Faculty Bibliography

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.

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.

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.

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.

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.

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.

Exposure to maternal hypothyroxinemia during pregnancy, which is characterized by low free T4 but normal thyroid-stimulating hormone (TSH) levels, can negatively affect the foetus. This review provides an overview of present findings concerning the association between maternal hypothyroxinemia during pregnancy and childhood cognitive functioning. Possible causes of maternal hypothyroxinemia and potential mechanisms underlying this association are also discussed. Clinical and epidemiological studies suggest that maternal hypothyroxinemia in the first half of pregnancy but not later in pregnancy impairs cognitive development in infancy and childhood. Animal models confirm that the first half of pregnancy may constitute a sensitive period in which maternal hypothyroxinemia alters neurogenesis and causes neuronal migration errors in the developing foetal brain. However, observational studies in humans cannot demonstrate causality of the association between hypothyroxinemia and neurodevelopment. In the only completed randomized trial of antenatal thyroid screening and subsequent levothyroxine treatment of mild maternal subclinical thyroid dysfunction, including hypothyroxinemia, the interventions did not affect offspring intelligence quotient (IQ). More randomized trials are needed investigating whether screening for hypothyroxinemia and its treatment earlier in the first trimester of pregnancy can improve child cognitive functioning or prevent neurodevelopmental changes. Long-term observational studies should identify molecular, neuroanatomical and neurophysiological factors involved in the association between maternal hypothyroxinemia and offspring cognitive functioning. Information on such mechanisms can be used for the development of innovative prevention and intervention studies that address maternal hypothyroxinemia and its potential consequences.

BACKGROUND: Neuroimaging findings have provided evidence for a relation between variations in brain structures and attention deficit/hyperactivity disorder (ADHD). However, longitudinal neuroimaging studies are typically confined to children who have already been diagnosed with ADHD. In a population-based study, we aimed to characterize the prospective association between brain structures measured during infancy and executive function and attention deficit/hyperactivity problems assessed at preschool age. METHODS: In the Generation R Study, the corpus callosum length, the gangliothalamic ovoid diameter (encompassing the basal ganglia and thalamus), and the ventricular volume were measured in 784 6-week-old children using cranial postnatal ultrasounds. Parents rated executive functioning at 4 years using the behavior rating inventory of executive function-preschool version in five dimensions: inhibition, shifting, emotional control, working memory, and planning/organizing. Attention deficit/hyperactivity problems were assessed at ages 3 and 5 years using the child behavior checklist. RESULTS: A smaller corpus callosum length during infancy was associated with greater deficits in executive functioning at 4 years. This was accounted for by higher problem scores on inhibition and emotional control. The corpus callosum length during infancy did not predict attention deficit/hyperactivity problem at 3 and 5 years, when controlling for the confounders. We did not find any relation between gangliothalamic ovoid diameter and executive function or Attention deficit/hyperactivity problem. CONCLUSIONS: Variations in brain structures detectible in infants predicted subtle impairments in inhibition and emotional control. However, in this population-based study, we could not demonstrate that early structural brain variations precede symptoms of ADHD.