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1.
J Am Heart Assoc ; 8(16): e012821, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31405324

RESUMO

Background An adverse fetal environment leads to fetal hemodynamic adaptations with cardiac flow alterations that may subsequently affect cardiac development. We examined the associations of third trimester placental and fetal cardiac hemodynamics with cardiac outcomes in school-age children. Methods and Results We performed a population-based prospective cohort study among 547 mothers and their children. At a gestational age of 30.4 (95% range 28.4-32.7) weeks, we measured umbilical and cerebral artery resistance, cardiac output, and tricuspid and mitral E/A waves with Doppler. At the median age of 10.0 years (95% range 9.4-11.7) we measured cardiac outcomes with cardiac magnetic resonance imaging. Cardiac outcomes included right ventricular end-diastolic volume) and right ventricular ejection fraction, left ventricular end diastolic volume and left ventricular ejection fraction, left ventricular mass, and left ventricular mass-to-volume ratio as left ventricular mass/left ventricular end diastolic volume. Higher third-trimester umbilical artery resistance was associated with higher childhood right ventricular ejection fraction (P value <0.05), but not with other cardiac outcomes. The third-trimester umbilical artery-cerebral artery pulsatility index ratio was not associated with childhood cardiac outcomes. Higher third-trimester fetal left cardiac output was associated with lower childhood left ventricular ejection fraction and higher left ventricular mass-to-volume ratio (P value <0.05). Third-trimester fetal right cardiac output was not associated with childhood cardiac outcomes. A higher third-trimester fetal tricuspid valve E/A ratio was associated with higher childhood right ventricular ejection fraction (P value <0.05). Conclusions Our findings suggest that fetal cardiac fetal blood flow redistribution may have long-term effects on cardiac structure and function. These results should be considered as hypothesis generating and need further replication.

2.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
3.
Pediatr Allergy Immunol ; 30(4): 443-450, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801809

RESUMO

BACKGROUND: Fetal growth restriction is associated with higher risks of childhood respiratory morbidity. Fetal blood flow adaptations might contribute to these associations. We examined the associations of fetal umbilical, cerebral, and pulmonary blood flow with wheezing patterns, lung function, and asthma in childhood. METHODS: In a population-based prospective cohort study among 903 children, we measured fetal umbilical, cerebral, and pulmonary blood flow by pulsed-wave Doppler at a median gestational age of 30.3 (95% range 28.8-32.3) weeks. We obtained information about wheezing patterns until the age of 6 years by questionnaires. Lung function was measured by spirometry and information about current asthma was obtained by questionnaire at the age of 10 years. RESULTS: Results showed a non-significant relationship between a higher umbilical artery pulsatility index (PI) and umbilical artery PI/cerebral artery PI ratio, indicating fetal blood flow redistribution at the expense of the trunk, with higher risks of early wheezing (OR [95% CI]: 2.07 (0.70-6.10) and 2.74 (0.60, 12.62) per unit increase, respectively). A higher pulmonary artery time velocity integral, indicating higher pulmonary vascular resistance, was associated with a higher risk of late/persistent wheezing (Z-score 1.14 [1.01-1.29]). A higher middle cerebral artery PI was associated with a higher FEV1 /FVC (Z-score [95% CI]: 0.21 [0.01-0.42]). Results did not materially change after additional adjustment for birth and growth characteristics. CONCLUSION: Third-trimester fetal blood flow patterns might be related to childhood respiratory health. These findings should be considered as hypothesis generating and need further replication.

4.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552196

RESUMO

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Assuntos
Antropometria , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Análise de Sequência de DNA/métodos , Estatura/genética , Estudos de Coortes , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Lipodistrofia/genética , Masculino , Metanálise como Assunto , Obesidade/genética , Mapeamento Físico do Cromossomo , Caracteres Sexuais , Síndrome , Reino Unido
5.
Nature ; 538(7624): 248-252, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27680694

RESUMO

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10-13), T2D (Rg = -0.27, P = 1.1 × 10-6) and coronary artery disease (Rg = -0.30, P = 6.5 × 10-9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.


Assuntos
Envelhecimento/genética , Peso ao Nascer/genética , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Antropometria , Pressão Sanguínea/genética , Montagem e Desmontagem da Cromatina , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Loci Gênicos/genética , Variação Genética/genética , Impressão Genômica/genética , Genótipo , Glucose/metabolismo , Glicogênio/biossíntese , Humanos , Insulina/metabolismo , Masculino , Fenótipo , Transdução de Sinais
6.
Eur J Epidemiol ; 31(12): 1243-1264, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-28070760

RESUMO

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. This multidisciplinary study focuses on several health outcomes including behaviour and cognition, body composition, eye development, growth, hearing, heart and vascular development, infectious disease and immunity, oral health and facial growth, respiratory health, allergy and skin disorders of children and their parents. Main exposures of interest include environmental, endocrine, genomic (genetic, epigenetic, microbiome), lifestyle related, nutritional and socio-demographic determinants. In total, 9778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Response at baseline was 61%, and general follow-up rates until the age of 10 years were around 80%. Data collection in children and their parents includes questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, lung function, Magnetic Resonance Imaging and biological sampling. Genome and epigenome wide association screens are available. Eventually, results from the Generation R Study contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.


Assuntos
Nível de Saúde , Projetos de Pesquisa , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Países Baixos , Gravidez , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
7.
Am J Kidney Dis ; 66(3): 412-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25641064

RESUMO

BACKGROUND: Fetal smoke exposure may result in developmental adaptations that permanently affect the developing kidney. In this study, the associations of maternal and paternal smoking during pregnancy with childhood kidney size and function were assessed. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: This study was conducted in a group of 5,622 children in Rotterdam, the Netherlands. PREDICTORS: Maternal and paternal smoking were assessed during pregnancy by questionnaires. OUTCOMES & MEASUREMENTS: At a median age of 6.0 (5th-95th percentile, 5.6-7.9) years, we measured childhood kidney volumes, estimated glomerular filtration rate (eGFR), and albumin-creatinine ratio. RESULTS: The confounder model, which included size at birth, shows that compared with children from mothers who did not smoke during pregnancy, those from mothers who continued smoking during pregnancy had smaller combined kidney volumes at the age of 6 years. The strongest effect estimate was observed for mothers who smoked 5 or more cigarettes per day during pregnancy (difference for combined kidney volume, -2.80 [95% CI, -5.15 to -0.45] cm(3)). Similarly, continued maternal smoking during pregnancy also was associated with a lower eGFR in childhood (difference, -2.25 [95% CI, -3.70 to -0.79] mL/min/1.73 m(2)). First-trimester-only smoking was associated with a higher risk of increased albumin-creatinine ratio (OR, 1.45; 95% CI, 1.05-2.01). Among mothers who did not smoke during pregnancy, paternal smoking was associated with smaller childhood combined kidney volume (difference, -1.78 [95% CI, -3.48 to -0.07] cm(3)), but not with childhood kidney function measures. LIMITATIONS: Smoking behavior was measured with questionnaires. Follow-up measurements were available for only 70% of the children. CONCLUSIONS: Continued maternal smoking during pregnancy is associated with smaller combined kidney volume and lower eGFR in school-aged children. Stronger effect estimates for maternal versus paternal smoking suggest that intrauterine adaptive responses may play a role as underlying mechanisms.


Assuntos
Feto/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Criança , Pré-Escolar , Creatinina/sangue , Feminino , Humanos , Masculino , Exposição Materna , Tamanho do Órgão , Exposição Paterna , Gravidez , Estudos Prospectivos , Poluição por Fumaça de Tabaco/efeitos adversos
8.
Hum Mol Genet ; 24(4): 1155-68, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25281659

RESUMO

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Estatura/genética , Estudos de Associação Genética , Variação Genética , Proteínas de Membrana/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Fatores Etários , Alelos , Biologia Computacional , Bases de Dados Genéticas , Genótipo , Humanos , Recém-Nascido , Proteínas de Membrana/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
9.
Eur J Epidemiol ; 29(12): 911-27, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25527369

RESUMO

The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. In total, 9,778 mothers were enrolled in the study. Data collection in children and their parents include questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, Magnetic Resonance Imaging and biological samples. Efforts have been conducted for collecting biological samples including blood, hair, faeces, nasal swabs, saliva and urine samples and generating genomics data on DNA, RNA and microbiome. In this paper, we give an update of the collection, processing and storage of these biological samples and available measures. Together with detailed phenotype measurements, these biological samples provide a unique resource for epidemiological studies focused on environmental exposures, genetic and genomic determinants and their interactions in relation to growth, health and development from fetal life onwards.


Assuntos
Bancos de Espécimes Biológicos , Coleta de Dados/métodos , Exame Físico/métodos , Manejo de Espécimes/métodos , Criança , Pré-Escolar , Meio Ambiente , Exposição Ambiental , Feminino , Desenvolvimento Fetal , Feto , Genômica , Humanos , Lactente , Recém-Nascido , Masculino , Vigilância da População , Gravidez , Estudos Prospectivos , Projetos de Pesquisa , Fatores Socioeconômicos , Inquéritos e Questionários
10.
J Am Soc Nephrol ; 25(11): 2616-24, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24812167

RESUMO

Impaired fetal abdominal blood flow may lead to smaller kidneys and subsequent impaired kidney function in later life. In a prospective cohort study among 923 pregnant women and their children, we measured fetal growth, kidney volumes, and umbilical and cerebral artery blood flow (median gestational age of 30.3 weeks; 95% range, 28.5-32.7 weeks). We used a higher umbilical/cerebral artery pulsatility index ratio as an indicator of preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs. At a median age of 5.9 years (95% range, 5.7-6.6 years), we measured childhood kidney volumes, creatinine and cystatin C blood levels, microalbuminuria, BP, and eGFR. A preferential fetal blood flow to the upper body parts at the expense of the intra-abdominal organs associated only with a smaller combined kidney volume in childhood. Fetal combined kidney volume positively associated with childhood combined kidney volume and eGFR, and inversely associated with childhood creatinine and cystatin C levels (all P values <0.05), but did not associate with childhood microalbuminuria and BP. Children within the highest tertile of fetal umbilical/cerebral ratio and the lowest tertile of fetal combined kidney volume had the lowest eGFR (difference, -6.36 ml/min per 1.73 m(2); 95% confidence interval, -11.78 to -0.94 compared with children within the middle tertiles). These data suggest that impaired fetal blood to the abdominal organs and smaller fetal kidney size are associated with subclinical changes in kidney outcomes in school-aged children.


Assuntos
Albuminúria/epidemiologia , Feto/irrigação sanguínea , Rim/embriologia , Rim/fisiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Albuminúria/diagnóstico por imagem , Albuminúria/patologia , Circulação Cerebrovascular/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Rim/patologia , Masculino , Tamanho do Órgão , Gravidez , Terceiro Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Estudos Prospectivos , Fluxo Pulsátil/fisiologia , Ultrassonografia Pré-Natal , Adulto Jovem
11.
J Hypertens ; 32(6): 1275-82, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24682032

RESUMO

OBJECTIVE: Low birth weight is associated with cardiovascular disease in adulthood. Hemodynamic adaptations related to fetal growth restriction may underlie these associations, through persistent influences on cardiovascular development. We examined the associations of third trimester fetal hemodynamics with cardiovascular outcomes in childhood. METHODS: In a prospective cohort study among 917 pregnant women and their children, we measured fetal growth, and fetal arterial and cardiac hemodynamic variables with ultrasound and Doppler examinations at a gestational age of 30.3 (95% range 28.8-32.3) weeks. At the age of 6 years, we measured blood pressure, carotid-femoral pulse wave velocity, and left cardiac structures and function. RESULTS: We observed that fetal hemodynamics were not associated with childhood blood pressure and carotid-femoral pulse wave velocity. The fetal aorta ascendens diameter and left cardiac output were positively associated with childhood aortic root diameter [0.14 standard deviation score (SDS), 95% confidence interval (CI) 0.07-0.22 and 0.08 SDS, 95% CI 0.01-0.15 per SDS change in diameter and output, respectively]. Fetal left ventricular diastolic filling pattern was inversely associated with aortic root diameter (-0.07 SDS, 95% CI -0.13 to 0.00 per SDS change in E/A ratio) at 6 years. Analyses adjusted and stratified for estimated fetal weight showed no differences in results. CONCLUSION: Our results suggest that third trimester fetal vascular resistance parameters do not affect blood pressure or arterial stiffness in childhood. Fetal cardiac functional and structural measures are associated with cardiac outcomes in childhood. Whether these early adaptations lead to greater risks of cardiovascular disease should be further studied.


Assuntos
Aorta/embriologia , Sistema Cardiovascular/fisiopatologia , Ventrículos do Coração/embriologia , Adulto , Aorta/diagnóstico por imagem , Peso ao Nascer , Pressão Sanguínea , Artérias Carótidas/patologia , Criança , Pré-Escolar , Feminino , Artéria Femoral/patologia , Desenvolvimento Fetal/fisiologia , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Hemodinâmica/fisiologia , Humanos , Masculino , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Análise de Onda de Pulso , Ultrassonografia Pré-Natal , Resistência Vascular , Rigidez Vascular
12.
Pediatr Nephrol ; 29(9): 1589-98, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24599444

RESUMO

BACKGROUND: Subclinical impaired kidney growth and function in childhood may lead to kidney diseases and high blood pressure in adulthood. We assessed the cross-sectional associations of childhood characteristics with kidney size and function in a multi-ethnic cohort. METHODS: This study was embedded in a population-based cohort study of 6,397 children with a median age of 6.0 years.Kidney volume, creatinine and cystatin C blood levels, microalbuminuria and blood pressure were measured, and glomerular filtration rate (GFR) was estimated. RESULTS: Childhood anthropometrics were positively associated with kidney volume, creatinine level and blood pressure (all p < 0.05). We observed ethnic differences in all kidney size and function measures (all p < 0.05). Children with smaller kidneys had higher creatinine and cystatin C blood levels, leading to a lower estimated GFR [difference 5.68 ml/min/1.73 m2 (95% confidence interval 5.14-6.12) per 1 standard deviation increase in kidney volume]. Larger kidney volume was associated with an increased risk of microalbuminuria. CONCLUSIONS: Childhood kidney volume and function are influenced by body mass index and ethnicity. Kidney volume is related with kidney function but not with blood pressure. These results may help to identify individuals at risk for kidney disease in an early stage.


Assuntos
Rim/anatomia & histologia , Rim/fisiologia , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Nefropatias/etnologia , Testes de Função Renal , Masculino , Tamanho do Órgão , Fatores de Risco
13.
J Pediatr ; 163(3): 791-9.e1-2, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23523279

RESUMO

OBJECTIVE: To describe and identify correlates of objectively measured physical activity and sedentary behavior in 2-year-old toddlers. STUDY DESIGN: A total of 347 children participating in a birth cohort study wore a unaxial ActiGraph accelerometer during 1 weekday and 1 weekend day. Information on potential correlates was assessed by parent-reported questionnaires, delivery reports, and regular visits to child health centers. Univariate and multivariable linear regression analyses were conducted to examine the associations between potential correlates and the following physical activity outcomes: percentage of time spent in sedentary behavior, percentage of time spent in moderate-to-vigorous physical activity, and mean counts per minute. RESULTS: A high percentage of monitored time was spent in sedentary behavior; 85.6% on weekdays and 84.5% on weekend days. Four correlates were significantly associated with at least 1 physical activity outcome in the multivariable regression models: child's sex, child's age, number of siblings, and season of measurement. The associations of gross motor development with moderate-to-vigorous physical activity and mean counts per minute approached significance. Associations of socioeconomic variables and child's body mass index z-score with physical activity outcomes were not significant. CONCLUSION: Two-year-old toddlers spend most of their time in sedentary behavior. No modifiable correlates were identified. Further research on physical activity and associated health benefits among very young children is warranted.


Assuntos
Comportamento Infantil , Atividade Motora , Acelerometria , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Países Baixos , Estudos Prospectivos , Estações do Ano , Fatores Socioeconômicos , Inquéritos e Questionários
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