Examining the association between prenatal cannabis exposure and child autism traits: A multi-cohort investigation in the environmental influences on child health outcome program.

This study examined the association between prenatal cannabis exposure and autism spectrum disorder (ASD) diagnoses and traits. A total sample of 11,570 children (ages 1-18; 53% male; 25% Hispanic; 60% White) from 34 cohorts of the National Institutes of Health-funded environmental influences on child health outcomes consortium were included in analyses. Results from generalized linear mixed models replicated previous studies showing that associations between prenatal cannabis exposure and ASD traits in children are not significant when controlling for relevant covariates, particularly tobacco exposure. Child biological sex did not moderate the association between prenatal cannabis exposure and ASD. In a large sample and measuring ASD traits continuously, there was no evidence that prenatal cannabis exposure increases the risk for ASD. This work helps to clarify previous mixed findings by addressing concerns about statistical power and ASD measurement.

Developmental characteristics and accuracy of autism screening among two-year-old toddlers in the ECHO program.

BACKGROUND: The Modified Checklist for Autism in Toddlers (M-CHAT) is a common pediatric screening tool with mixed accuracy findings. Prior evidence supports M-CHAT screening for developmental concerns, especially in toddlers born preterm. This study examined M-CHAT accuracy in a large, nationwide sample. METHODS: 3393 participants from the Environmental influences on Child Health Outcomes (ECHO) program were included. Harmonized M-CHAT (M-CHAT-H) results were compared with parent-reported autism diagnosis and autism-related characteristics to assess accuracy for term and preterm children, together and separately. Generalized estimating equations, clustering for ECHO cohort and controlling for demographic covariates, were used to examine associations between developmental and behavioral characteristics with M-CHAT-H accuracy. RESULTS: Sensitivity of the M-CHAT-H ranged from 36 to 60%; specificity ranged from 88 to 99%. Positive M-CHAT-H was associated with more developmental delays and behavior problems. Children with severe motor delays and more autism-related problems were more likely to have a false-negative M-CHAT-H. Children with fewer behavior problems and fewer autism-related concerns were more likely to have a false-positive screen. CONCLUSION: The M-CHAT-H accurately detects children at low risk for autism and children at increased risk with moderate accuracy. These findings support use of the M-CHAT-H in assessing autism risk and developmental and behavioral concerns in children. IMPACT: Previous literature regarding accuracy of the Modified Checklist for Autism in Toddlers (M-CHAT) is mixed but this study provides evidence that the M-CHAT performs well in detecting children at low risk for autism and consistently detects children with developmental delays and behavioral problems. The M-CHAT moderately detects children at increased risk for autism and remains a useful screening tool. This study examines M-CHAT accuracy in a large-scale, nationwide sample, examining associations between screening accuracy and developmental outcomes. These findings impact pediatric screening for autism, supporting continued use of the M-CHAT while further elucidating the factors associated with inaccurate screens.

Perinatal Factors and Emotional, Cognitive, and Behavioral Dysregulation in Childhood and Adolescence.

OBJECTIVE: This cohort study assessed perinatal factors known to be related to maternal and neonatal inflammation and hypothesized that several would be associated with emotional, cognitive, and behavioral dysregulation in youth. METHOD: The Environmental influences on Child Health Outcomes (ECHO) is a research consortium of 69 pediatric longitudinal cohorts. A subset of 18 cohorts that had both Child Behavior Checklist (CBCL) data on children (6-18 years) and information on perinatal exposures including maternal prenatal infections was used. Children were classified as having the CBCL-Dysregulation Profile (CBCL-DP) if the sum of their T scores for 3 CBCL subscales (attention, anxious/depressed, and aggression) was ≥180. Primary exposures were perinatal factors associated with maternal and/or neonatal inflammation, and associations between these and outcome were assessed. RESULTS: Approximately 13.4% of 4,595 youth met criteria for CBCL-DP. Boys were affected more than girls (15.1% vs 11.5%). More youth with CBCL-DP (35%) were born to mothers with prenatal infections compared with 28% of youth without CBCL-DP. Adjusted odds ratios indicated the following were significantly associated with dysregulation: having a first-degree relative with a psychiatric disorder; being born to a mother with lower educational attainment, who was obese, had any prenatal infection, and/or who smoked tobacco during pregnancy. CONCLUSION: In this large study, a few modifiable maternal risk factors with established roles in inflammation (maternal lower education, obesity, prenatal infections, and smoking) were strongly associated with CBCL-DP and could be targets for interventions to improve behavioral outcomes of offspring. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Prenatal exposure to persistent and non-persistent chemical mixtures and associations with adverse birth outcomes in the Atlanta African American Maternal-Child Cohort.

BACKGROUND: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. OBJECTIVE: We examined the individual and mixture effects of non-persistent chemicals and persistent organic pollutants (POPs) on gestational age at birth and birthweight for gestational age z-scores within a prospective cohort of pregnant AAs. METHODS: First-trimester serum and urine samples obtained from participants within the Atlanta African American Maternal-Child cohort were analyzed for 43 environmental chemicals, including per-and polyfluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDEs), organochlorine pesticides, pyrethroid insecticides, phthalates, bisphenol A, nicotine, and the primary metabolite of delta-9-tetrahydrocannabinol. Linear regression was used to estimate individual associations between chemicals and gestational age and birthweight z-scores (N ranging from 107 to 523). Mixture associations were estimated using quantile g-computation, principal component (PC) analyses, and hierarchical Bayesian kernel machine regression among complete cases (N = 86). RESULTS: Using quantile g-computation, increasing all chemical exposures by one quantile was modestly associated with a reduction in gestational age (mean change per quartile increase = -0.47, 95% CI = -1.56, 0.61) and birthweight z-scores (mean change per quartile increase = -0.49, 95% CI = -1.14, 0.15). All PCs were associated with a reduction in birthweight z-scores; associations were greatest in magnitude for the two PCs reflecting exposure to combined tobacco, insecticides, PBDEs, and phthalates. In single pollutant models, we observed inconsistent and largely non-significant associations. SIGNIFANCE: We conducted multiple targeted exposure assessment methods to quantify levels of environmental chemicals and leveraged mixture methods to quantify their joint effects on gestational age and birthweight z-scores. Our findings suggest that prenatal exposure to multiple classes of persistent and non-persistent chemicals is associated with reduced gestational age and birthweight z-scores in AAs. IMPACT: African Americans (AAs) experience higher rates of preterm birth and fetal growth restriction relative to other pregnant populations. Differential in utero exposure to environmental chemicals may partially explain these health disparities, as AAs are disproportionately exposed to environmental hazards. In the present study, we analyzed serum and urine samples for levels of 43 environmental chemicals. We used quantile g-computation, principal component analysis, and BKMR to assess associations between chemical exposure mixtures and adverse birth outcomes. Our findings suggest that prenatal exposure to multiple classes of chemicals is associated with reduced birthweight z-scores, a proxy for fetal growth, in AAs.

Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program.

BACKGROUND: Single-cohort studies have identified distinct neurobehavioral profiles that are associated with prenatal and neonatal factors based on the NICU Network Neurobehavioral Scale (NNNS). We examined socioeconomic, medical, and substance use variables as predictors of NNNS profiles in a multi-cohort study of preterm and term-born infants with different perinatal exposures. METHODS: We studied 1112 infants with a neonatal NNNS exam from the Environmental influences on Child Health Outcomes (ECHO) consortium. We used latent profile analysis to characterize infant neurobehavioral profiles and generalized estimating equations to determine predictors of NNNS profiles. RESULTS: Six distinct neonatal neurobehavioral profiles were identified, including two dysregulated profiles: a hypo-aroused profile (16%) characterized by lethargy, hypotonicity, and nonoptimal reflexes; and a hyper-aroused profile (6%) characterized by high arousal, excitability, and stress, with low regulation and poor movement quality. Infants in the hypo-aroused profile were more likely to be male, have younger mothers, and have mothers who were depressed prenatally. Infants in the hyper-aroused profile were more likely to be Hispanic/Latino and have mothers who were depressed or used tobacco prenatally. CONCLUSIONS: We identified two dysregulated neurobehavioral profiles with distinct perinatal antecedents. Further understanding of their etiology could inform targeted interventions to promote positive developmental outcomes. IMPACT: Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings. In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated. Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents. Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.

Per- and polyfluoroalkyl substances and psychosocial stressors have a joint effect on adverse pregnancy outcomes in the Atlanta African American Maternal-Child cohort.

BACKGROUND: African Americans (AAs) experience high rates of adverse pregnancy outcomes relative to Whites. Differential in utero exposure to environmental chemicals and psychosocial stressors may explain some of the observed health disparities, as exposures to per- and polyfluoroalkyl substances (PFAS) and experiences of discrimination have been linked to adverse birth outcomes. Few studies have examined chemicals and non-chemical stressors together as an exposure mixture, which may better reflect real-life exposure patterns. Here, we adapted methods designed for the analysis of exposure mixtures to examine joint effects of PFAS and psychosocial stress on birth outcomes among AAs. METHODS: 348 participants from the Atlanta African American Maternal-Child cohort were included in this study. Four PFAS were measured in first trimester serum samples. Self-report questionnaires were administered during the first trimester and were used to assess psychosocial stress (perceived stress, depression, anxiety, gendered racial stress). Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to estimate the joint effects between PFAS and psychosocial stressors on gestational age at delivery and birthweight for gestational age z-scores. All models were adjusted for maternal education, maternal age, parity, and any alcohol, tobacco and marijuana use. RESULTS: Our analytic sample included a socioeconomically diverse group of pregnant women, with 79 % receiving public health insurance. In quantile g-computation models, a simultaneous one-quartile increase in all PFAS, perceived stress, depression, anxiety, and gendered racial stress was associated with a reduction in birthweight z-scores (mean %change per quartile increase = -0.24, 95 % confidence interval = -0.43, -0.06). BKMR similarly showed that increasing all exposures in the mixture was associated with a modest decrease in birthweight z-scores, but not a reduced length of gestation. DISCUSSION: Using methods designed for analyzing exposure mixtures, we found that a simultaneous increase in in utero PFAS and psychosocial stressors was associated with reduced birthweight for gestational age z-scores.

Simultaneous quantification of urinary tobacco and marijuana metabolites using solid-supported liquid-liquid extraction coupled with liquid chromatography tandem mass spectrometry.

Co-exposure to tobacco and marijuana has become common in areas where recreational marijuana use is legal. To assist in the determination of the combined health risks of this co-exposure, an analytical method capable of simultaneously measuring tobacco and marijuana metabolites is needed to reduce laboratory costs and the required sample volume. So far, no such analytical method exists. Thus, we developed and validated a method to simultaneously quantify urinary levels of trans-3'-hydroxycotinine (3OH-COT), cotinine (COT), and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC) to assess co-exposure to tobacco and marijuana. Urine (200 µL) was spiked with labelled internal standards and enzymatically hydrolyzed to liberate the conjugated analytes before extraction using solid-supported liquid-liquid extraction (SLE) with ethyl acetate serving as an eluent. The target analytes were separated on a C18 (4.6 × 100 mm, 5 µm) analytical column with a gradient mobile phase elution and analyzed using tandem mass spectrometry with multiple reaction monitoring of target ion transitions. Positive electrospray ionization (ESI) was used for 3OH-COT and COT, while negative ESI was used for COOH-THC. The total run time was 13 min. The extraction recoveries were 18.4-23.9 % (3OH-COT), 65.1-96.8 % (COT), and 80.6-95.4 % (COOH-THC). The method limits of quantification were 5.0 ng/mL (3OH-COT) and 2.5 ng/mL (COT and COOH-THC). The method showed good accuracy (82.5-98.5 %) and precision (1.22-6.21 % within-day precision and 1.42-6.26 % between-day precision). The target analytes were stable for at least 144 h inside the autosampler (10 °C). The analyses of reference materials and 146 urine samples demonstrated good method performance. The use of a 96-well plate for preparation makes the method useful for the analysis of large numbers of samples.

Polybrominated Diphenyl Ether Serum Concentrations and Depressive Symptomatology in Pregnant African American Women.

(1) Polybrominated diphenyl ethers (PBDEs) were widely produced in the United States until 2004 but remain highly persistent in the environment. The potential for PBDEs to disrupt normal neuroendocrine pathways resulting in depression and other neurological symptoms is largely understudied. This study examined whether PBDE exposure in pregnant women was associated with antenatal depressive symptomatology. (2) Data were collected from 193 African American pregnant women at 8-14 weeks gestation. Serum PBDEs and depressive symptoms were analyzed and a mixture effect was calculated. (3) Urban pregnant African American women in the Southeastern United States had a high risk of depression (27%) compared to the National average. Increased levels of PBDEs were found. BDE-47 and -99 exposures are significantly associated with depressive symptomatology in the pregnant cohort. The weighted body burden estimate of the PBDE mixture was associated with a higher risk of mild to moderate depression using an Edinburgh Depression Scale cutoff score of ≥10 (OR = 2.93; CI 1.18, 7.82). (4) Since antenatal depression may worsen in postpartum, reducing PBDE exposure may have significant clinical implications.

Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and IL1ß in youth.

AIMS: Close to one third of patients with major depression show increases in pro-inflammatory cytokines, which are in turn associated with risk for inflammatory disease. Genetic variants that enhance immune reactivity may thus enhance inflammatory and depressive reactions to stress. The aim of the present study was to investigate a trio of functional SNPs in the promoter regions of IL6 (-174G>C, rs1800795), IL1ß (-511C>T, rs16944), and TNF (-308G>A, rs1800629) as moderators of the relationship between chronic stress exposure and elevations in depressive symptoms. METHODS: Participants were 444 Australian youth (mean age=20.12) whose exposure to chronic stress in the past 6months was assessed using the semi-structured UCLA Life Stress Interview, and who completed the Beck Depression Inventory II at ages 15 and 20. Between ages 22 and 25, all participants in the selected sample provided blood samples for genotyping. RESULTS: In line with a hypothesized moderation effect, -174G allele carriers at IL6 had fewer depressive symptoms following interpersonal stress, relative to C/C homozygotes with equal interpersonal stress exposure. However, IL6 genotype did not moderate the effects of non-interpersonal stress exposure (i.e., financial, work and health-related difficulties) on depression. Also in line with hypotheses, the -511C allele in IL1ß, previously associated with higher IL-1ß expression, was associated with more severe depression following chronic interpersonal stress exposure, relative to T/T homozygotes. Again, the moderating effect was specific to interpersonal stressors and did not generalize to non-interpersonal stress. TNF was not a moderator of the effects of either interpersonal or non-interpersonal stress on later depression outcomes. CONCLUSION: Findings were consistent with the hypothesis that pro-inflammatory genetic variation increases the risk of stress-induced depression. The present results provide evidence of a genetic mechanism contributing to individual differences in depressive symptomatology following interpersonal stress exposure.

A developmental pathway from early life stress to inflammation: the role of negative health behaviors.

Early life stressors are associated with elevated inflammation, a key physiological risk factor for disease. However, the mechanisms by which early stress leads to inflammation remain largely unknown. Using a longitudinal data set, we examined smoking, alcohol consumption, and body mass index (BMI) as health-behavior pathways by which early adversity might lead to inflammation during young adulthood. Contemporaneously measured early adversity predicted increased BMI and smoking but not alcohol consumption, and these effects were partially accounted for by chronic stress in young adulthood. Higher BMI in turn predicted higher levels of soluble tumor necrosis factor receptor type II (sTNF-RII) and C-reactive protein (CRP), and smoking predicted elevated sTNF-RII. These findings establish that early adversity contributes to inflammation in part through ongoing stress and maladaptive health behavior. Given that maladaptive health behaviors portend inflammation in young adulthood, they serve as promising targets for interventions designed to prevent the negative consequences of early adversity.

DNA methylation in neonates born to women receiving psychiatric care.

Prenatal exposure both to maternal psychiatric illness and psychiatric medication has been linked with adverse child outcomes that affect physiological, emotional and psychiatric development. Studies suggest that epigenetic mechanisms, such as DNA methylation, may facilitate these effects. In this report, we explore the association between maternal psychiatric illness and treatment during pregnancy and neonatal DNA methylation patterns in a prospectively-characterized clinical cohort of 201 dyads. Associations between the percent of umbilical cord blood DNA methylated at 27,578 CpG sites and maternal psychiatric diagnosis, symptoms and antidepressant use were evaluated by fitting a separate linear mixed effects model for each CpG site. There were no significant changes in neonatal DNA methylation attributable to maternal psychiatric diagnosis or depressive symptoms during pregnancy. Exposure to an antidepressant medication was associated with differential methylation of CpG sites in TNFRSF21 and CHRNA2 (false discovery rate < 0.05), but the average difference in methylation for both CpG sites was less than 3% between each group. The results were not specific to type of antidepressant or duration of the exposure. This study suggests that there are no large effects of maternal psychiatric illness, depressive symptoms or prenatal exposure to antidepressants on neonatal DNA methylation. Delineation of the influence of maternal psychiatric illness and pharmacological exposures on the developing fetuses has critical implications for clinical care during pregnancy.

Interactions between the COMT Val108/158Met polymorphism and maternal prenatal smoking predict aggressive behavior outcomes.

The purpose of the current study is to examine the moderating influence of the catechol O methyltransferase gene (COMT) on the maternal prenatal smoking/offspring externalizing disorder relationship. The sample consisted of 430 young adults born between 1981 and 1984 at the Mater Misericordiae Mother's Hospital in Brisbane, Australia, as well as their mothers and peers. Mothers reported their prenatal smoking status during pregnancy, and genetic data was obtained from the youth at a later follow-up in adulthood. The outcome measures in this study were mother and teacher reports of youth attention problems and aggression at age 15, and youth, mother and peer reports of youth attention problems and aggression at age 20 (combined to create latent factors of attention problems and aggression at each age). The COMT Val108/158Met polymorphism (rs4680) significantly interacted with maternal cigarette smoking during pregnancy to predict youth aggressive behavior at ages 15 and 20. This gene-environment interaction was not significant for youth attention problems.

The medical and ethical aspects of photography in the sexual assault examination: why does it offend?

This paper reviews the literature in respect to the photo-colposcopic examination of anogenital injury in the sexually assaulted child, considered to be the 'gold standard' of examination, and how this compares with gross visualisation, still the standard procedure in adult examinations. It then examines the claim that, because the presence of injury does not provide a distinction between consensual and non-consensual intercourse in adults, photo-documentation is unnecessary medically and constitutes an invasive procedure which is ethically unacceptable. The paper questions whether the unwillingness of forensic physicians to extend photo-colposcopy to the examination of adult victims is related more to political and gender issues than to claims made on ethical and medical grounds, and concludes that any move to ban anogenital photography in adult forensic examinations (currently under consideration in the author's own jurisdiction) would possibly constitute an interference with independent clinical judgment and an incursion into the patient's right to evidence-based medicine.

Early adversity and the prospective prediction of depressive and anxiety disorders in adolescents.

The current study was a prospective exploration of the specificity of early childhood adversities as predictors of anxiety and depressive disorders in adolescents. Participants were 816 adolescents (414 males, 402 females) with diagnostic information collected at age 15; information on early adversities had been collected from the mothers during pregnancy, at birth, age 6 months, and age 5 years for a related study. Adolescents with "pure" anxiety disorders were compared with adolescents with "pure" depressive disorders (major depressive disorder, dysthymia), and these groups were compared to never-ill controls. Analyses controlled for gender and maternal depression and anxiety disorders. Results indicated that adolescents with anxiety disorders were more likely than depressed youth to have been exposed to various early stressors, such as maternal prenatal stress, multiple maternal partner changes, and more total adversities, whereas few early childhood variables predicted depressive disorders. Even when current family stressors at age 15 were controlled, early adversity variables again significantly predicted anxiety disorders. Results suggest that anxiety disorders may be more strongly related to early stress exposure, while depressive disorders may be related to more proximal stressors or to early stressors not assessed in the current study.

Relationship of maternal smoking during pregnancy with criminal arrest and hospitalization for substance abuse in male and female adult offspring.

OBJECTIVE: Maternal prenatal smoking has been found to be related to externalizing behavior problems in male offspring, but this relationship has rarely been examined in female offspring. Preliminary evidence suggests that maternal prenatal smoking may be particularly related to antisocial behavior outcomes in male offspring and substance abuse problems in female offspring. This study attempted to replicate these findings in a large-scale, longitudinal community cohort study. METHOD: Subjects were a birth cohort of 4,169 male and 3,943 female offspring born between 1959 and 1961 in Copenhagen, Denmark. During the third trimester of pregnancy, the subjects' mothers self-reported the number of cigarettes smoked on a daily basis. When the offspring were adults, their criminal arrest histories and psychiatric hospitalizations for substance abuse were checked in national registers. Additional data were collected concerning maternal rejection of the infant, socioeconomic status, maternal age, pregnancy and delivery complications, use of drugs in pregnancy, paternal criminal history, and parental psychiatric hospitalization. RESULTS: Results indicate a dose-response relationship between the amount of maternal prenatal smoking and both criminal arrest and psychiatric hospitalization for substance abuse in male and female offspring. These relationships remained significant after potential demographic, parental, and perinatal risk confounds were controlled. Hospitalization of offspring for substance abuse mediated the relationship between maternal prenatal smoking and criminal arrest for female but not for male offspring. CONCLUSIONS: Maternal prenatal smoking is related to criminal and substance abuse outcomes in male and female offspring. Higher rates of index arrests for female offspring may be related to their substance abuse problems.