Generation R Study Group

Rotterdam, Netherlands

Generation R Study Group

Rotterdam, Netherlands
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Van Den Hooven E.H.,Generation R Study Group | Van Den Hooven E.H.,TNO | Van Den Hooven E.H.,Erasmus Medical Center | De Kluizenaar Y.,TNO | And 8 more authors.
Hypertension | Year: 2011

Exposure to air pollution is associated with elevated blood pressure and cardiovascular disease. We assessed the associations of exposure to particulate matter (PM10) and nitrogen dioxide (NO2) levels with blood pressure measured in each trimester of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in 7006 women participating in a prospective cohort study in the Netherlands. Information on gestational hypertensive disorders was obtained from medical records. PM10 exposure was not associated with first trimester systolic and diastolic blood pressure, but a 10-μg/m increase in PM10 levels was associated with a 1.11-mm Hg (95% confidence interval [CI] 0.43 to 1.79) and 2.11-mm Hg (95% CI 1.34 to 2.89) increase in systolic blood pressure in the second and third trimester, respectively. Longitudinal analyses showed that elevated PM10 exposure levels were associated with a steeper increase in systolic blood pressure throughout pregnancy (P<0.01), but not with diastolic blood pressure patterns. Elevated NO2 exposure was associated with higher systolic blood pressure levels in the first, second, and third trimester (P<0.05), and with a more gradual increase when analyzed longitudinally (P<0.01). PM10 exposure, but not NO2 exposure, was associated with an increased risk of pregnancy-induced hypertension (odds ratio 1.72 [95% CI 1.12 to 2.63] per 10-μg/m increase). In conclusion, our results suggest that air pollution may affect maternal cardiovascular health during pregnancy. The effects might be small but relevant on a population level. © 2011 American Heart Association, Inc.


Korevaar T.I.M.,Generation R Study Group | Korevaar T.I.M.,Erasmus Medical Center | Medici M.,Generation R Study Group | Medici M.,Erasmus Medical Center | And 11 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Abnormal maternal thyroid function during pregnancy is associated with various complications. International guidelines advocate the use of population-based trimester-specific reference ranges for thyroid function tests. When unavailable, an upper TSH limit of 2.5 for the first trimester and 3.0 mU/L for the second and third trimesters is recommended. Although interindividual differences in thyroid function tests can partially be explained by ethnicity, data on the influence of ethnicity on TSH and free T4 reference ranges during pregnancy are sparse. Design: Serum TSH, free T4, T4, and TPO-A ntibody levels were determined during early pregnancy in 3944 women from the Generation R study, Rotterdam, The Netherlands. Results: The study population consisted of 2765 Dutch, 308 Moroccan, 421 Turkish, and 450 Surinamese women. Mean TSH levels were higher in Dutch and Turkish women than in Moroccan or Surinamesewomen(1.50-1.48 vs 1.29-1.33 mU/L; P.01). Although no differences in free T4 were seen, T4 was lowest in Dutch women (142 vs 150-156 nmol/L; P .01). Turkish women had the highest frequency of TPO-A ntibody positivity (9.3% vs 5.0-5.8%; P.05) and of elevated TSH levels in the second trimester (11.0% vs 3.8-7.3%; P.01). A comparison of disease prevalence between a population-based vs an ethnicity-specific reference range changed the diagnosis for 18% of women who were initially found to have abnormal thyroid function test results. Conclusions: We show ethnic differences in serum TSH, T4, and TPO-A ntibody positivity and found significant diagnostic discrepancies depending on whether population or ethnicity-specific reference ranges were used to diagnose thyroid disease. Copyright © 2013 by The Endocrine Society.


PubMed | Erasmus Medical Center, Generation R Study Group and University of Queensland
Type: Journal Article | Journal: The American journal of clinical nutrition | Year: 2016

Maternal vitamin D deficiency during pregnancy may affect fetal outcomes.The objective of this study was to examine whether maternal 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy affect fetal growth patterns and birth outcomes.This was a population-based prospective cohort in Rotterdam, Netherlands in 7098 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.3 wk (range: 18.5-23.3 wk). Vitamin D concentrations were analyzed continuously and in quartiles. Fetal head circumference and body length and weight were estimated by repeated ultrasounds, and preterm birth (gestational age <37 wk) and small size for gestational age (less than the fifth percentile) were determined.Adjusted multivariate regression analyses showed that, compared with mothers with second-trimester 25(OH)D concentrations in the highest quartile, those with 25(OH)D concentrations in the lower quartiles had offspring with third-trimester fetal growth restriction, leading to a smaller head circumference, shorter body length, and lower body weight at birth (all P < 0.05). Mothers who had 25(OH)D concentrations in the lowest quartile had an increased risk of preterm delivery (OR: 1.72; 95% CI: 1.14, 2.60) and children who were small for gestational age (OR: 2.07; 95% CI: 1.33, 3.22). The estimated population attributable risk of 25(OH)D concentrations <50 nmol/L for preterm birth or small size for gestational age were 17.3% and 22.6%, respectively. The observed associations were not based on extreme 25(OH)D deficiency, but presented within the common ranges.Low maternal 25(OH)D concentrations are associated with proportional fetal growth restriction and with an increased risk of preterm birth and small size for gestational age at birth. Further studies are needed to investigate the causality of these associations and the potential for public health interventions.


PubMed | Erasmus Medical Center, Generation R Study Group and Donders Institute for Brain
Type: Journal Article | Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience | Year: 2014

Genetic variance has been associated with variations in brain morphology, cognition, behavior, and disease risk. One well studied example of how common genetic variance is associated with brain morphology is the serotonin transporter gene polymorphism within the promoter region (5-HTTLPR). Because serotonin is a key neurotrophic factor during brain development, genetically determined variations in serotonin activity during maturation, in particular during early prenatal development, may underlie the observed association. However, the intrauterine microenvironment is not only determined by the childs, but also the mothers genotype. Therefore, we hypothesized that maternal 5-HTTLPR genotype influences the childs brain development beyond direct inheritance. To test this hypothesis, we investigated 76 children who were all heterozygous for the 5-HTTLPR (sl) and who had mothers who were either homozygous for the long (ll) or the short allele (ss). Using MRI, we assessed brain morphology as a function of maternal genotype. Gray matter density of the somatosensory cortex was found to be greater in children of ss mothers compared with children of ll mothers. Behavioral assessment showed that fine motor task performance was altered in children of ll mothers and the degree of this behavioral effect correlated with somatosensory cortex density across individuals. Our findings provide initial evidence that maternal genotype can affect the childs phenotype beyond effects of classical inheritance. Our observation appears to be explained by intrauterine environmental differences or by differences in maternal behavior.


PubMed | Child and Adolescent Psychiatry, Erasmus Medical Center, Generation R Study Group, Child and Adolescent Psychiatry. and 3 more.
Type: Journal Article | Journal: The Journal of nutrition | Year: 2016

Dietary composition has been associated with sleep indexes. However, most of the evidence is based on cross-sectional data, and studies in young children are lacking.The aim of this study was to explore the longitudinal associations of macronutrient composition of the diet with sleep duration and consolidation (number of awakenings) in infancy and early childhood.The study was performed in 3465 children from the Generation R Study, a population-based cohort study in the Netherlands. Mothers reported their childs food intake at 13 mo of age by using a validated food-frequency questionnaire and their childs sleep patterns at 2 and 3 y of age. We used nutrient substitution models to assess the associations of relative macronutrient intakes with sleep indexes and adjusted the models for sociodemographic and lifestyle factors.Isocaloric substitution of fat intake by protein or carbohydrate in infancy was associated with longer total sleep duration at 2 but not 3 y of age. For each 5% increase in energy intake of either protein or carbohydrate at the expense of fat, sleep duration at 2 y of age was longer by 6 min (95% CI: 0.4, 12 min) and 4 min (95% CI: 2, 6 min), respectively. Further exploration of macronutrient subtypes indicated no consistent differences between saturated or unsaturated fat and that intake of plant compared with animal protein or Trp did not explain the association of higher total protein intake with longer sleep duration at 2 y of age. Replacing unsaturated with saturated fat was associated with 7 min (95% CI: -13, -1 min) shorter total sleep duration at 3 y of age. Macronutrient intakes were not associated with sleep consolidation.Our results suggest that the macronutrient composition of the diet is associated with sleep duration in young children. Future research should further study the causality of this association and explore the underlying mechanisms.


PubMed | Erasmus Medical Center, Generation R Study Group, Rotterdam, Erasmus University Rotterdam and University of Chicago
Type: Journal Article | Journal: Biological psychiatry | Year: 2016

Cannabis use during pregnancy has been associated with negative behavioral outcomes and psychopathology in offspring. However, there has been little research evaluating alterations in brain structure as a result of maternal cannabis use. In this prospective study, we investigated the association between prenatal cannabis exposure and brain morphology in young children.We matched 96 children prenatally exposed to tobacco only (without cannabis) with 113 unexposed control subjects on the basis of age and gender and subsequently selected 54 children exposed to prenatal cannabis (mostly combined with tobacco exposure). These children (aged 6 to 8 years) were part of a population-based study in the Netherlands, the Generation R Study, and were followed from pregnancy onward. We assessed brain volumetric measures and cortical thickness in magnetic resonance imaging scans using FreeSurfer. We performed vertexwise analyses in FreeSurfer and linear regression analyses adjusting for relevant covariates using Statistical Package for the Social Sciences.Prenatal cannabis exposure was not associated with global brain volumes, such as total brain volume, gray matter volume, or white matter volume. However, prenatal cannabis exposure was associated with differences in cortical thickness: compared with nonexposed control subjects, cannabis-exposed children had thicker frontal cortices. Prenatal tobacco exposure compared with nonexposed control subjects was associated with cortical thinning, primarily in the superior frontal and superior parietal cortices.Our findings suggest an association between prenatal cannabis exposure and cortical thickness in children. Further research is needed to explore the causal nature of this association.


Ghassabian A.,Generation R Study Group | Ghassabian A.,Erasmus MC Sophia Childrens Hospital | Herba C.M.,University of Quebec at Montréal | Herba C.M.,Ste Justines Hospital Research Center | And 12 more authors.
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2013

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. © 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association for Child and Adolescent Mental Health.


Roman G.C.,Methodist Neurological Institute | Roman G.C.,New York Medical College | Ghassabian A.,Generation R Study Group | Ghassabian A.,Erasmus Medical Center | And 8 more authors.
Annals of Neurology | Year: 2013

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. © 2013 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of the American Neurological Association.


Gabriele C.,Erasmus Medical Center | Gabriele C.,Salesi Childrens Hospital | Gabriele C.,Generation R Study Group | Jaddoe V.W.,Erasmus Medical Center | And 7 more authors.
European Respiratory Journal | Year: 2012

We assessed whether exhaled nitric oxide fraction (FeNO), a marker of eosinophilic airway inflammation, at 6 months was associated with the risk of wheezing during the first 2 yrs of life. In the Generation R birth cohort, pre- and post-natal risk factors for respiratory morbidity and respiratory symptoms were assessed by questionnaires at 6 and 24 months. In 428 infants, off-line mixed oral/nasal FeNO was successfullymeasured during tidal breathing at 6 months. Complete data on FeNO and respiratory symptoms within the first 6 months of life were available for 294 infants. FeNO was higher in males, was positively associated with age and was negatively associated with upper and lower respiratory symptoms within the first 6 months. Logistic regression analysis showed that for every ppb increase of FeNO measured at 6 months, infants had a 1.06 (95% confidence interval 1.01-1.11)-fold increased risk of wheezing in the second year of life. High FeNO (>17.5 ppb) showed a limited added value in predicting wheezing in the second year. We conclude that FeNO at 6 months is positively associated with the risk of wheezing, but has limited added value in predicting wheezing in the second year of life in individual children. Copyright©ERS 2012.


Duijts L.,Generation R Study Group | Duijts L.,Erasmus Medical Center | Jaddoe V.W.V.,Generation R Study Group | Jaddoe V.W.V.,Erasmus Medical Center | And 2 more authors.
Pediatrics | Year: 2010

OBJECTIVE: To examine the associations of duration of exclusive breastfeeding with infections in the upper respiratory (URTI), lower respiratory (LRTI), and gastrointestinal tracts (GI) in infancy. METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward in the Netherlands. Rates of breastfeeding during the first 6 months (never; partial for <4 months, not thereafter; partial for 4-6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended infections in the URTI, LRTI, and GI until the age of 12 months were assessed by questionnaires and available for 4164 subjects. RESULTS: Compared with never-breastfed infants, those who were breastfed exclusively until the age of 4 months and partially thereafter had lower risks of infections in the URTI, LRTI, and GI until the age of 6 months (adjusted odds ratio [aOR]: 0.65 [95% confidence interval (CI): 0.51-0.83]; aOR: 0.50 [CI: 0.32-0.79]; and aOR: 0.41 [CI: 0.26-0.64], respectively) and of LRTI infections between the ages of 7 and 12 months (aOR: 0.46 [CI: 0.31-0.69]). Similar tendencies were observed for infants who were exclusively breastfed for 6 months or longer. Partial breastfeeding, even for 6 months, did not result in significantly lower risks of these infections. CONCLUSIONS: Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants. Our findings support healthpolicy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries. Copyright © 2010 by the American Academy of Pediatrics.

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