Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children.

BACKGROUND: Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. METHODS: We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. RESULTS: Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. CONCLUSIONS: Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course.

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

Epigenome-wide association studies in asthma: A systematic review.

OBJECTIVE: Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome-wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans. DESIGN: Structured systematic literature search following PRISMA guidelines, Newcastle-Ottawa Scale (NOS) for cohort studies was used for bias assessment. DATA SOURCES: We searched PubMed and Embase databases from 2005 to 2019. ELIGIBILITY CRITERIA: Epigenome-wide association studies testing association between differential methylation and asthma in humans. RESULTS: Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory-related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty-one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples. CONCLUSION: Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma.

Fetal and Infant Growth Patterns and Risk of Lower Lung Function and Asthma. The Generation R Study.

RATIONALE: Children with lower birth weight are at increased risk of asthma symptoms. OBJECTIVES: To examine associations of fetal and infant growth with childhood lung function and asthma. METHODS: This study was embedded in a population-based prospective cohort study of 5,635 children. Growth was estimated by repeated ultrasounds in the second and third trimesters, and measured at birth and at 3, 6, and 12 months. At age 10 years, spirometry was performed and asthma was assessed by parental questionnaire. Restricted and accelerated growth were defined as the growth percentile change between time periods less than -0.67 and more than 0.67 SD scores (SDSs), respectively. We applied multiple regression analyses, including conditional regression analyses, to account for correlations between repeated growth measures. MEASUREMENTS AND MAIN RESULTS: Overall greater weight in the second and third trimesters, at birth, and at 12 months was associated with higher FEV1 and FVC (range of z-score difference, 0.04-0.08, per SDS increase in weight). Greater weight at 3 months was associated with lower FEV1/FVC and forced expiratory flow at 75% of the pulmonary volume (FEF75%) (z-score differences [95% confidence interval]: -0.09 [-0.14 to -0.05] and -0.09 [-0.13 to -0.05] per SDS increase in weight, respectively). Restricted fetal weight growth was associated with lower childhood lung-function measures, partly depending on infant weight growth patterns (range of z-score difference, -0.25 to -0.13). Accelerated fetal weight growth was associated with higher FVC and lower FEV1/FVC only if followed by accelerated infant weight growth. Fetal and infant weight growth was not associated with childhood asthma. CONCLUSIONS: Both restricted fetal weight growth, partly depending on infant weight growth, and accelerated fetal and infant weight growth predispose children to lower lung function and a potential risk for respiratory diseases later in life.

The effect of early growth patterns and lung function on the development of childhood asthma: a population based study.

BACKGROUND: Infant weight gain is associated with lower lung function and a higher risk of childhood asthma. Detailed individual childhood growth patterns might be better predictors of childhood respiratory morbidity than the difference between two weight and height measurements. We assessed the associations of early childhood growth patterns with lung function and asthma at the age of 10 years and whether the child's current body mass index (BMI) influenced any association. METHODS: We derived peak height and weight growth velocity, BMI at adiposity peak, and age at adiposity peak from longitudinally measured weight and height data in the first 3 years of life of 4435 children enrolled in a population-based prospective cohort study. At 10 years of age, spirometry was performed and current asthma was assessed by questionnaire. Spirometry outcomes included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, and forced expiratory flow after exhaling 75% of vital capacity (FEF75). RESULTS: Greater peak weight velocity was associated with higher FVC but lower FEV1/FVC and FEF75. Greater BMI at adiposity peak was associated with higher FVC and FEV1 but lower FEV1/FVC and FEF75. Greater age at adiposity peak was associated with higher FVC, FEV1, FEV1/FVC and FEF75, particularly in children with a small size at birth, and lower odds of current asthma in boys. The child's current BMI only explained the associations of peak weight velocity and BMI at adiposity peak with FVC and FEV1. Peak height velocity was not consistently associated with impaired lung function or asthma. CONCLUSION: Peak weight velocity and BMI at adiposity peak were associated with reduced airway patency in relation to lung volume, whereas age at adiposity peak was associated with higher lung function parameters and lower risk of asthma at 10 years, particularly in boys.

A population-based prospective cohort study examining the influence of early-life respiratory tract infections on school-age lung function and asthma.

BACKGROUND: Early-life respiratory tract infections could affect airway obstruction and increase asthma risk in later life. However, results from previous studies are inconsistent. OBJECTIVE: We examined the associations of early-life respiratory tract infections with lung function and asthma in school-aged children. METHODS: This study among 5197 children born between April 2002 and January 2006 was embedded in a population-based prospective cohort study. Information on physician-attended upper and lower respiratory tract infections until age 6 years (categorised into ≤ 3 and >3-6 years) was obtained by annual questionnaires. Spirometry measures and physician-diagnosed asthma were assessed at age 10 years. RESULTS: Upper respiratory tract infections were not associated with adverse respiratory outcomes. Compared with children without lower respiratory tract infections ≤3 years, children with lower respiratory tract infections ≤3 years had a lower FEV1, FVC, FEV1:FVC and forced expiratory flow at 75% of FVC (FEF75) (Z-score (95% CI): ranging from -0.22 (-0.31 to -0.12) to -0.12 (-0.21 to -0.03)) and an increased risk of asthma (OR (95% CI): 1.79 (1.19 to 2.59)). Children with lower respiratory tract infections >3-6 years had an increased risk of asthma (3.53 (2.37 to 5.17)) only. Results were not mediated by antibiotic or paracetamol use and not modified by inhalant allergic sensitisation. Cross-lagged modelling showed that results were not bidirectional and independent of preschool wheezing patterns. CONCLUSION: Early-life lower respiratory tract infections ≤3 years are most consistently associated with lower lung function and increased risk of asthma in school-aged children.

Maternal blood pressure and hypertensive disorders during pregnancy and childhood respiratory morbidity: the Generation R Study.

Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific.

Influence of genetic variants on childhood lung function - The Generation R Study.

Genetic variants associated with adult lung function could already exert the effects on childhood lung function. We aimed to examine the associations of adult lung function-related genetic variants with childhood lung function and asthma, and whether these associations were modified by atopic predisposition, tobacco smoke exposure, or early growth characteristics. In a population-based prospective cohort study among 3347 children, we selected 7 and 20 single nucleotide polymorphisms (SNPs) associated with adult forced expiratory volume in 1 second (FEV1 ) and FEV1 /forced vital capacity (FEV1 /FVC), respectively. Weighted genetic risk scores (GRSs) for FEV1 and FEV1 /FVC were constructed. At age 10, FEV1 , FVC, FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), and forced expiratory flow at 75% (FEF75 ) of FVC were measured, and information on asthma was obtained by parental-reported questionnaires. The FEV1 -GRS was associated with lower childhood FEV1 , FEV1 /FVC, and FEF75 (Z-score (95% CI): -0.03 (-0.05, -0.01), -0.03 (-0.05, -0.01), and -0.04 (-0.05, -0.01), respectively, per additional risk allele). The FEV1 /FVC-GRS was associated with lower childhood FEV1 /FVC and FEF75 (Z-score (95% CI): -0.04 (-0.05, -0.03) and -0.03 (-0.05, -0.02), respectively, per additional risk allele). Effect estimates of FEV1 -GRS with FEF25-75 , FEV1 , FEF75 , and FVC, and of FEV1 /FVC-GRS with FEV1 /FVC and FEF25-75 were stronger among children exposed to non-atopic mothers, smoking during pregnancy or in childhood, or those born with a lower birthweight, respectively (P-values for interaction < .05). Genetic risk scores were not associated with asthma. Adult lung function-related genetic variants were associated with childhood lung function. Maternal atopy, smoking during pregnancy or in childhood, and birthweight modified the observed effects.

Body fat mass distribution and interrupter resistance, fractional exhaled nitric oxide, and asthma at school-age.

BACKGROUND: Obesity and asthma often coexist. We hypothesized that detailed body fat distribution measures might be more strongly associated than body mass index (BMI) with childhood asthma. OBJECTIVE: We examined the associations of total body and abdominal fat measures with respiratory resistance (Rint), fractional exhaled nitric oxide (Feno), and risks of wheezing and asthma in school-aged children. METHODS: In a population-based prospective cohort study among 6178 children aged 6 years, we measured BMI, fat mass index, android/gynoid ratio, and preperitoneal and subcutaneous fat mass by physical examinations, dual-energy x-ray absorptiometry, and ultrasound, respectively. We performed Rint and Feno measurements, and assessed physician-diagnosed wheezing and asthma by questionnaires. RESULTS: A higher BMI was associated with a higher Rint (Z score [95% CI], 0.06 [0.01-0.12]) and increased risk of wheezing (odds ratio [95% CI], 1.07 [1.00-1.14], per Z score BMI increase), but not with Feno or asthma. A high fat mass index was associated with a higher Rint (Z score [95% CI], 0.40 [0.13-0.68]). A high android/gynoid fat mass ratio was associated with a lower Feno (Sym% [95% CI], -9.8 [-16.3 to -3.4]), whereas a high preperitoneal fat mass was associated with a higher Feno (Sym% [95% CI], 6.5 [0.1-12.9]). Subcutaneous fat mass was not associated with any respiratory outcome. CONCLUSIONS: Studying detailed body fat distribution measures might provide better insight into the obesity-asthma paradigm.

TRPA1 gene polymorphisms and childhood asthma.

BACKGROUND: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. METHODS: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. RESULTS: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. CONCLUSION: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words).

Duration and exclusiveness of breastfeeding and school-age lung function and asthma.

BACKGROUND: Breastfeeding reduces the risk of asthma in early childhood, but it is not clear whether its effect on respiratory morbidity is still present in later childhood. OBJECTIVE: To examine the associations of any breastfeeding, breastfeeding duration, and breastfeeding exclusiveness with lung function and asthma in school-aged children and whether associations were influenced by respiratory tract infections and maternal or child's atopic status. METHODS: This study of 4,464 children was embedded in a population-based prospective cohort study. Information on breastfeeding was obtained by multiple questionnaires from birth until 1 year of age. At 10 years of age, lung function was measured by spirometry, and information on asthma was obtained by questionnaire. Adjusted linear and logistic regression models were used to examine the associations. RESULTS: Shorter duration of breastfeeding was associated with a lower forced expiratory volume in 1 second (FEV1) only (z score change, -0.01; 95% confidence interval [CI], -0.02 to -0.00) per month shorter breastfeeding, but not asthma. When categorized, breastfeeding for 2 to 4 months was associated with a lower forced vital capacity (FVC) (z score change, -0.11; 95% CI, -0.20 to -0.03) compared with breastfeeding for 6 months or longer. Nonexclusive breastfeeding for 4 months was associated with a lower FVC (z score change, -0.08; 95% CI, -0.16 to -0.01) compared with exclusive breastfeeding for 4 months. Results did not materially change after additional adjustment for lower respiratory tract infections and were not modified by maternal history of asthma or atopy, child's eczema, or inhalant allergic sensitization. CONCLUSION: Shorter duration and nonexclusivity of breastfeeding were associated with a lower FEV1 and FVC but not asthma at school-age.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Breastfeeding and asthma outcomes at the age of 6 years: The Generation R Study.

BACKGROUND: Breastfeeding is associated with a lower risk of asthma symptoms in early childhood, but its effect at older ages remains unclear. We examined the associations of duration and exclusiveness of breastfeeding with asthma outcomes in children aged 6 years, and whether these associations were explained by atopic or infectious mechanisms. METHODS: We performed a population-based prospective cohort study among 5675 children. Information about breastfeeding was collected by questionnaires. At age 6 years, we measured interrupter resistance (Rint) and fractional exhaled nitric oxide (FeNO). Information about wheezing patterns (early (≤3 years only), late (>3 years only), persistent (≤3 and >3 years)), and current asthma at 6 years was derived from repeated questionnaires. RESULTS: Compared to children who were ever breastfed, those who were never breastfed had lower FeNO levels (sympercent (95% CI): -16.0 (-24.5, -7.5)) and increased risks of late and persistent wheezing (OR(95% CI): 1.69 (1.06, 2.69) and 1.44 (1.00, 2.07), respectively). Shorter duration of breastfeeding was associated with early wheezing and current asthma (1.40 (1.14, 1.73) and 2.19 (1.29, 3.71), respectively). Less exclusive breastfeeding was associated with early wheezing (1.28 (1.08, 1.53)). Breastfeeding duration and exclusiveness were not associated with FeNO or Rint. The associations were not explained by inhalant allergies, partly by lower respiratory tract infections in early life, and to a lesser extent by lower respiratory tract infections in later life. CONCLUSIONS: Breastfeeding patterns may influence wheezing and asthma in childhood, which seems to be partly explained by infectious mechanisms.

Early childhood growth patterns and school-age respiratory resistance, fractional exhaled nitric oxide and asthma.

BACKGROUND: Greater infant weight gain is associated with lower lung function and increased risk of childhood asthma. The role of early childhood peak growth patterns is unclear. We assessed the associations of individually derived early childhood peak growth patterns with respiratory resistance, fractional exhaled nitric oxide, wheezing patterns, and asthma until school-age. METHODS: We performed a population-based prospective cohort study among 5364 children. Repeated growth measurements between 0 and 3 years of age were used to derive standard deviation scores (s.d.s) of peak height and weight velocities (PHV and PWV, respectively), and body mass index (BMI) and age at adiposity peak. Respiratory resistance and fractional exhaled nitric oxide were measured at 6 years of age. Wheezing patterns and asthma were prospectively assessed by annual questionnaires. We also assessed whether any association was explained by childhood weight status. RESULTS: Greater PHV was associated with lower respiratory resistance [Z-score (95% CI): -0.03 (-0.04, -0.01) per s.d.s increase] (n = 3382). Greater PWV and BMI at adiposity peak were associated with increased risks of early wheezing [relative risk ratio (95% CI): 1.11 (1.06, 1.16), 1.26 (1.11, 1.43), respectively] and persistent wheezing [relative risk ratio (95% CI): 1.09 (1.03, 1.16), 1.37 (1.17, 1.60), respectively] (n = 3189 and n = 3005, respectively). Childhood weight status partly explained these associations. No other associations were observed. CONCLUSIONS: PWV and BMI at adiposity peak are critical for lung developmental and risk of school-age wheezing. Follow-up studies at older ages are needed to elucidate whether these effects persist at later ages.

Role of environmental exposures and filaggrin mutations on associations of ethnic origin with risk of childhood eczema. The Generation R Study.

BACKGROUND: The prevalence of childhood eczema varies considerably between ethnic groups. However, data from longitudinal studies remain scarce. METHODS: We examined the associations of ethnic origin with the development of eczema from birth until the age of 4 years, and whether known environmental and genetic risk factors explain these associations. This study was performed in a multiethnic population-based prospective cohort among 5,082 children. Ethnic origin was based on the parents' country of birth. Data on physician-diagnosed eczema were obtained by annual questionnaires. Information on environmental risk factors was mostly obtained by questionnaires. Filaggrin (FLG) mutations (2282del4, R2447X, R501X, and S3247X) were genotyped for 3,096 children. We used generalized estimating equation models to examine the associations of ethnic origin with the longitudinal odds of eczema at 6 months and 1, 2, 3, and 4 years of age overall and independently. RESULTS: Compared with Dutch children, Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had overall increased risks of eczema (OR (95%-CI): 1.53 (1.15, 2.03), 1.60 (1.21, 2.12), 1.95 (1.56, 2.44), and 2.06 (1.65, 2.57), respectively). Effect estimates for the associations of Cape Verdean and Dutch Antillean origin with eczema became non-significant after adjustment for genetic risk factors or both environmental and genetic risk factors, respectively. Surinamese-Creole and Surinamese-Hindustani children remained to have increased risks of eczema. CONCLUSIONS: Cape Verdean, Dutch Antillean, Surinamese-Creole, and Surinamese-Hindustani children had increased risks of eczema in the first 4 years of life. Environmental and genetic risk factors partly weakened these associations.

Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood eczema: The Generation R Study.

BACKGROUND: Exposure to low levels of vitamin D in fetal life might affect the developing immune system, and subsequently the risk of childhood eczema. We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with the risk of eczema until the age of 4 years. METHODS: In a population-based prospective cohort study of 3019 mothers and their children, maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels (severely deficient <25.0 nmol/l, deficient 25.0-49.9 nmol/l, sufficient 50.0-74.9 nmol/l, optimal ≥75.0 nmol/l). Eczema was prospectively assessed by annual questionnaires until the age of 4 years. Eczema patterns included never, early (age ≤1 year only), late (age >1 year only), and persistent eczema (age ≤ and >1 year). Data were assessed using the generalized estimating equations and multinomial regression models. RESULTS: Compared with the optimal 25-hydroxyvitamin D group, sufficient, deficient, and severely deficient groups of 25-hydroxyvitamin D level in mid-gestation were not associated with the risk of overall eczema (odds ratios [95% confidence interval]: 1.09 [0.82, 1.43], 1.04 [0.87, 1.25], and 0.94 [0.81, 1.10], p-values for trend >0.05), nor with eczema per year or eczema patterns in children up to the age of 4 years. Similarly, we observed no associations of 25-hydroxyvitamin D groups at birth with any eczema outcome. CONCLUSION: Our results suggest that levels of 25-hydroxyvitamin D in mid-gestation and at birth are not associated with the risk of overall eczema, eczema per year, or eczema patterns among children until the age of 4 years.

Mode of delivery and childhood fractional exhaled nitric oxide, interrupter resistance and asthma: the Generation R study.

BACKGROUND: Previous studies suggest that caesarean section may influence the risk of childhood asthma. We examined the associations of different modes of delivery with childhood wheezing patterns, asthma, fractional exhaled nitric oxide (FeNO) and airway interrupter resistance (Rint) up to school age. METHODS: This study among 6,128 children was embedded in a population-based prospective cohort study. Information on mode of delivery was obtained from midwives and hospital registries. Wheezing patterns from birth onwards and ever physician-diagnosed asthma at age 6 yr were assessed by questionnaires. FeNO and Rint were measured at age 6 yr. We used multivariate polynomial, logistic and linear regression models. RESULTS: Compared with vaginal delivery, caesarean section was associated with increased risks of early and persistent wheezing up to school age [odds ratios (95% confidence interval): 1.36 (1.06, 1.75) and 1.73 (1.24, 2.40), respectively]. The effect sizes of elective and emergency caesarean section with wheezing outcomes were similar. Only elective caesarean section was associated with a higher FeNO level [sympercent (95% CI): 12.7 (0.6, 24.8)]. We did not observe associations of mode of delivery with asthma or Rint. Also, vacuum- or forceps-assisted vaginal delivery was not associated with any asthma or related outcome. CONCLUSIONS: Both elective and emergency caesarean sections are associated with increased risks of early and persistent wheezing up to school age. This might be explained by increased airway inflammation reflected by higher FeNO levels.