortisol stress response were assessed at seven points over the first postnatal month using a handling paradigm in which saliva cortisol was assessed before, during, and following a standard neurobehavioral assessment (NICU Network Neurobehavioral Scale). A significant exposure group by offspring sex interaction emerged for baseline cortisol over the first postnatal month (p = .043); MJ + TOB-exposed males showed 35-36% attenuation of baseline cortisol levels vs. unexposed and TOB-exposed males (ps ≤ .003), while no effects of exposure emerged for females. Both MJ + TOB and TOB-exposed infants showed a 22% attenuation of cortisol stress response over the first postnatal month vs. unexposed infants (ps < .03), with evidence for sex-specific effects in exploratory analyses. Although results are preliminary, this is the first human study to investigate the impact of prenatal MJ exposure on infant cortisol and the first to reveal a sex-specific impact of prenatal MJ + TOB on cortisol regulation in humans. Future, larger-scale studies are needed to elucidate mechanisms and consequences of sex-specific effects of MJ and MJ + TOB on the developing neuroendocrine stress system., Competing Interests: Declaration of competing interest The authors have no biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Tobacco and marijuana are some of the most common prenatal substance exposures worldwide. The social acceptability and political landscape of marijuana and its potency have changed dramatically in the last two decades leading to increased use by pregnant women. Despite evidence for increasing marijuana use and high rates of co-use of tobacco (TOB) and marijuana (MJ) during pregnancy, the impact of prenatal exposure to each substance is typically studied in isolation. We investigated the influence of co-exposure to TOB and MJ on infant neurobehavioral development over the first postnatal month. Participants were 111 mother-infant pairs from a low-income, diverse sample (Mean age = 25 ± 5; 54% minorities). TOB and MJ use were assessed by Timeline Followback interview with biochemical confirmation. Three groups were identified: (a) prenatal MJ + TOB, (b) prenatal TOB only, (c) controls. Newborn neurobehavior was assessed at seven time points over the first postnatal month using the NICU Network Neurobehavioral Scale. MJ + TOB-exposed infants showed decreased ability to self-soothe (Self-regulation) and attend to stimuli (Attention), and increased need for examiner soothing (Handling) and low motor activity (Lethargy) versus unexposed infants. Despite low levels of MJ use in MJ + TOB co-users, co-exposure was associated with nearly double the impact on infant self-soothing and need for examiner soothing versus TOB-exposure alone. Effects of MJ + TOB co-exposure appeared more pronounced for daughters than for sons. Although results are preliminary, they highlight additional risk from dual exposure to MJ + TOB vs. TOB exposure alone, particularly for daughters. Results also highlight the critical importance of investigating prenatal exposures in concert and the need for intervention efforts to address MJ co-use in pregnant TOB users., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Use and co-use of tobacco and marijuana during pregnancy are associated with the development of social, cognitive, and behavioral problems for infants and children. However, less is known about the potential developmental impact of the use of tobacco and marijuana in tandem. The present study examined an etiological model for the development of externalizing behavior problems (EBP) in early childhood in a high risk sample (N = 247) of mother-infant dyads with prospective data from pregnancy to 36 months of child age. Co-use during pregnancy and continued maternal tobacco and marijuana use from infancy through early childhood were investigated. Although direct pathways from exposure during pregnancy to EBP were not significant, there was a significant indirect pathway from prenatal tobacco use to EBP via lower breastfeeding duration to lower maternal warmth/sensitivity to EBP, and a pathway from higher maternal affective dysregulation to higher EBP. These results highlight the importance of considering cascading effects of substance use during pregnancy on parental processes within the context of developmental risk and protection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tobacco and cannabis are often used together in pregnancy and both have effects on children's regulatory system. Yet, little is known about the impact of co-use on the development of emotion regulation at the developmentally salient age of 2 years. One pathway linking co-exposure to tobacco and cannabis to toddler regulation may be via poor autonomic regulation in infancy. In addition, substance using mothers may be more dysregulated themselves, which may have direct effects on toddler regulation, but may also affect parenting, particularly maternal sensitivity during mother-child interactions. Thus, a second pathway linking exposure to toddler regulation may be via maternal dysregulation and low maternal sensitivity. We examined a conceptual model linking prenatal exposure to toddler regulation via these two pathways in a prospective sample (N = 247) of mother-child dyads recruited in the first trimester of pregnancy. Results indicated significant effects of co-exposure on poor autonomic regulation in infancy, which in turn predicted poor toddler emotion regulation. Mothers who used both tobacco and cannabis displayed lower sensitivity during play interactions with their infants. Maternal sensitivity was modestly stable from infant to toddler period and was predictive of higher toddler emotion regulation. Continued postnatal exposure to tobacco was also a significant, unique predictor of lower toddler emotion regulation. Results highlight the importance of examining co-exposure effects and suggest that this common pattern of use may be associated with higher infant/toddler risks., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Methodologic challenges related to the concomitant use (co-use) of substances and changes in policy and potency of marijuana contribute to ongoing uncertainty about risks to fetal neurodevelopment associated with prenatal marijuana use. In this study, we examined two biomarkers of fetal neurodevelopmental risk-birth weight and length of gestation-associated with prenatal marijuana use, independent of tobacco (TOB), alcohol (ALC), other drug use (OTH), and socioeconomic risk (SES), in a pooled sample (N = 1191) derived from 3 recent developmental cohorts (2003-2015) with state-of-the-art substance use measures. We examined differential associations by infant sex, and multiplicative effects associated with co-use of MJ and TOB., Methods: Participants were mother-infant dyads with complete data on all study variables derived from Growing Up Healthy (n = 251), Behavior and Mood in Babies and Mothers (Cohorts 1 and 2; n = 315), and the Early Growth and Development Study (N = 625). We estimated direct effects on birth weight and length of gestation associated with MJ, TOB, and co-use (MJ x TOB), using linear regression analysis in the full sample, and in male (n = 654) and female (n = 537) infants, separately., Results: Mean birth weight and length of gestation were 3277 g (SD = 543) and 37.8 weeks (SD = 2.0), respectively. Rates of prenatal use were as follows: any use, n = 748 (62.8%); MJ use, n = 273 (22.9%); TOB use, n = 608 (51.0%); co-use of MJ and TOB, n = 230 (19.3%); ALC use, n = 464 (39.0%); and OTH use n = 115 (9.7%.) For all infants, unique effects on birth weight were observed for any MJ use [B(SE) = -84.367(38.271), 95% C.I. -159.453 to -9.281, p = .028], any TOB use [B(SE) = -0.99.416(34.418), 95% C.I. -166.942 to -31.889, p = .004], and each cigarette/day in mean TOB use [B(SE) = -12.233(3.427), 95% C.I. -18.995 to -5.510, p < .001]. Additional effects of co-use on birth weight, beyond these drug-specific effects, were not supported. In analyses stratified by sex, while TOB use was associated with lower birth weight in both sexes, MJ use during pregnancy was associated with lower birth weight of male infants [B(SE) = -153.1 (54.20); 95% C.I. -259.5 to -46.7, p = .005], but not female infants [B(SE) = 8.3(53.1), 95% C.I. -96.024 to 112.551, p = .876]. TOB, MJ, and their co-use were not associated with length of gestation., Conclusions: In this sample, intrauterine co-exposure to MJ and TOB was associated with an estimated 18% reduction in birth weight not attributable to earlier delivery, exposure to ALC or OTH drugs, nor to maternal SES. We found evidence for greater susceptibility of male fetuses to any prenatal MJ exposure. Examination of dose-dependence in relationships found in this study, using continuous measures of exposure, is an important next step. Finally, we underscore the need to consider (a) the potential moderating influence of fetal sex on exposure-related neurodevelopmental risks; and (b) the importance of quantifying expressions of risk through subtle alterations, rather than dichotomous outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cortical thickness abnormalities have been identified in youth using both alcohol and marijuana. However, limited studies have followed individuals pre- and post initiation of alcohol and marijuana use to help identify to what extent discrepancies in structural brain integrity are pre-existing or substance-related. Adolescents (N=69) were followed from ages 13 (pre-initiation of substance use, baseline) to ages 19 (post-initiation, follow-up). Three subgroups were identified, participants that initiated alcohol use (ALC, n=23, >20 alcohol use episodes), those that initiated both alcohol and marijuana use (ALC+MJ, n=23, >50 marijuana use episodes) and individuals that did not initiate either substance regularly by follow-up (CON, n=23, <3 alcohol use episodes, no marijuana use episodes). All adolescents underwent neurocognitive testing, neuroimaging, and substance use and mental health interviews. Significant group by time interactions and main effects on cortical thickness estimates were identified for 18 cortical regions spanning the left and right hemisphere (ps<0.05). The vast majority of findings suggest a more substantial decrease, or within-subjects effect, in cortical thickness by follow-up for individuals who have not initiated regular substance use or alcohol use only by age 19; modest between-group differences were identified at baseline in several cortical regions (ALC and CON>ALC+MJ). Minimal neurocognitive differences were observed in this sample. Findings suggest pre-existing neural differences prior to marijuana use may contribute to initiation of use and observed neural outcomes. Marijuana use may also interfere with thinning trajectories that contribute to morphological differences in young adulthood that are often observed in cross-sectional studies of heavy marijuana users., (Copyright © 2016. Published by Elsevier Inc.)

Cortical thickness abnormalities have been identified in youth using both alcohol and marijuana. However, limited studies have followed individuals pre- and post initiation of alcohol and marijuana use to help identify to what extent discrepancies in structural brain integrity are pre-existing or substance-related. Adolescents (N=69) were followed from ages 13 (pre-initiation of substance use, baseline) to ages 19 (post-initiation, follow-up). Three subgroups were identified, participants that initiated alcohol use (ALC, n=23, >20 alcohol use episodes), those that initiated both alcohol and marijuana use (ALC+MJ, n=23, >50 marijuana use episodes) and individuals that did not initiate either substance regularly by follow-up (CON, n=23, <3 alcohol use episodes, no marijuana use episodes). All adolescents underwent neurocognitive testing, neuroimaging, and substance use and mental health interviews. Significant group by time interactions and main effects on cortical thickness estimates were identified for 18 cortical regions spanning the left and right hemisphere (ps<0.05). The vast majority of findings suggest a more substantial decrease, or within-subjects effect, in cortical thickness by follow-up for individuals who have not initiated regular substance use or alcohol use only by age 19; modest between-group differences were identified at baseline in several cortical regions (ALC and CON>ALC+MJ). Minimal neurocognitive differences were observed in this sample. Findings suggest pre-existing neural differences prior to marijuana use may contribute to initiation of use and observed neural outcomes. Marijuana use may also interfere with thinning trajectories that contribute to morphological differences in young adulthood that are often observed in cross-sectional studies of heavy marijuana users., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prenatal exposure to tobacco has consistently predicted later problem behavior for children. However, little is known about developmental mechanisms underlying this association. We examined a conceptual model for the association between prenatal tobacco exposure and child problem behavior in toddlerhood via indirect paths through fetal growth, maternal depression, and maternal aggressive disposition in early infancy and via maternal warmth and sensitivity and infant negative affect in later infancy. The sample consisted of 258 mother-child dyads recruited during pregnancy and assessed periodically at 2, 9, and 16months of child age. Pathways via maternal depression and infant negative affect to toddler problem behavior were significant. Further, combined tobacco and marijuana exposure during pregnancy and reduced fetal growth also demonstrated important associations with infant negative affect and subsequent problem behavior. These results highlight the importance of considering the role of maternal negative affect and poor fetal growth as risk factors in the context of prenatal exposure., (Copyright © 2016. Published by Elsevier Inc.)

This study reviews the findings from the Infant Development, Environment, and Lifestyle (IDEAL) study, a multisite, longitudinal, prospective study designed to determine maternal outcome and child growth and developmental findings following prenatal methamphetamine exposure from birth up to age 7.5 years. These findings are presented in the context of the home environment and caregiver characteristics to determine how the drug and the environment interact to affect the outcome of these children. No neonatal abstinence syndrome requiring pharmacologic intervention was observed but heavy drug exposure was associated with increased stress responses in the neonatal period. Poorer inhibitory control was also observed in heavy methamphetamine exposed children placing them at high risk for impaired executive function. Independent of methamphetamine exposure, children with more responsive home environments to developmental and emotional needs demonstrated lower risks for internalizing and externalizing behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The purpose of this study was to examine the association between prenatal exposure to cigarettes and heart rate during an object manipulation task at 9 months of age. Second-by-second heart rate was recorded for 181 infants who were prenatally exposed to cigarettes and 77 nonexposed infants during the manipulation of four standardized toys. A series of longitudinal multilevel models were run to examine the association of prenatal smoking on the intercept and slope of heart rate during four 90-second object manipulation tasks. After controlling for maternal age, prenatal marijuana and alcohol use, duration of focused attention and activity level, results indicated that the heart rates of exposed infants significantly increased during the object manipulation task. These findings suggest casual rather than focused attention and a possible increase in physiological arousal during object manipulation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Despite the evidence that women world-wide are using methamphetamine (MA) during pregnancy little is known about the neurodevelopment of their children., Design: The controlled, prospective longitudinal New Zealand (NZ) Infant Development, Environment and Lifestyle (IDEAL) study was carried out in Auckland, NZ. Participants were 103 children exposed to MA prenatally and 107 who were not exposed. The Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development, Second Edition (BSID-II) measured cognitive and motor performances at ages 1, 2 and 3, and the Peabody Developmental Motor Scale, Second Edition (PDMS-II) measured gross and fine motor performances at 1 and 3. Measures of the child's environment included the Home Observation of Measurement of the Environment and the Maternal Lifestyle Interview. The Substance Use Inventory measured maternal drug use., Results: After controlling for other drug use and contextual factors, prenatal MA exposure was associated with poorer motor performance at 1 and 2 years on the BSID-II. No differences were observed for cognitive development (MDI). Relative to non-MA exposed children, longitudinal scores on the PDI and the gross motor scale of the PDMS-2 were 4.3 and 3.2 points lower, respectively. Being male and of Maori descent predicted lower cognitive scores (MDI) and being male predicted lower fine motor scores (PDMS-2)., Conclusions: Prenatal exposure to MA was associated with delayed gross motor development over the first 3 years, but not with cognitive development. However, being male and of Maori descent were both associated with poorer cognitive outcomes. Males in general did more poorly on tasks related to fine motor development., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The primary purpose of this study was to examine pathways from prenatal cigarette exposure to physiological regulation at 2 months of age. Specifically, we explored the possibility that any association between prenatal cigarette exposure and infant physiological regulation was moderated by fetal growth, prenatal or postnatal environmental tobacco smoke (ETS) exposure or maternal depressive symptomatology during pregnancy. We evaluated whether exposed infants who were also exposed to ETS after birth, were small for gestational age (SGA) or had mothers with higher depressive symptoms during pregnancy had the highest levels of physiological dysregulation. Respiratory sinus arrhythmia (RSA) was obtained from 234 (166 exposed and 68 nonexposed) infants during sleep. As expected, cigarette-exposed infants had significantly lower RSA than nonexposed infants. This association was not moderated by prenatal or postnatal ETS exposure, or maternal depressive symptomatology during pregnancy. However, small for gestational age status did moderate this association such that nonexposed infants who were not small for gestational age had a significantly higher RSA than nonexposed small for gestational age infants and exposed infants. These findings provide additional evidence that prenatal cigarette exposure is directly associated with dysregulation during infancy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Preclinical studies have identified alterations in cocaine and alcohol self-administration and behavioral responses to pharmacological challenges in adolescent offspring following prenatal exposure. To date, no published human studies have evaluated the relation between prenatal cocaine exposure and postnatal adolescent cocaine use. Human studies of prenatal cocaine-exposed children have also noted an increase in behaviors previously associated with substance use/abuse in teens and young adults, specifically childhood and teen externalizing behaviors, impulsivity, and attention problems. Despite these findings, human research has not addressed prior prenatal exposure as a potential predictor of teen drug use behavior. The purpose of this study was to evaluate the relations between prenatal cocaine exposure and teen cocaine use in a prospective longitudinal cohort (n=316) that permitted extensive control for child, parent and community risk factors. Logistic regression analyses and Structural Equation Modeling revealed that both prenatal exposure and postnatal parent/caregiver cocaine use were uniquely related to teen use of cocaine at age 14 years. Teen cocaine use was also directly predicted by teen community violence exposure and caregiver negativity, and was indirectly related to teen community drug exposure. These data provide further evidence of the importance of prenatal exposure, family and community factors in the intergenerational transmission of teen/young adult substance abuse/use., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Methamphetamine (MA) use among pregnant women is a world-wide problem, but little is known of its impact on exposed infants., Design: The prospective, controlled longitudinal Infant Development, Environment and Lifestyle (IDEAL) study of prenatal MA exposure from birth to 36 months was conducted in the US and NZ. The US cohort has 183 exposed and 196 comparison infants; the NZ cohort has 85 exposed and 95 comparison infants. Exposure was determined by self-report and meconium assay with alcohol, marijuana, and tobacco exposures present in both groups. The NICU Neurobehavior Scale (NNNS) was administered within 5 days of life. NNNS summary scores were analyzed for exposure including heavy exposure and frequency of use by trimester and dose-response relationship with the amphetamine analyte., Results: MA exposure was associated with poorer quality of movement, more total stress/abstinence, physiological stress, and CNS stress with more nonoptimal reflexes in NZ but not in the USA. Heavy MA exposure was associated with lower arousal and excitability. First trimester MA use predicted more stress and third trimester use more lethargy and hypotonicity. Dose-response effects were observed between amphetamine concentration in meconium and CNS stress., Conclusion: Across cultures, prenatal MA exposure was associated with a similar neurobehavioral pattern of under arousal, low tone, poorer quality of movement and increased stress., (Copyright © 2010 Elsevier Inc. All rights reserved.)