Faculty Bibliography

BACKGROUND:Exposure to air pollution during pregnancy may increase attention-deficit/ hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS:Air pollution concentrations [nitrogen dioxide (NO2) and particulate matter (PM)] were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cut-offs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputation and applied inverse probability weighting methods to correct for loss to follow-up. RESULTS:We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio (OR) for ADHD symptoms of 0.95, 95% confidence interval (CI) 0.89-1.01 per 10µg/m increase in NO2 and 0.98, 95%CI 0.80-1.19 per 5µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS:There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3 to 10 years.

BACKGROUND:Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. METHODS:We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. RESULTS:Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings. CONCLUSIONS:Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood.

Concerns remain about the health of children conceived by infertility treatment. Studies to date have predominantly not identified substantial long-term health effects after accounting for plurality, which is reassuring given the increasing numbers of children conceived by infertility treatment worldwide. However, as technological advances in treatment arise, ongoing studies remain critical for monitoring health effects. To study whether the techniques used in infertility treatment cause health differences, however, remains challenging due to identification of an appropriate comparison group, heterogeneous treatment, and confounding by the underlying causes of infertility. In fact, the factors that are associated with underlying infertility, including parental obesity and other specific male and female factors, may be important independent factors to consider. This review will summarize key methodological considerations in studying children conceived by infertility treatment including the evidence of associations between underlying infertility factors and child health.

Gestational inflammation may contribute to brain abnormalities associated with childhood neuropsychiatric disorders. Limited knowledge exists regarding the associations of maternal cytokine levels during pregnancy with offspring neurocognitive development. We assayed the concentrations of five cytokines (interleukin (IL)-6, IL-1β, IL-8, tumor necrosis factor alpha (TNF-α), and IL-10) up to four times in the 2nd and 3rd trimesters of pregnancy using stored prenatal sera from 1366 participants in the New England Family Study (enrollment 1959-1966). Intelligence (IQ), academic achievement, and neuropsychological functioning of singleton offspring were assessed at age 7 years using standardized tests. We used linear mixed models with random effects to estimate the cumulative exposure to each cytokine during 2nd and 3rd trimesters, and then related cumulative cytokine exposure to a wide range of offspring neurocognitive outcomes. We found that children of women with higher levels of the pro-inflammatory cytokine, TNF-α, in the 2nd and 3rd trimesters had lower IQ (B = -2.51, 99% CI: -4.84,-0.18), higher problem scores in visual-motor maturity (B = 0.12, 99% CI: 0.001,0.24), and lower Draw-a-Person test scores (B = -1.28, 99% CI: -2.49,-0.07). Higher gestational levels of IL-8, another pro-inflammatory molecule, were associated with better Draw-a-Person test scores and tactile finger recognition scores. Other cytokines were not associated with our outcome of interest. The opposing directions of associations observed between TNF-α and IL-8 with childhood outcomes suggest pleiotropic effects of gestational inflammation across the domains of neurocognitive functioning. Although the path to psychopathological disturbances in children is no doubt multifactorial, our findings point to a potential role for immune processes in the neurocognitive development of children.

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

BACKGROUND: Large amounts of various chemical contaminants, including perfluoroalkyl substances (PFASs), were released at the time of the World Trade Center (WTC) disaster. Thousands of children who lived and/or attended school near the disaster site were exposed to these substances but few studies have examined the possible consequences related to these exposures. OBJECTIVES: To examine the relationship of PFASs serum levels with cardiometabolic profile in children and adolescents enrolled in the World Trade Center Health Registry (WTCHR) and a matched comparison group. METHODS: We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group consisting of individuals who were ineligible for WTCHR participation upon distance of their home, school or work from the WTC and lack of participation in rescue and recovery activities. Matching was based on date of birth, sex, race, ethnicity, and income. We assessed exposure to PFASs, as measured by serum levels and association with cardiometabolic profile as measured by arterial wall stiffness, body mass index, insulin resistance, fasting total cholesterol, HDL, LDL and triglycerides. RESULTS: A total of 402 participants completed the study and serum samples were analyzed from 308 participants, 123 in the WTCHR group and 185 in the comparison group. In multivariable regression analysis, after adjusting for relevant confounders, we observed a significant, positive association of perfluorooctanoic acid (PFOA) with triglycerides (beta coefficient=0.14, 95% CI: 0.02, 0.27, 15.1% change), total cholesterol (beta coefficient=0.09, 95% CI: 0.04, 0.14, 9.2% change), and LDL cholesterol (beta coefficient=0.11, 95% CI: 0.03, 0.19, 11.5% change). Perfluorohexanesulfonic acid levels were associated with decreased insulin resistance (beta coefficient=-0.09, 95% CI: -0.18, -0.003, -8.6% change); PFOA and perfluorononanoic acid were associated with increased brachial artery distensibility. CONCLUSIONS: This research adds to our knowledge of the physical health impacts in a large group of children exposed to the WTC disaster. Abnormal lipid levels in young adults might be an early marker of atherosclerosis and cardiovascular diseases and our findings highlight the importance of conducting longitudinal studies in this population.

BACKGROUND: Research of adults and school-aged children suggest a neurodevelopmental basis for psychiatric disorders. We examined whether infant neuromotor development predicted internalizing and externalizing problems in young children. METHODS: In Generation R, a population-based cohort in the Netherlands (2002-2006), trained research assistants evaluated the neuromotor development of 4006 infants aged 2 to 5 months by using an adapted version of Touwen's Neurodevelopmental Examination (tone, responses, and senses and other observations). We defined nonoptimal neuromotor development as scores in the highest tertile. Mothers and fathers rated their children's behavior at ages 1.5, 3, 6, and 10 years with the Child Behavior Checklist (n = 3474, response: 86.7%). The associations were tested with generalized linear mixed models. RESULTS: Overall, neuromotor development predicted internalizing scores, but no association was observed with externalizing scores. Nonoptimal muscle tone was associated with higher internalizing scores (mothers' report: beta = .07; 95% confidence interval [CI]: 0.01 to 0.13; fathers' report: beta = .09, 95% CI: 0.00 to 0.16). In particular, nonoptimal low muscle tone was associated with higher internalizing scores (mothers' report: beta = .11; 95% CI: 0.05 to 0.18; fathers' report: beta = .13; 95% CI: 0.04 to 0.22). We also observed an association between senses and other observations with internalizing scores. There was no relationship between high muscle tone or reflexes and internalizing scores. CONCLUSIONS: Common emotional problems in childhood have a neurodevelopmental basis in infancy. Neuromotor assessment in infancy may help identify vulnerability to early internalizing symptoms and offer the opportunity for targeted interventions.

Background: The relation between breastfeeding and early motor development is difficult to characterize because of the problems in existing studies such as incomplete control for confounding, retrospective assessment of infant feeding, and even the assessment of some motor skills too early.Objective: We sought to estimate associations between infant feeding and time to achieve major motor milestones in a US cohort.Design: The Upstate New York Infant Development Screening Program (Upstate KIDS Study) enrolled mothers who delivered live births in New York (2008-2010). Mothers of 4270 infants (boys: 51.7%) reported infant motor development at 4, 8, 12, 18, and 24 mo postpartum; information on infant feeding was reported at 4 mo. Accelerated failure time models were used to compare times to standing or walking across feeding categories while adjusting for parental characteristics, daycare, region, and infant plurality, sex, rapid weight gain, and baseline neurodevelopmental test results. Main models were stratified by preterm birth status.Results: The prevalence of exclusive breastfeeding in preterm infants was lower than in term infants at 4 mo postpartum (8% compared with 19%). After adjustment for confounders, term infants who were fed solids in addition to breast milk at 4 mo postpartum achieved both standing [acceleration factor (AF): 0.93; 95% CI: 0.87, 0.99] and walking (AF: 0.93; 95% CI: 0.88, 0.98) 7% faster than did infants who were exclusively breastfed, but these findings did not remain statistically significant after correction for multiple testing. We did not identify feeding-associated differences in motor milestone achievement in preterm infants.Conclusion: Our results suggest that differences in feeding likely do not translate into large changes in motor development. The Upstate KIDS Study was registered at clinicaltrials.gov as NCT03106493.

Although the Child Behavior Checklist 1½-5's 12-item Diagnostic and Statistical Manual of Mental Disorders-Autism Spectrum Problems Scale (formerly called Pervasive Developmental Problems scale) has been used in several studies as an autism spectrum disorder screener, the base rate and stability of its items and its measurement model have not been previously studied. We therefore examined the structure, longitudinal invariance, and stability of the Child Behavior Checklist 1½-5's Diagnostic and Statistical Manual of Mental Disorders-Autism Spectrum Problems Scale in the diverse Generation R (Rotterdam) sample based on mothers' ratings at 18 months ( n = 4695), 3 years ( n = 4571), and 5 years ( n = 5752). Five items that seemed especially characteristic of autism spectrum disorder had low base rates at all three ages. The rank order of base rates for the 12 items was highly correlated over time ( Qs ⩾ 0.86), but the longitudinal stability of individual items was modest (phi coefficients = 0.15-0.34). Confirmatory factor analyses indicated that the autism spectrum disorder scale model manifested configural, metric, and scalar longitudinal invariance over the time period from 18 months to 5 years, with large factor loadings. Correlations over time for observed autism spectrum disorder scale scores (0.25-0.50) were generally lower than the correlations across time of the latent factors (0.45-0.68). Results indicated significant associations of the autism spectrum disorder scale with later autism spectrum disorder diagnoses.