Faculty Bibliography

Animal models and epidemiological studies suggest that mild maternal thyroid hormone deficiency in early gestation has adverse consequences on the cognitive abilities of the children. However, methodological problems, lack of a consistent definition for mild thyroid hormone deficiency, and short follow-up of the children reduce the confidence in the conclusion of existing studies. In this review, we summarize the main findings of a series of studies performed in Generation R, a population-based birth cohort in Rotterdam, the Netherlands. In this iodine sufficient region, we aimed to investigate the relation between mild maternal thyroid hormone deficiency in early gestation and children's verbal and nonverbal cognitive function and executive function. We discuss the main findings of these studies, present recommendations for clinicians and formulate suggestions for future research.

There is mounting evidence that bisphenol A (BPA), a chemical used in the production of polycarbonate plastics and the linings of aluminum cans, may have adverse health consequences. The Food and Drug Administration has banned BPA from baby bottles and sippy cups but has deferred further action on other food uses-that is, uses in metal-based food and beverage containers. This article quantifies the potential social costs of childhood obesity and adult coronary heart disease attributable to BPA exposure in the United States in 2008 and models the potential health and economic benefits associated with replacing BPA in all food uses. BPA exposure was estimated to be associated with 12,404 cases of childhood obesity and 33,863 cases of newly incident coronary heart disease, with estimated social costs of $2.98 billion in 2008. Removing BPA from food uses might prevent 6,236 cases of childhood obesity and 22,350 cases of newly incident coronary heart disease per year, with potential annual economic benefits of $1.74 billion (sensitivity analysis: $889 million-$13.8 billion per year). Although more data are needed, these potentially large health and economic benefits could outweigh the costs of using a safer substitute for BPA.

BACKGROUND: There is increasing evidence of the role that exposure to industrial chemicals plays in the development of childhood disease. The USA and the European Union (EU) have taken divergent policy approaches to managing this issue, and economic estimates of disease costs attributable to environmental exposures in children are available in the USA but not the EU. We undertook the first economic evaluation of the impacts of childhood environmental chemical exposures in the EU. METHODS: We used a cost-of-illness approach to estimate health care system costs, and used environmentally attributable fraction modelling to estimate the proportion of childhood disease due to environmental exposures. We analysed data on exposures, disease prevalence and costs at a country level, and then aggregated costs across EU member states to estimate overall economic impacts within the EU. RESULTS: We found the combined environmentally attributable costs of lead exposure, methylmercury exposure, developmental disabilities, asthma and cancer to be $70.9 billion in 2008 (range: $58.9-$90.6 billion). These costs amounted to ~0.480% of the gross domestic product of the EU in 2008. CONCLUSIONS: Childhood chemical exposures present a significant economic burden to the EU. Our study offers an important baseline of disease costs before the implementation of Registration, Evaluation and Authorization of Chemicals, which is important for studying the impacts of this policy regime.

BACKGROUND: Low-grade albuminuria is an indicator of endothelial dysfunction and is associated with an increased risk of cardiovascular disease. A graded level of exposure to bisphenol A was recently identified to be associated with increased risk of low-grade albuminuria in children and adults. Because bisphenol A and phthalates coexist as dietary contaminants, this study investigated whether exposure to phthalates is also associated with low-grade albuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were examined from 667 children who participated in the 2009-2010 National Health and Nutrition Examination Survey and who had results for urinary phthalate metabolites and albumin excretion. Urinary albumin and creatinine concentrations were measured in a first morning specimen using a solid-phase fluorescent immunoassay and a Roche/Hitachi Modular P Chemistry Analyzer with an enzymatic method, respectively. Phthalate metabolites were analyzed in a separate spot urine sample from each participant, using high-performance liquid chromatography and tandem mass spectroscopy. RESULTS: For each (roughly) 3-fold increase in metabolites of di-2-ethylhexylphthalate (a high molecular weight phthalate commonly found in foods), a 0.55 mg/g increase in albumin/creatinine ratio (ACR) was identified (P=0.02), whereas a 1.30-fold odds of a higher ACR quartile was also identified for each (roughly) 3-fold increase (P=0.02). Higher ACR was not identified in relationship to metabolites of lower molecular phthalates commonly found in lotions or shampoos, suggesting specificity. CONCLUSIONS: Although reverse causation and unmeasured confounders represent alternative explanations, these findings, in conjunction with our earlier data on bisphenol A, indicate that a wide array of environmental toxins may adversely affect albuminuria and potentially increase the risk of cardiovascular disease. In view of the potential long-term health implications of ongoing exposure in this vulnerable subpopulation, our data support both further study and renewed regulatory efforts to limit exposure during childhood.

AIM: To characterise the relationship between preschool lexical delay and language comprehension and nonverbal intelligence at school age. METHODS: The mothers of 2724 children completed the MacArthur Communicative Development Inventory when their child reached 1.5 years and the Language Development Survey and the Parent Report of Children's Ability at 2.5 years. When the children were 6 years old, we assessed vocabulary comprehension and nonverbal intelligence using Dutch batteries for language and nonverbal intelligence. RESULTS: Demographic factors explained 9.9% of the variance in vocabulary comprehension and 8.7% of the variance in nonverbal intelligence at 6 years. Male gender, low maternal education and non-Western ethnic background predicted vocabulary comprehension delay at 6 years. Lexical development at 1.5 and 2.5 years explained only 3.8% of the variance in language comprehension at the age of six. Late onset expressive vocabulary delay increased the risk of language comprehension and nonverbal intelligence delay at 6 years (OR=2.31, 95% CI: 1.62-3.29 and OR=1.74, 95% CI: 1.17-2.58, respectively). CONCLUSION: Sociodemographic factors are important predictors of delays in language and nonverbal abilities as children enter school. In contrast, early expressive lexical delays, in particular before the age of two, have limited predictive power for language delays at the age of six.

OBJECTIVE: Describe the attitudes, beliefs, and practices of U.S. obstetricians on the topic of prenatal environmental exposures. STUDY DESIGN: A national online survey of American Congress of Obstetricians and Gynecologists (ACOG) fellows and 3 focus groups of obstetricians. RESULTS: We received 2,514 eligible survey responses, for a response rate of 14%. The majority (78%) of obstetricians agreed that they can reduce patient exposures to environmental health hazards by counseling patients; but 50% reported that they rarely take an environmental health history; less than 20% reported routinely asking about environmental exposures commonly found in pregnant women in the U.S.; and only 1 in 15 reported any training on the topic. Barriers to counseling included: a lack of knowledge of and uncertainty about the evidence; concerns that patients lack the capacity to reduce harmful exposures; and fear of causing anxiety among patients. CONCLUSION: U.S. obstetricians in our study recognized the potential impact of the environment on reproductive health, and the role that physicians could play in prevention, but reported numerous barriers to counseling patients. Medical education and training, evidence-based guidelines, and tools for communicating risks to patients are needed to support the clinical role in preventing environmental exposures that threaten patient health.

In this longitudinal population-based study (N = 544), we investigated whether early parenting and corpus callosum length predict child executive function abilities at 4 years of age. The length of the corpus callosum in infancy was measured using postnatal cranial ultrasounds at 6 weeks of age. At 3 years, two aspects of parenting were observed: maternal sensitivity during a teaching task and maternal discipline style during a discipline task. Parents rated executive function problems at 4 years of age in five domains of inhibition, shifting, emotional control, working memory, and planning/organizing, using the Behavior Rating Inventory of Executive Function-Preschool Version. Maternal sensitivity predicted less executive function problems at preschool age. A significant interaction was found between corpus callosum length in infancy and maternal use of positive discipline to determine child inhibition problems: The association between a relatively shorter corpus callosum in infancy and child inhibition problems was reduced in children who experienced more positive discipline. Our results point to the buffering potential of positive parenting for children with biological vulnerability.

It has been shown in adults that individual differences in intelligence are related to the integrity of the interaction between parietal and frontal brain regions. Since connectivity between distant brain regions strengthens during childhood, it is unclear when in the course of development this relationship emerges. Thus, the goal of this study was to determine whether parietal-frontal functional connectivity is associated with intelligence in young children. We performed independent component analyses on resting-state fMRI data of 115 children (6-8 years old) to select seed and target regions for a seed/target region correlation analysis. We found that higher nonverbal intelligence was associated with increased functional connectivity between right parietal and right frontal regions, and between right parietal and dorsal anterior cingulate regions. The association between intelligence and functional connectivity between certain brain regions was stronger in girls than boys. In conclusion, we found that connectivity between the parietal and frontal lobes is critically involved in intelligence in young children.

OBJECTIVE: Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6-18) and autistic symptoms in children. METHODS: The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation=1.9, range=5.9-17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4<5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score>98th percentile and SRS score in the top 5% of the sample (n=81, 2.0%). RESULTS: Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio=3.89, 95% confidence interval [CI]=1.83-8.20, p<0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B=0.23, 95% CI=0.03-0.37); SRS results were similar. No risk was found for children of TPO-antibody-positive mothers (n=308). INTERPRETATION: We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions.

BACKGROUND: Di-2-ethylhexylphthalate (DEHP) is an ester of phthalic acid commonly found in processed foods. DEHP may contribute to obesity and insulin resistance in children and adolescents, yet dietary exposures have been not been studied in this vulnerable subpopulation. OBJECTIVE: To assess diet and its relation to urinary phthalates in a nationally representative sample of US children and adolescents. DESIGN: Cross-sectional analysis of 24-h dietary recall and urinary phthalate metabolites from 2743 6-19 year olds participating in the 2003-8 National Health and Nutrition Examination Surveys. Regression analyses examined relationships of food consumption with log-transformed metabolite concentrations, examined as low-molecular weight, high molecular weight and di-2-ethylhexylphthalate categories, controlling for urinary creatinine, age group, body mass index category, race/ethnicity, caloric intake and gender. RESULTS: We identified a -0.04% (95% CI: -0.08, -0.01) increment in di-2-ethylhexylphthalate metabolite concentration/additional gram fruit consumption, a +0.01% increment/additional calorie dietary intake (95% CI: +0.003, +0.02), and a +0.09% (95% CI: +0.02, +0.17) increment/additional gram meat/poultry/fish consumption. Soy consumption (-0.40% increment/additional gram consumed, 95% CI: -0.66, -0.14) was inversely associated with di-2-ethylhexylphthalate, while poultry (+0.23% increment/additional gram consumed, 95% CI: +0.12, +0.35) was positively associated. Findings were robust to examination of metabolite concentrations per unit body mass index and weight, and inclusion of fasting time. CONCLUSIONS: Diet contributes to urinary phthalate concentrations in children and adolescents. Further study is needed to examine the implications of di-2-ethylhexylphthalate exposure, especially earlier in life, when more permanent metabolic changes may occur.