Faculty Bibliography

IMPORTANCE: Maternal thyroid hormone insufficiency during pregnancy can affect children's cognitive development. Nevertheless, the behavioral outcomes of children exposed prenatally to mild thyroid hormone insufficiency are understudied. OBJECTIVE: To examine whether exposure to maternal mild thyroid hormone insufficiency in early pregnancy was related to symptoms of attention-deficit/hyperactivity disorder (ADHD) in children at 8 years of age. DESIGN, SETTING, AND PARTICIPANTS: The study was embedded within the Generation R, a population-based birth cohort in the Netherlands. Children in the Generation R Study are followed up from birth (April 1, 2002, through January 31, 2006) until young adulthood. Of the 4997 eligible mother-child pairs with data on maternal thyroid levels (excluding twins), 3873 pairs of children and caregivers (77.5%) visited the Generation R research center for in-depth assessments and were included in the main analyses. Data collection in Generation R started December 1, 2001 (enrollment of pregnant women), and is ongoing. For this study, we used the data that were collected until January 1, 2014. Data analyses started on January 31 and finished June 30, 2014. MAIN OUTCOMES AND MEASURES: Maternal hypothyroxinemia, characterized by low levels of free thyroxine coexisting with reference thyrotropin levels, and children's symptoms of ADHD. Maternal thyroid hormone levels (thyrotropin, free thyroxine, thyroid peroxidase antibodies) were measured at a mean (SD) of 13.6 (1.9) weeks of gestation. Children's ADHD symptoms were assessed at 8 years of age using the Conners' Parent Rating Scale-Revised Short Form; higher scores indicate more ADHD symptoms (possible range, 0-36). RESULTS: Maternal hypothyroxinemia (n = 127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (ie, sex, ethnicity, maternal age, maternal educational level, and income) (increase in ADHD scores, 7% [95% CI, 0.3%-15%]). The results remained essentially unchanged when women with elevated levels of thyroid peroxidase antibodies were excluded from the analyses (increase in ADHD scores, 8% [95% CI, 1%-16%]). Additional adjustment for children's IQ or comorbid autistic symptoms attenuated the association (increase in ADHD scores adjusted for autistic symptoms, 7% [95% CI, 1%-15%]; increase in ADHD scores adjusted for IQ, 6% [95% CI, 1%-14%]). CONCLUSIONS AND RELEVANCE: Children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring.

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.

OBJECTIVE: Recent evidence suggests that symptoms of social impairment in autism spectrum disorder (ASD) form a spectrum that extends into the general population. However, it is unclear whether the neuroanatomy of ASD also shows a similar continuum in the general population. Therefore, the goal of the present study was to investigate the relationship between cortical morphology and autistic traits along a continuum in a large population-based sample of young children. METHOD: The study included 717 children, aged 6-10 years, who are participants in the Generation R Study, a large population-based cohort. Autistic traits were measured using the Social Responsiveness Scale when the children were approximately 6 years old. High-resolution MRI was obtained, and morphological measures of the cortex, including cortical thickness and gyrification, were quantified brain-wide. RESULTS: Children with more autistic traits showed widespread areas of decreased gyrification. After excluding children with the highest autistic traits and confirmed ASD, the association remained present in a large cluster involving the left hemisphere temporal and precuneus regions. Comparable, but nonsignificant, effects when comparing a small sample of confirmed ASD case subjects with age- and gender-matched control subjects were observed. CONCLUSIONS: Differences in cortical morphology related to autistic traits along a continuum in a large population-based sample of school-aged children were found. Part of these differences remained after excluding the most severely affected children. These findings lend support to an extension of the neurobiology of autistic traits to the general population.

OBJECTIVE: Maternal prepregnancy obesity is associated with several poor infant health outcomes; however, studies that investigated motor development have been inconsistent. Thus, maternal prepregnancy weight status and infants' gross motor development were examined. METHODS: Participants consisted of 4,901 mother-infant pairs from the Upstate KIDS study, a longitudinal cohort in New York. Mothers indicated dates when infants achieved each of six gross motor milestones when infants were 4, 8, 12, 18, and 24 months old. Failure time modeling under a Weibull distribution was utilized to compare time to achievement across three levels of maternal prepregnancy BMI. Hazard ratios (HR) below one indicate a lower "risk" of achieving the milestone and translate to later achievement. RESULTS: Compared to infants born to thin and normal-weight mothers (BMI < 25), infants born to mothers with obesity (BMI > 30) were slower to sit without support (HR = 0.91, P = 0.03) and crawl on hands and knees (HR = 0.86, P < 0.001), after adjusting for maternal and birth characteristics. Increased gestational age was associated with faster achievement of all milestones, but additional adjustment did not impact results. CONCLUSIONS: Maternal prepregnancy obesity was associated with a slightly longer time for infant to sit and crawl, potentially due to a compromised intrauterine environment or reduced physically active play.

During early childhood, girls outperform boys on key dimensions of cognitive functions, including inhibitory control, sustained attention, and working memory. The role of parenting in these sex differences is unknown despite evidence that boys are more sensitive to the effects of the early environment. In this study, we measured parental sensitivity at 14 and 36 months of age, and children's cognitive and executive functions (sustained attention, inhibitory control, and forward/backward memory) at 52 months of age, in a longitudinal cohort (N=752). Boys scored significantly lower than girls on inhibitory control (more Go/NoGo "commission errors") and short-term memory (forward color recall task), but boys did not differ from girls on attention (Go/NoGo "omission errors") or working memory (backward color recall task). In stratified analyses, parental sensitivity at 36 months of age was negatively associated with number of errors of commission (p=.05) and omission (p=.02) in boys, whereas child's age was the only significant predictor of commission and omission errors in girls. A combined analysis of both sexes confirmed an interaction between sex and parenting for omission errors (p=.03). The results indicate that sex differences in cognitive functions are evident in preschoolers, although not across all dimensions we assessed. Boys appear to be more vulnerable to early parenting effects, but only in association with omission errors (attention) and not with the other cognitive function dimensions.

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.

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.

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.

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.