Kimberly Yolton

Low-Level Environmental Lead Exposure and Children's Intellectual Function: An International Pooled Analysis

Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 μg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 μg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5–10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 μg/dL and declined to 9.4 μg/dL by 5–7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 μg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 μg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2–9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 μg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 μg/dL, 10 to 20 μg/dL, and 20 to 30 μg/dL were 3.9 (95% CI, 2.4–5.3), 1.9 (95% CI, 1.2–2.6), and 1.1 (95% CI, 0.7–1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 μg/dL was significantly greater than that observed for those with a maximal blood lead level ≥7.5 μg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 μg/dL is associated with intellectual deficits.

Impact of Early-Life Bisphenol A Exposure on Behavior and Executive Function in Children

OBJECTIVES: To estimate the impact of gestational and childhood bisphenol A (BPA) exposures on behavior and executive function at 3 years of age and to determine whether child gender modified those associations. METHODS: We used a prospective birth cohort of 244 mothers and their 3-year-old children from the greater Cincinnati, Ohio, area. We characterized gestational and childhood BPA exposures by using the mean BPA concentrations in maternal (16 and 26 weeks of gestation and birth) and child (1, 2, and 3 years of age) urine samples, respectively. Behavior and executive function were measured by using the Behavior Assessment System for Children 2 (BASC-2) and the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). RESULTS: BPA was detected in >97% of the gestational (median: 2.0 μg/L) and childhood (median: 4.1 μg/L) urine samples. With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on the BASC-2 and poorer emotional control and inhibition on the BRIEF-P. The magnitude of the gestational BPA associations differed according to child gender; BASC-2 and BRIEF-P scores increased 9 to 12 points among girls, but changes were null or negative among boys. Associations between childhood BPA exposure and neurobehavior were largely null and not modified by child gender. CONCLUSIONS: In this study, gestational BPA exposure affected behavioral and emotional regulation domains at 3 years of age, especially among girls. Clinicians may advise concerned patients to reduce their exposure to certain consumer products, but the benefits of such reductions are unclear.

Prenatal Bisphenol A Exposure and Early Childhood Behavior

Background Prenatal exposure to bisphenol A (BPA) increases offspring aggression and diminishes differences in sexually dimorphic behaviors in rodents. Objective We examined the association between prenatal BPA exposure and behavior in 2-year-old children. Methods We used data from 249 mothers and their children in Cincinnati, Ohio (USA). Maternal urine was collected around 16 and 26 weeks of gestation and at birth. BPA concentrations were quantified using high-performance liquid chromatography–isotope-dilution tandem mass spectrometry. Child behavior was assessed at 2 years of age using the second edition of the Behavioral Assessment System for Children (BASC-2). The association between prenatal BPA concentrations and BASC-2 scores was analyzed using linear regression. Results Median BPA concentrations were 1.8 (16 weeks), 1.7 (26 weeks), and 1.3 (birth) ng/mL. Mean (± SD) BASC-2 externalizing and internalizing scores were 47.6 ± 7.8 and 44.8 ± 7.0, respectively. After adjustment for confounders, log10-transformed mean prenatal BPA concentrations were associated with externalizing scores, but only among females [β = 6.0; 95% confidence interval (CI), 0.1–12.0]. Compared with 26-week and birth concentrations, BPA concentrations collected around 16 weeks were more strongly associated with externalizing scores among all children (β = 2.9; 95% CI, 0.2–5.7), and this association was stronger in females than in males. Among all children, measurements collected at ≤ 16 weeks showed a stronger association (β = 5.1; 95% CI, 1.5–8.6) with externalizing scores than did measurements taken at 17–21 weeks (β = 0.6; 95% CI, −2.9 to 4.1). Conclusions These results suggest that prenatal BPA exposure may be associated with externalizing behaviors in 2-year-old children, especially among female children.

Exposure to Environmental Tobacco Smoke and Cognitive Abilities among U.S. Children and Adolescents

We used the Third National Health and Nutrition Examination Survey (NHANES III), conducted from 1988 to 1994, to investigate the relationship between environmental tobacco smoke (ETS) exposure and cognitive abilities among U.S. children and adolescents 6–16 years of age. Serum cotinine was used as a biomarker of ETS exposure. Children were included in the sample if their serum cotinine levels were ≤15 ng/mL, a level consistent with ETS exposure, and if they denied using any tobacco products in the previous 5 days. Cognitive and academic abilities were assessed using the reading and math subtests of the Wide Range Achievement Test–Revised and the block design and digit span subtests of the Wechsler Intelligence Scale for Children–III. Analyses were conducted using SUDAAN software. Of the 5,365 6- to 16-year-olds included in NHANES III, 4,399 (82%) were included in this analysis. The geometric mean serum cotinine level was 0.23 ng/mL (range, 0.035–15 ng/mL); 80% of subjects had levels < 1 ng/mL. After adjustment for sex, race, region, poverty, parent education and marital status, ferritin, and blood lead concentration, there was a significant inverse relationship between serum cotinine and scores on reading (β= −2.69, p = 0.001), math (β= −1.93, p = 0.01), and block design (β= −0.55, p < 0.001) but not digit span (β= −0.08, p = 0.52). The estimated ETS-associated decrement in cognitive test scores was greater at lower cotinine levels. A log-linear analysis was selected as the best fit to characterize the increased slope in cognitive deficits at lower levels of exposure. These data, which indicate an inverse association between ETS exposure and cognitive deficits among children even at extremely low levels of exposure, support policy to further restrict children’s exposure.

Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes

OBJECTIVES To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Developments Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006-2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008-2011 (period 2). STUDY DESIGN Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates. RESULTS Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001). CONCLUSION Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.

Prenatal Exposure to Bisphenol A and Phthalates and Infant Neurobehavior

OBJECTIVE To examine the association of prenatal exposure to bisphenol A and select common phthalates with infant neurobehavior measured at 5 weeks. METHODS We compared the concentration of maternal urinary metabolites of bisphenol A and phthalates at two distinct time points in pregnancy (16w, 26w) with scores on the NICU Network Neurobehavioral Scale (NNNS) at 5 weeks of age in a cohort of 350 mother/infant pairs. RESULTS Prenatal exposure to BPA was not significantly associated with neurobehavioral outcomes at 5 weeks. Significant associations between prenatal exposure to measured phthalates and infant neurobehavioral outcomes differed by type of phthalate and were only seen with exposure measured at 26 weeks. Higher total di-butyl phthalate (DBP) metabolites at 26w were associated with improved behavioral organization evidenced by decreased arousal (p=.04), increased self-regulation (p=.052), and decreased handling (p=.02). In males, higher total di-2-ethylhexyl phthalate (DEHP) metabolites at 26w were associated with more nonoptimal reflexes (p=.02). CONCLUSION The association between prenatal phthalate exposure and infant neurobehavior differed by type of phthalate and was evident only with exposure measured at 26w. Prenatal exposure to DBP was associated with improved behavioral organization in 5-week-old infants. Prenatal exposure to DEHP was associated with nonoptimal reflexes in male infants. There was no evidence of an association between prenatal BPA exposure and infant neurobehavior.

Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial

BACKGROUND Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P=0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P=0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P=0.046). CONCLUSIONS We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.).

Gestational Exposure to Endocrine-Disrupting Chemicals and Reciprocal Social, Repetitive, and Stereotypic Behaviors in 4- and 5-Year-Old Children: The HOME Study

Background: Endocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult. Objective: Our goal was to identify gestational EDC exposures associated with autistic behaviors. Methods: We measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs. Results: Most of the EDCs were associated with negligible absolute differences in SRS scores (≤ 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (β = 2.5; 95% CI: –0.6, 5.6) or trans-nonachlor (β = 4.1; 95% CI: 0.8–7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (β = –3.0; 95% CI: –6.3, 0.2), β-hexachlorocyclohexane (β = –3.3; 95% CI: –6.1, –0.5), or PBDE-85 (β = –3.2; 95% CI: –5.9, –0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (β = –2.0; 95% CI: –4.4, 0.4). Conclusions: Some EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, β-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors. Citation: Braun JM, Kalkbrenner AE, Just AC, Yolton K, Calafat AM, Sjödin A, Hauser R, Webster GM, Chen A, Lanphear BP. 2014. Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME Study. Environ Health Perspect 122:513–520; http://dx.doi.org/10.1289/ehp.1307261

Prenatal Polybrominated Diphenyl Ether Exposures and Neurodevelopment in U.S. Children through 5 Years of Age: The HOME Study

Background: Polybrominated diphenyl ethers (PBDEs) are persistent chemicals that have been widely used as flame retardants in furniture, carpet padding, car seats, and other consumer products during the past three decades. Objective: We examined whether in utero exposure to PBDEs is associated with child cognitive function and behavior in a U.S. study sample. Methods: In a prospective birth cohort, we measured maternal serum concentrations of BDE-47 and other PBDE congeners in 309 women at 16 weeks of gestation during 2003–2006 and followed their children in Cincinnati, Ohio. We measured cognitive and motor abilities using the Bayley Scales of Infant Development-II at ages 1, 2, and 3 years; intelligence using the Wechsler Preschool and Primary Scale of Intelligence-III at age 5 years; and children’s behaviors using the Behavioral Assessment System for Children-2 annually at ages 2–5 years. We used linear mixed models or generalized estimating equations with adjustment for potential confounders to estimate associations between these outcomes and log10-transformed PBDE concentrations. Results: The geometric mean of BDE-47 in maternal serum (20.1 ng/g lipid) was comparable with U.S. adult national reference values. Prenatal BDE-47 was not significantly associated with Bayley Mental or Psychomotor Development Indices at 1–3 years, but a 10-fold increase in prenatal BDE-47 was associated with a 4.5-point decrease (95% CI: –8.8, –0.1) in Full-Scale IQ and a 3.3-point increase (95% CI: 0.3, 6.3) in the hyperactivity score at age 5 years. Conclusions: Prenatal exposure to PBDEs was associated with lower IQ and higher hyperactivity scores in children. Citation: Chen A, Yolton K, Rauch SA, Webster GM, Hornung R, Sjödin A, Dietrich KN, Lanphear BP. 2014. Prenatal polybrominated diphenyl ether exposures and neurodevelopment in U.S. children through 5 years of age: the HOME study. Environ Health Perspect 122:856–862; http://dx.doi.org/10.1289/ehp.1307562

Prevalence, Patterns, and Persistence of Sleep Problems in the First 3 Years of Life

OBJECTIVE: Examine the prevalence, patterns, and persistence of parent-reported sleep problems during the first 3 years of life. METHODS: Three hundred fifty-nine mother/child pairs participated in a prospective birth cohort study. Sleep questionnaires were administered to mothers when children were 6, 12, 24, and 36 months old. Sleep variables included parent response to a nonspecific query about the presence/absence of a sleep problem and 8 specific sleep outcome domains: sleep onset latency, sleep maintenance, 24-hour sleep duration, daytime sleep/naps, sleep location, restlessness/vocalization, nightmares/night terrors, and snoring. RESULTS: Prevalence of a parent-reported sleep problem was 10% at all assessment intervals. Night wakings and shorter sleep duration were associated with a parent-reported sleep problem during infancy and early toddlerhood (6–24 months), whereas nightmares and restless sleep emerged as associations with report of a sleep problem in later developmental periods (24–36 months). Prolonged sleep latency was associated with parent report of a sleep problem throughout the study period. In contrast, napping, sleep location, and snoring were not associated with parent-reported sleep problems. Twenty-one percent of children with sleep problems in infancy (compared with 6% of those without) had sleep problems in the third year of life. CONCLUSIONS: Ten percent of children are reported to have a sleep problem at any given point during early childhood, and these problems persist in a significant minority of children throughout early development. Parent response to a single-item nonspecific sleep query may overlook relevant sleep behaviors and symptoms associated with clinical morbidity.