Faculty Bibliography

In a population-based study, we examined the associations of maternal plasma folate concentrations at 13 weeks of gestation and prenatal folic acid supplement use with autistic traits in the offspring at the age of six years. Parent-reported autistic traits were assessed using the Social Responsiveness Scale short form. Maternal folate was not associated with autistic traits in the offspring. In contrast, prenatal folic acid use was associated with less child autistic traits. Future research should focus on the timing of the potential effect of prenatal folate on the development of autistic traits in combination with clinical diagnosis of autism in the offspring.

BACKGROUND: Accumulating evidence from laboratory animal and human studies suggests that air pollution exposure during pregnancy affects cognitive and psychomotor development in childhood. METHODS: We analyzed data from 6 European population-based birth cohorts-GENERATION R (The Netherlands), DUISBURG (Germany), EDEN (France), GASPII (Italy), RHEA (Greece), and INMA (Spain)-that recruited mother-infant pairs from 1997 to 2008. Air pollution levels-nitrogen oxides (NO2, NOx) in all regions and particulate matter (PM) with diameters of <2.5, <10, and 2.5-10 mum (PM2.5, PM10, and PMcoarse, respectively) and PM2.5 absorbance in a subgroup-at birth addresses were estimated by land-use regression models, based on monitoring campaigns performed primarily between 2008 and 2011. Levels were back-extrapolated to exact pregnancy periods using background monitoring sites. Cognitive and psychomotor development was assessed between 1 and 6 years of age. Adjusted region-specific effect estimates were combined using random-effects meta-analysis. RESULTS: A total of 9482 children were included. Air pollution exposure during pregnancy, particularly NO2, was associated with reduced psychomotor development (global psychomotor development score decreased by 0.68 points [95% confidence interval = -1.25 to -0.11] per increase of 10 mug/m in NO2). Similar trends were observed in most regions. No associations were found between any air pollutant and cognitive development. CONCLUSIONS: Air pollution exposure during pregnancy, particularly NO2 (for which motorized traffic is a major source), was associated with delayed psychomotor development during childhood. Due to the widespread nature of air pollution exposure, the public health impact of the small changes observed at an individual level could be considerable.

OBJECTIVE: Reports from populations with an insufficient iodine intake suggest that children of mothers with mild iodine deficiency during pregnancy are at risk for cognitive impairments. However, it is unknown whether, even in iodine-sufficient areas, low levels of iodine intake occur that influence cognitive development in the offspring. This study investigated the association between maternal low urinary iodine concentration (UIC) in pregnancy and children's cognition in a population-based sample from a country with an optimal iodine status (the Netherlands). SETTING AND PARTICIPANTS: In 1525 mother-child pairs in a Dutch multiethnic birth cohort, we investigated the relation between maternal UIC<150 mug/g creatinine, assessed <18 weeks gestation and children's cognition. OUTCOMES MEASURES: Non-verbal IQ and language comprehension were assessed during a visit to the research centre using Dutch test batteries when the children were 6 years. RESULTS: In total, 188 (12.3%) pregnant women had UIC<150 mug/g creatinine, with a median UIC equal to 119.3 mug/g creatinine. The median UIC in the group with UIC>150 mug/g creatinine was 322.9 mug/g and in the whole sample 296.5 mug/g creatinine. There was a univariate association between maternal low UIC and children's suboptimum non-verbal IQ (unadjusted OR=1.44, 95% CI 1.02 to 2.02). However, after adjustment for confounders, maternal low UIC was not associated with children's non-verbal IQ (adjusted OR=1.33, 95% CI 0.92 to 1.93). There was no relation between maternal UIC in early pregnancy and children's language comprehension at 6 years. CONCLUSIONS: The lack of a clear association between maternal low UIC and children's cognition probably reflects that low levels of iodine were not frequent and severe enough to affect neurodevelopment. This may result from the Dutch iodine fortification policy, which allows iodised salt to be added to almost all processed food and emphasises the monitoring of iodine intake in the population.

Temperament and psychopathology are intimately related; however, research on the prospective associations between positive emotionality, defined as a child's positive mood states and high engagement with the environment, and psychopathology is inconclusive. We examined the longitudinal relation between positive emotionality and internalizing problems in young children from the general population. Furthermore, we explored whether executive functioning mediates any observed association. Within a population-based Dutch birth cohort, we observed positive emotionality in 802 children using the laboratory temperament assessment battery at age 3 years. Child behavior checklist (CBCL) internalizing problems (consisting of Emotionally Reactive, Anxious/Depressed, and Withdrawn scales) were assessed at age 6 years. Parents rated their children's executive functioning at ages 4 years. Children with a lower positive emotionality at age 3 had a higher risk of withdrawn problems at age 6 years (OR = 1.20 per SD decrease in positive emotionality score, 95 % CI: 1.01, 1.42). This effect was not explained by preexisting internalizing problems. This association was partly mediated by more problems in the shifting domain of executive functioning (p < 0.001). We did not find any relation between positive emotionality and the CBCL emotionally reactive or anxious/depressed scales. Although the effect sizes were moderate, our results suggest that low levels of positive emotionality at preschool age can result in children's inflexibility and rigidity later in life. The inflexibility and rigidity are likely to affect the child's drive to engage with the environment, and thereby lead to withdrawn problems. Further research is needed to replicate these findings.

CONTEXT: Although maternal hypothyroxinemia is suggested to be related to various adverse consequences in a child's neurodevelopment, the underlying neurobiology is largely unknown. OBJECTIVE: The objective of the study was to examine the relationship between maternal hypothyroxinemia in early pregnancy and children's nonverbal intelligence quotient (IQ). Furthermore, we explored whether global brain volumes, cortical thickness, and brain surface area differed between children exposed prenatally to hypothyroxinemia and healthy controls. DESIGN AND SETTING: The study included a large population-based prospective birth cohort in The Netherlands. PARTICIPANTS: A total of 3727 mother-child pairs with data on prenatal thyroid function at less than 18 weeks of gestation and nonverbal IQ at 6 years participated in the study. In 652 children, brain imaging was performed at 8 years of age. MAIN MEASURES: Maternal hypothyroxinemia was defined as free T4 in the lowest 5% of the sample, whereas TSH was in the normal range. At 6 years, children's IQ was assessed using a Dutch test battery. Global brain volumetric measures, cortical thickness, and surface area were assessed using high-resolution structural magnetic resonance imaging. RESULTS: The children of mothers with hypothyroxinemia in early pregnancy scored 4.3 points IQ lower than the children of mothers with normal thyroid status (95% confidence interval -6.68, -1.81; P = .001). After adjustment for multiple testing, we did not find any differences in brain volumetric measures, cortical thickness, and surface area between children exposed prenatally to hypothyroxinemia and controls. CONCLUSIONS: Our findings confirm a large adverse effect of maternal hypothyroxinemia on children's nonverbal IQ at school age. However, we found no evidence that maternal hypothyroxinemia is associated with differences in brain morphology in school-age children.

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.

Executive function and intelligence are negatively associated with aggression, yet the role of executive function has rarely been examined in the context of school bullying. We studied whether different domains of executive function and non-verbal intelligence are associated with bullying involvement in early elementary school. The association was examined in a population-based sample of 1,377 children. At age 4 years we assessed problems in inhibition, shifting, emotional control, working memory and planning/organization, using a validated parental questionnaire (the BRIEF-P). Additionally, we determined child non-verbal IQ at age 6 years. Bullying involvement as a bully, victim or a bully-victim in grades 1-2 of elementary school (mean age 7.7 years) was measured using a peer-nomination procedure. Individual bullying scores were based on the ratings by multiple peers (on average 20 classmates). Analyses were adjusted for various child and maternal socio-demographic and psychosocial covariates. Child score for inhibition problems was associated with the risk of being a bully (OR per SD = 1.35, 95%CI: 1.09-1.66), victim (OR per SD = 1.21, 95%CI: 1.00-1.45) and a bully-victim (OR per SD = 1.55, 95%CI: 1.10-2.17). Children with higher non-verbal IQ were less likely to be victims (OR = 0.99, 95%CI: 0.98-1.00) and bully-victims (OR = 95%CI: 0.93-0.98, respectively). In conclusion, our study showed that peer interactions may be to some extent influenced by children's executive function and non-verbal intelligence. Future studies should examine whether training executive function skills can reduce bullying involvement and improve the quality of peer relationships.

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.

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.

OBJECTIVE: Iodine deficiency during pregnancy results in thyroid dysfunction and has been associated with adverse obstetric and foetal effects, leading to worldwide salt iodization programmes. As nowadays 69% of the world's population lives in iodine-sufficient regions, we investigated the effects of variation in iodine status on maternal and foetal thyroid (dys)function in an iodine-sufficient population. DESIGN, PARTICIPANTS AND MEASUREMENTS: Urinary iodine, serum TSH, free T4 (FT4) and TPO-antibody levels were determined in early pregnancy (13.3 (1.9) week; mean (SD)) in 1098 women from the population-based Generation R Study. Newborn cord serum TSH and FT4 levels were determined at birth. RESULTS: The median urinary iodine level was 222.5 mug/l, indicating an iodine-sufficient population. 30.8% and 11.5% had urinary iodine levels <150 and >500 mug/l, respectively. When comparing mothers with urinary iodine levels <150 vs >/=150 mug/l, and >500 vs 500 mug/l had a higher risk of a newborn with decreased cord TSH levels (5.6 +/- 1.4 (mean +/- SE) vs 2.1 +/- 0.5%, P = 0.04), as well as a higher risk of a hyperthyroid newborn (3.1 +/- 0.9 vs 0.6 +/- 0.3%, P = 0.02). These mothers had newborns with higher cord FT4 levels (21.7 +/- 0.3 vs 21.0 +/- 0.1 pm, P = 0.04). Maternal urinary iodine levels <150 mug/l were not associated with newborn thyroid dysfunction. CONCLUSIONS: In an iodine-sufficient population, higher maternal urinary iodine levels are associated with an increased risk of a hyperthyroid newborn.