Vincent V. W. Jaddoe

Maternal Thyroid Function during Early Pregnancy and Cognitive Functioning in Early Childhood: The Generation R Study

CONTEXT Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and childrens cognitive development are sparse. OBJECTIVE Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T(4)(FT(4)) levels across the entire range with cognitive functioning in early childhood. DESIGN AND SETTING We conducted a population-based cohort in The Netherlands. PARTICIPANTS Participants included 3659 children and their mothers. MAIN MEASURES In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT(4) concentrations below the 10th and 5th percentile, respectively. Childrens expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Childrens Abilities measuring verbal and nonverbal cognitive functioning. RESULTS Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT(4) predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). CONCLUSIONS Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood.

Maternal Early Pregnancy and Newborn Thyroid Hormone Parameters: The Generation R Study

CONTEXT Abnormal maternal thyroid parameters are associated with adverse pregnancy outcomes, with consequences for both mother and child. Although various studies have studied maternal thyroid parameters during the first half of pregnancy, little is known about their relations with thyroid parameters of the child. OBJECTIVE The objective was to study maternal thyroid parameters during the first half of pregnancy as well as their relations with cord thyroid parameters. DESIGN, SETTING, AND PARTICIPANTS Serum TSH, free T(4) (FT4), T(4), and thyroid peroxidase antibody (TPOAb) levels were determined once between gestational wk 9 and 18 in 5393 pregnant women from the population-based Generation R study. Cord serum TSH and FT4 levels were determined in 3036 newborns. RESULTS Between gestational wk 9 and 18, the maternal TSH reference range (2.5th to 97.5th percentile) was 0.03-4.04 mU/liter. Gestational age was positively correlated with maternal TSH (r = 0.06, P = 6.3 × 10(-5)) and total T(4) (r = 0.21, P = 1.4 × 10(-44)) and negatively with FT4 (r = -0.27, P=7.3 × 10(-76)) and TPOAb-positivity (r=-0.04, P = 0.01). TPOAb positivity was associated with more subclinical (20.1 vs. 2.4%, P = 1.5 × 10(-39)) and overt hypothyroidism (3.3 vs. 0.1%, P = 1.4 × 10(-10)). Maternal and cord TSH were positively associated (β = 0.47 ± 0.15, P = 1.3 × 10(-5)) as well as maternal and cord FT4 (β = 0.11 ± 0.02, P = 4.5 × 10(-6)). CONCLUSIONS We confirm correlations of maternal thyroid parameters with gestational age during the first half of pregnancy and show a substantially increased risk of (subclinical) hypothyroidism in TPOAb-positive mothers. A substantial part of the mothers had a TSH level above 2.5 mU/liter, underlining the importance of using population-specific reference ranges. Maternal and cord thyroid parameters were positively correlated, the exact biological basis of which remains to be determined.

Epigenome-Wide Meta-Analysis of Methylation in Children Related to Prenatal NO2 Air Pollution Exposure

Background: Prenatal exposure to air pollution is considered to be associated with adverse effects on child health. This may partly be mediated by mechanisms related to DNA methylation. Objectives: We investigated associations between exposure to air pollution, using nitrogen dioxide (NO2) as marker, and epigenome-wide cord blood DNA methylation. Methods: We meta-analyzed the associations between NO2 exposure at residential addresses during pregnancy and cord blood DNA methylation (Illumina 450K) in four European and North American studies (n = 1,508) with subsequent look-up analyses in children ages 4 (n = 733) and 8 (n = 786) years. Additionally, we applied a literature-based candidate approach for antioxidant and anti-inflammatory genes. To assess influence of exposure at the transcriptomics level, we related mRNA expression in blood cells to NO2 exposure in 4- (n = 111) and 16-year-olds (n = 239). Results: We found epigenome-wide significant associations [false discovery rate (FDR) p < 0.05] between maternal NO2 exposure during pregnancy and DNA methylation in newborns for 3 CpG sites in mitochondria-related genes: cg12283362 (LONP1), cg24172570 (3.8 kbp upstream of HIBADH), and cg08973675 (SLC25A28). The associations with cg08973675 methylation were also significant in the older children. Further analysis of antioxidant and anti-inflammatory genes revealed differentially methylated CpGs in CAT and TPO in newborns (FDR p < 0.05). NO2 exposure at the time of biosampling in childhood had a significant impact on CAT and TPO expression. Conclusions: NO2 exposure during pregnancy was associated with differential offspring DNA methylation in mitochondria-related genes. Exposure to NO2 was also linked to differential methylation as well as expression of genes involved in antioxidant defense pathways. Citation: Gruzieva O, Xu CJ, Breton CV, Annesi-Maesano I, Antó JM, Auffray C, Ballereau S, Bellander T, Bousquet J, Bustamante M, Charles MA, de Kluizenaar Y, den Dekker HT, Duijts L, Felix JF, Gehring U, Guxens M, Jaddoe VV, Jankipersadsing SA, Merid SK, Kere J, Kumar A, Lemonnier N, Lepeule J, Nystad W, Page CM, Panasevich S, Postma D, Slama R, Sunyer J, Söderhäll C, Yao J, London SJ, Pershagen G, Koppelman GH, Melén E. 2017. Epigenome-wide meta-analysis of methylation in children related to prenatal NO2 air pollution exposure. Environ Health Perspect 125:104–110; http://dx.doi.org/10.1289/EHP36

Angiogenic and fibrinolytic factors in blood during the first half of pregnancy and adverse pregnancy outcomes.

OBJECTIVE: To estimate whether the imbalance of angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor) and fibrinolytic factors (plasminogen activator inhibitor-2 [PAI-2]) might affect placentation in early pregnancy. METHODS: We studied the associations of maternal soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 concentrations in the first trimester (before 18 weeks of gestation) and soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in the second trimester (18–25 weeks of gestation) with placental function and adverse pregnancy outcomes. This study was embedded in a population-based prospective cohort study. Data were used from 7,519 women. Biomarker concentrations were divided into deciles and evaluated in multivariable linear and logistic regression models. RESULTS: First-trimester high soluble fms-like tyrosine kinase-1 was associated with a 5.2% lower uterine artery index in the second-trimester and a 1.6% higher birth weight (55 g, confidence interval [CI] 15–95). Neither in the first nor in the second trimester were soluble fms-like tyrosine kinase-1 concentrations significantly associated with preeclampsia. First-trimester low placental growth factor was associated with a 6.1% higher uterine artery index and a 3.4% lower birth weight (−115 g, CI −157 to −74). First-trimester low placental growth factor was associated with fetal growth restriction (odds ratio [OR] 2.62, CI 1.68–4.08) and preeclampsia (OR 2.46, CI 1.49–4.08). First-trimester low PAI-2 was associated with a 1.9% higher uterine artery index and a 2.7% lower birth weight (−94 g, CI −136 to −51). First-trimester low PAI-2 was associated with a higher risk of fetal growth restriction (OR 2.22, CI 1.39–3.55). CONCLUSION: First-half-of-pregnancy concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and PAI-2 are associated with uteroplacental vascular resistance, placental weight, and birth weight. Moreover, first-trimester placental growth factor and PAI-2 are associated with an increased risk of adverse pregnancy outcomes. LEVEL OF EVIDENCE: II

Are parents’ anxiety and depression related to child fussy eating?

Objective To examine the association between parental anxiety and depression with child fussy eating—that is, consistent rejection of particular food items. Design This study was embedded in Generation R, a prospective cohort from fetal life onwards in the Netherlands. Setting Population-based. Participants 4746 4-year-old children and their parents. Exposure Parental internalising problems (ie, symptoms of anxiety and depression) were assessed with the Brief Symptoms Inventory during pregnancy and the preschool period (child age 3 years). Main outcome measure The food fussiness scale of the Childrens Eating Behaviour Questionnaire. Results Maternal anxiety during pregnancy and during the childs preschool period was related to higher food fussiness sum-scores in children. For instance, per point on the anxiety scale in pregnancy, children had on average a 1.02 higher sum-score (95% CI 0.59 to 1.46) on the food fussiness scale, after adjustment for confounders. Likewise, mothers’ depressive symptoms at both time points were associated with fussy eating behaviour in their children (eg, in the antenatal period: per point on the depression scale, children had a 0.91 point higher sum-score on the food fussiness scale, 95% CI 0.49 to 1.33). We found largely similar associations between fathers’ internalising problems and childrens fussy eating. However, fathers’ anxiety during the antenatal period was not related to child fussy eating. Conclusions Maternal and paternal internalising problems were prospectively associated with fussy eating in preschoolers. Healthcare practitioners should be aware that non-clinical symptoms of anxiety and depression in parents are risk factors for child fussy eating.

Breastfeeding duration and non-verbal IQ in children

Background Breastfeeding has been related to better cognitive development in children. However, due to methodological challenges, such as confounding, recall bias or insufficient power, the mechanism and nature of the relation remains subject to debate. Methods We included 3761 participants of a population-based cohort study from fetal life onwards and examined the association of breastfeeding duration with non-verbal intelligence in children of age 6 years. Maternal and paternal lifestyle, sociodemographic factors, child factors and maternal IQ were tested for their confounding effects on the association. Results We observed an initial association between breastfeeding duration and child IQ conferring an advantage of 0.32 (0.20 to 0.44) points for each additional month of breastfeeding. This association strongly attenuated to 0.09 (−0.03 to 0.21) points after adjustment for child factors, sociodemographic factors, parental lifestyle factors and maternal IQ. Similarly, the associations with breastfeeding duration as a categorical variable largely disappeared after confounding factors were added to the models. Conclusions The association between breastfeeding and child IQ can be largely explained by sociodemographic factors, parental lifestyle and maternal IQ. Our results cannot confirm beneficial effects of breastfeeding on child intelligence.

Letter by Lagro et al Regarding Article, “Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease”

To the Editor: We read with interest the article by Ludvigsson et al,1 which provides observational evidence that individuals with celiac disease or small intestinal inflammation are at increased risk of ischemic heart disease. Their study was based on a large number a subjects from a nationwide population-based study. The authors suggested that the mechanism underlying the positive associations between celiac disease and ischemic heart disease is the chronic inflammation that is a major risk factor for ischemic heart disease in the general population.1 A major limitation of their study is the lack …

The child's perspective on discomfort during medical research procedures: a descriptive study

Objective The evaluation of discomfort in paediatric research is scarcely evidence-based. In this study, we make a start in describing childrens self-reported discomfort during common medical research procedures and compare this with discomfort during dental check-ups which can be considered as a reference level of a ‘minimal discomfort’ medical procedure. We exploratory study whether there are associations between age, anxiety-proneness, gender, medical condition, previous experiences and discomfort. We also describe childrens suggestions for reducing discomfort. Design Cross-sectional descriptive study. Setting Paediatric research at three academic hospitals. Patients 357 children with and without illnesses (8–18 years, mean=10.6 years) were enrolled: 307 from paediatric research studies and 50 from dental care. Main outcome measures We measured various generic forms of discomfort (nervousness, annoyance, pain, fright, boredom, tiredness) due to six common research procedures: buccal swabs, MRI scans, pulmonary function tests, skin prick tests, ultrasound imaging and venepunctures. Results Most children reported limited discomfort during the research procedures (means: 1–2.6 on a scale from 1 to 5). Compared with dental check-ups, buccal swab tests, skin prick tests and ultrasound imaging were less discomforting, while MRI scans, venepunctures and pulmonary function tests caused a similar degree of discomfort. 60.3% of the children suggested providing distraction by showing movies to reduce discomfort. The exploratory analyses suggested a positive association between anxiety-proneness and discomfort. Conclusions The findings of this study support the acceptability of participation of children in the studied research procedures, which stimulates evidence-based research practice. Furthermore, the present study can be considered as a first step in providing benchmarks for discomfort of procedures in paediatric research.