Faculty Bibliography

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.

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.

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.

BACKGROUND: Prenatal exposure to air pollutants has been suggested as a possible etiologic factor for the occurrence of autism spectrum disorder. OBJECTIVES: We aimed to assess whether prenatal air pollution exposure is associated with childhood autistic traits in the general population. METHODS: Ours was a collaborative study of four European population-based birth/child cohorts-CATSS (Sweden), Generation R (the Netherlands), GASPII (Italy), and INMA (Spain). Nitrogen oxides (NO2, NOx) and particulate matter (PM) with diameters of