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Objective To investigate whether birth weight and postnatal growth rates are independently related to the development of overweight and wheeze up to age 3 years. Study design Children from the LucKi Birth Cohort Study with complete follow-up for repeated questionnaires (at age 0, 7, and 14 months and 3 years) and informed consent to use height and weight data (measured by trained personnel at age 0, 7, and 14 months and 2 and 3 years) were included (n = 566). Wheeze (parental-reported) and overweight (body mass index [BMI] >85th percentile) were regressed with generalized estimating equations on birth weight and relative growth rates (difference SDS for weight, height, and BMI). Results Higher birth weight and higher weight and BMI growth rates were associated with increased risk of overweight, but not of wheeze, up to age 3 years. Higher height growth rate was associated with lower risk of wheeze up to 3 years, independent of overweight (aOR, 0.65; 95% CI, 0.53-0.79). In time-lag models, wheeze was associated with subsequently reduced height growth up to age 14 months, but not vice versa. Conclusion Only height growth rate, and not weight and BMI growth rate, is associated with preschool wheeze, independent of overweight. Children who wheeze demonstrate a subsequent reduction in height growth up to age 14 months, but not vice versa. Because height growth rate is not associated with overweight, preschool wheeze and overweight are not associated throughout early life growth. [ABSTRACT FROM AUTHOR]

Ethical, legal, and social issues related to the collection, storage, and use of biospecimens and data derived from children raise critical concerns in the international debate. So far, a number of studies have considered a variety of the individual issues crucial to pediatric biobanking such as decision making, privacy protection, minor recontact, and research withdrawal by focusing on theoretical or empirical perspectives. Our research attempted to analyze such issues in a comprehensive manner by exploring practices, rules, and researcher opinions regarding proxy consent, minor assent, specimens and data handling, and return of results as faced in 10 European countries. Because of the lack of comparative analyses of these topics, a pilot study was designed. Following a qualitative methodology, a questionnaire draft mostly including open-ended queries was developed, tested, and sent by e-mail to a selected group of researchers dealing with pediatric biobanking (n = 57). Returned questionnaires (n = 31) highlighted that the collection, storage, distribution, and use of biospecimens and data from children were widely practiced in the contacted laboratories. In most cases, pediatric biobanking was subjected to national or local regulations covering adult biobanks (n = 26). Informed consent was generally given by parents or legal representatives (n = 17). Children's opinions were frequently sought and taken into account (n = 16). However, minors were usually not recontacted at the age of maturity to express their own choices (n = 26). Based on the collected data, dedicated recommendations are needed to govern unique ethical and regulatory issues surrounding pediatric biobanking. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between the child-care environment and physical activity of 2- and 3-year-olds. Based on an ecological view of environmental influences on health behavior, we hypothesized that the social and physical environment, as well as child characteristics (age and gender), would show independent and interactive effects on children's physical activity intensity. Design: Observations of physical activity intensity were performed among children {N = 175) at 9 Dutch child-care centers. Aspects of the child-care environment were assessed using the validated Environment and Policy Assessment and Observation (EPAO) Instrument. Multilevel linear regression analyses examined the association of environment and child characteristics with children's activity intensity. Moderation was tested by including interaction terms in the analyses, with subsequent post hoc analyses for significant interaction terms. Main Outcome Measure: Observed child physical activity intensity, measured with the Observational System for Recording Physical Activity in Children - Preschool Version. Results: A large proportion of the observed activities were classified as sedentary, while far fewer observations were classified as moderate or vigorous. Activity opportunities in the physical environment (assessed using EPAO) and prompts by staff and peers were significantly and positively related to physical activity intensity, while group size was negatively related to activity intensity. The influence of the physical environment was moderated by social environment (peer group size), while the social environment in turn interacted with child characteristics (age and gender) in determining activity intensity. Conclusion: Our findings are in line with the ecological perspective regarding environmental influences on behavior, and stress the importance of incorporating the child-care environment in efforts to prevent childhood overweight and obesity. [ABSTRACT FROM AUTHOR]

Objective: To examine clustering of energy balance-related behaviors (EBRBs) in young children. This is crucial because lifestyle habits are formed at an early age and track in later life. This study is the first to examine EBRB clustering in children as young as 2 years. Study design: Cross-sectional data originated from the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study. Parents of 2578 2-year-old children completed a questionnaire. Correlation analyses, principal component analyses, and linear regression analyses were performed to examine clustering of EBRBs. Results: We found modest but consistent correlations in EBRBs. Two clusters emerged: a “sedentary-snacking cluster” and a “fiber cluster.” Television viewing clustered with computer use and unhealthy dietary behaviors. Children who frequently consumed vegetables also consumed fruit and brown bread more often and white bread less often. Lower maternal education and maternal obesity were associated with high scores on the sedentary-snacking cluster, whereas higher educational level was associated with high fiber cluster scores. Conclusions: Obesity-prone behavioral clusters are already visible in 2-year-old children and are related to maternal characteristics. The findings suggest that obesity prevention should apply an integrated approach to physical activity and dietary intake in early childhood. [Copyright &y& Elsevier]

Objective: To investigate the potential effect of modification by maternal allergic status on the relationship between breast-feeding duration and infant atopic manifestations in the first 2 years of life. Study design: Data from 2705 infants of the KOALA Birth Cohort Study (The Netherlands) were analyzed. The data were collected by repeated questionnaires at 34 weeks of gestation and 3, 7, 12, and 24 months postpartum. Total and specific immunoglobulin E measurements were performed on venous blood samples collected during home visits at age 2 years. Relationships were analyzed using logistic regression analyses. Results: Longer duration of breast-feeding was associated with a lower risk for eczema in infants of mothers without allergy or asthma (Ptrend = .01) and slightly lower risk in those of mothers with allergy but no asthma (Ptrend = .14). There was no such association for asthmatic mothers (Ptrend = .87). Longer breast-feeding duration decreased the risk of recurrent wheeze independent of maternal allergy (Ptrend = .02) or asthma status (Ptrend = .06). Conclusions: Our findings show that the relationship between breast-feeding and infant eczema in the first 2 years of life is modified by maternal allergic status. The protective effect of breast-feeding on recurrent wheeze may be associated with protection against respiratory infections. [Copyright &y& Elsevier]

Objective: To examine the timing, frequency, and type of antibiotic exposure during the first 10 years of life in association with (over)weight across this period in a cohort of 979 children.Study Design: Within the Child, Parents and Health: Lifestyle and Genetic Constitution Birth Cohort Study, antibiotic exposure record was obtained from general practitioners. Anthropometric outcomes (age- and sex-standardized body mass index, weight and height z-scores, and overweight) were measured repeatedly at 7 time points during the first 10 years of life. Generalized estimating equations method was used for statistical analysis.Results: After adjusting for confounding factors, children exposed to one course of antibiotics compared with none in the first 6 months of life had increased weight- (adjusted generalized estimating equations estimates [adjβ] 0.24; 95% CI 0.03-0.44) and height (adjβ 0.23; 95% CI 0.0002-0.46) z-scores; exposure to ≥2 courses during the second year of life was associated with both increased weight (adjβ 0.34; 95% CI 0.07-0.60), and height z-scores (adjβ 0.29; 95% CI -0.003 to 0.59). Exposure later in life was not associated with anthropometric outcomes. Associations with weight z-scores were mainly driven by exposure to broad- (≥2 courses: adjβ 0.11; 95% CI 0.003-0.22) and narrow-spectrum β-lactams (1 course: adjβ 0.18; 95% CI 0.005-0.35) during the follow-up period. Specific antibiotic used was not associated with body mass index z-scores and overweight.Conclusions: Repeated exposure to antibiotics early in life, especially β-lactam agents, is associated with increased weight and height. If causality of obesity can be established in future studies, this further highlights the need for restrictive antibiotic use and avoidance of prescriptions when there is minimal clinical benefit. [ABSTRACT FROM AUTHOR]

Background: It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in childhood. Objective: We investigated whether replicated genes for COPD associate with transient early wheeze (TEW) and lung function levels in 6- to 8-year-old children and whether cigarette smoke exposure in utero and after birth (environmental tobacco smoke [ETS]) modifies these effects. Methods: The association of COPD-related genotypes of 20 single nucleotide polymorphisms in 15 genes with TEW, FEV1, forced vital capacity (FVC), and FEV1/FVC ratio was studied in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort (n = 1996) and replicated in the Child, parents and health: lifestyle and genetic constitution (KOALA) and Avon Longitudinal Study of Parents and Children (ALSPAC) cohorts. Results: AGER showed replicated association with FEV1/FVC ratio. TNS1 associated with more TEW in PIAMA and lower FEV1 in ALSPAC. TNS1 interacted with ETS in PIAMA, showing lower FEV1 in exposed children. HHIP rs1828591 interacted with cigarette smoke exposure in utero in PIAMA and with ETS in ALSPAC, with lower lung function in nonexposed children. SERPINE2, FAM13A, and MMP12 associated with higher FEV1 and FVC, and SERPINE2, HHIP, and TGFB1 interacted with cigarette smoke exposure in utero in PIAMA only, showing adverse effects of exposure on FEV1 being limited to children with genotypes conferring the lowest risk of COPD. Conclusion: Our findings indicate relevant involvement of at least 3 COPD genes in lung development and lung growth by demonstrating associations pointing toward reduced airway caliber in early childhood. Furthermore, our results suggest that COPD genes are involved in the infant's lung response to smoke exposure in utero and in early life. [Copyright &y& Elsevier]

Background: Perturbations in the intestinal microbiota may disrupt mechanisms involved in the development of immunologic tolerance. The present study aimed to examine the establishment of the infant microbiota and its association to the development of atopic dermatitis (AD). Methods: Within a randomized, placebo-controlled trial on the prevention of AD by oral supplementation of a bacterial lysate between week 5 and the end of month 7, feces was collected at the ages of 5 weeks (n = 571), 13 weeks (n = 332), and 31 weeks (n = 499) and subjected to quantitative PCRs to detect bifidobacteria, bacteroides, lactobacilli, Escherichia coli, Clostridium difficile, and Clostridium cluster I. Results: Birth mode, breast-feeding but also birth order had a strong effect on the microbiota composition. With increasing number of older siblings the colonization rates at age 5 weeks of lactobacilli (P < .001) and bacteroides (P = .02) increased, whereas rates of clostridia decreased (P < .001). Colonization with clostridia, at the age of 5 and 13 weeks was also associated with an increased risk of developing AD in the subsequent 6 months of life (odds ratioadjusted = 2.35; 95% CI, 1.36-3.94 and 2.51; 1.30-4.86, respectively). Mediation analyses demonstrated that there was a statistically significant indirect effect via Clostridium cluster I colonization for both birth mode and birth order in association to AD. Conclusion: The results of this study are supportive for a role of the microbiota in the development of AD. Moreover, the “beneficial” influence of older siblings on the microbiota composition suggests that this microbiota may be one of the biological mechanisms underlying the sibling effect. [Copyright &y& Elsevier]

Background: Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of the microbiota in the association between birth mode and atopic manifestations has not been studied yet. Objectives: We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. Methods: The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. Results: Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. Conclusion: Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations. [ABSTRACT FROM AUTHOR]

Background: Regulatory T–cell dysfunction is associated with development of the complex genetic conditions atopy and asthma. Therefore, we hypothesized that single nucleotide polymorphisms in genes involved in the development and function of regulatory T cells are associated with atopy and asthma development. Objective: To evaluate main effects and gene-gene interactions of haplotype tagging single nucleotide polymorphisms of genes involved in regulatory T–cell function—IL6, IL6R, IL10, heme-oxygenase 1 (HMOX1), IL2, Toll-like receptor 2 (TLR2), TGFB1, TGF-β receptor (TGFBR)–1, TGFBR2, IL2RA, and forkhead box protein 3 (FOXP3)—in relation to atopy and asthma. Methods: Single-locus and multilocus associations with total IgE (3rd vs 1st tertile); specific IgE to egg, milk, and indoor allergens; and asthma were evaluated by χ2 tests and the multifactor dimensionality-reduction method in 3 birth cohorts (Allergenic study). Results: Multiple statistically significant multilocus associations existed. IL2RA rs4749926 and TLR2 rs4696480 associated with IgE in both age groups tested (1-2 and 6-8 years). TGFBR2 polymorphisms associated with total and specific IgE in both age groups and with asthma. TGFBR2 rs9831477 associated with specific IgE for milk at age 1 to 2 years and indoor allergens at age 6 to 8 years. For milk-specific IgE, interaction between TGFBR2 and FOXP3 polymorphisms was confirmed by logistic regression and consistent in 2 birth cohorts and when stratified for sex, supplying internal replications. Conclusion: Genes involved in the development and function of regulatory T cells, specifically IL2RA, TLR2, TGFBR2, and FOXP3, associate with atopy and asthma by gene-gene interaction. Modeling of multiple gene-gene interactions is important to unravel further the genetic susceptibility to atopy and asthma. [ABSTRACT FROM AUTHOR]

Background: Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy. Objective: We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations. Methods: Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli. Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction. Results: Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 (P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing. Conclusion: The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development. [Copyright &y& Elsevier]