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Background Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood. Objective To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age. Methods This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire. Results The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference −0.10 (95% CI −0.20 to –0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV1 ) and FVC (−0.13 (95% CI −0.24 to –0.01) and −0.13 (95% CI −0.24 to –0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity. Conclusion Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory

Background Although maternal psychological distress during pregnancy is associated with increased risks of respiratory morbidity in preschool children, it is unknown whether this association persists into later childhood. Objective To examine the association between parental psychological distress during pregnancy and lung function and asthma in children of school age. Methods This study of 4231 children was embedded in a population-based prospective cohort. Parental psychological distress was assessed by the Brief Symptom Inventory during and 3 years after pregnancy, and in mothers also at 2 and 6 months after pregnancy. At age 10 years, lung function was obtained by spirometry and asthma by questionnaire. Results The prevalence of asthma was 5.9%. Maternal overall psychological distress during pregnancy was associated with a lower forced vital capacity (FVC) (z-score difference −0.10 (95% CI −0.20 to –0.01) per 1-unit increase), maternal depressive symptoms during pregnancy with a lower forced expiratory volume in the first second (FEV1 ) and FVC (−0.13 (95% CI −0.24 to –0.01) and −0.13 (95% CI −0.24 to –0.02) when using clinical cut-offs) in their children. All maternal psychological distress measures during pregnancy were associated with an increased risk of asthma (range OR: 1.46 (95% CI 1.12 to 1.90) to 1.91 (95% CI 1.26 to 2.91)). Additional adjustment for paternal psychological distress during pregnancy and parental psychological distress after pregnancy did not materially change the associations. Paternal psychological distress during pregnancy was not associated with childhood respiratory morbidity. Conclusion Maternal, but not paternal, psychological distress during pregnancy is associated with an increased risk of asthma and partly lower lung function in children. This suggests intrauterine programming for the risk of later-life respiratory disease.

Introduction: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. Aims and Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward. Results: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. Conclusions: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose–response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. Implications: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly l

Fatty acids might play a role in asthma and allergy development as they can modulate immune responses. We examined among 4260 mother-child pairs participating in a population-based cohort the associations of maternal plasma fatty acid patterns during pregnancy with a child’s respiratory and allergy outcomes at school-age. In mid-pregnancy, 22 individual fatty acids were measured from maternal blood. Three patterns were previously identified by principal component analysis: A ‘high n-6 polyunsaturated fatty acid (PUFA)’, a ‘monounsaturated and saturated fatty acid’, and a ‘high n-3 PUFA’ pattern. At the age of 10 years, a child’s lung function was assessed by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. A higher ‘high n-6 PUFA’ pattern was associated with a higher forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow after exhaling 75% of forced vital capacity (Z-score difference (95% CI) 0.04 (0, 0.07) and 0.04 (0.01, 0.07), respectively, per SD increase in the fatty acid pattern). We observed no associations of maternal fatty acid patterns with a child’s asthma or allergy outcomes. Our results showed limited associations of maternal patterns of high n-6 PUFA concentrations in pregnancy with a better lung function in school-aged children.

Background Airway bacterial carriage might play a role in respiratory disease. We hypothesize that nasal carriage with Staphylococcus aureus or nasopharyngeal carriage with Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae predisposes individuals to adverse respiratory health. Objective To examine the association of early‐life airway bacterial carriage with respiratory tract infections and vice versa, and of early‐life airway bacterial carriage with wheezing, lung function, and asthma in later childhood. Methods We collected upper airway swabs for bacterial culturing for S aureus, H influenzae, M catarrhalis, and H influenzae at six timepoints between the ages of 6 weeks and 6 years among 945 children participating in a population‐based prospective cohort study. Information on respiratory tract infections and wheezing until age 6 years, and asthma at age 10 years was obtained by questionnaires. Lung function at age 10 years was measured by spirometry. We tested possible bidirectional associations between airway bacterial carriage and respiratory tract infections by cross‐lagged models, and associations of repeatedly measured airway bacterial carriage with wheezing, lung function, and asthma by generalized estimating equations models and regression models. Results Cross‐lagged modeling showed that early‐life airway bacterial carriage was not consistently associated with upper and lower respiratory tract infections or vice versa. Nasopharyngeal carriage with any bacteria in infancy was associated with an increased risk of wheezing (OR [95% CI]: 1.66 [1.31, 2.10]). Airway bacterial carriage was not consistently associated with school‐age lung function or asthma. Conclusion Nasopharyngeal carriage with any bacteria is associated with wheezing, but not respiratory tract infections, asthma, or lung function.

Background: We aimed to assess which sociodemographic factors are associated with current asthma and indicators of lung function in 10-year-old children. Methods: We analysed data of 5237 children (Mean age: 9.7, SD: 0.3) from the Generation R Study (2012-2016), a population-based cohort study in the Netherlands.

Objectives: To prospectively evaluate quality of life (QoL) and psychosocial outcomes in children with severe acute asthma (SAA) after pediatric intensive care (PICU) admission compared to children with SAA who were admitted to a general ward (GW). In addition, we assessed posttraumatic stress (PTS) and asthma-related QoL in the parents. Methods: A preplanned follow-up of 3 to 9 months of our nationwide prospective multicenter study, in which children with SAA admitted to a Dutch PICU (n = 110) or GW (n = 111) were enrolled between 2016 and 2018. Asthma-related QoL, PTS symptoms, emotional and behavioral problems, and social impact in children and/or parents were assessed with validated web-based questionnaires. Results: We included 100 children after PICU and 103 after GW admission, with a response rate of 50% for the questionnaires. Median time to follow-up was 5 months (range: 1-12 months). Time to reach full schooldays after admission was significantly longer in the PICU group (mean of 10 vs 4 days, P =.001). Parents in the PICU group reported more PTS symptoms (intrusion P =.01, avoidance P =.01, arousal P =.02) compared to the GW group. Conclusion: No significant differences were found between PICU and GW children on self-reported outcome domains, except for the time to reach full schooldays. PICU parents reported PTS symptoms more often than the GW group. Therefore, monitoring asthma symptoms and psychosocial screening of children and parents after PICU admission should both be part of standard care after SAA. This should identify those who are at risk for developing PTSD, to timely provide appropriate interventions.

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

INTRODUCTION: Chlamydia trachomatis is the most commonly reported sexually transmitted disease and although infection during pregnancy is associated with neonatal complications, long-term respiratory consequences are unknown. We aimed to determine whether C. trachomatis infection during pregnancy is associated with asthma-related symptoms across childhood METHODS: This study among 2475 children and their mothers was embedded in a population-based prospective cohort study. Maternal urine samples were tested for C. trachomatis infection during pregnancy. Questionnaires provided information on childhood physician-attended lower respiratory tract infections and wheezing, and current asthma at age 10 years. Lung function was measured by spirometry at age 10 years. RESULTS: The prevalence of C. trachomatis infection during pregnancy was 3.2% (78 out of 2475). C. trachomatis infection during pregnancy was not associated with lower respiratory tract infections until age 6 years, but was associated with a higher odds of wheezing in children until age 10 years (OR 1.50 (95% CI 1.10-2.03)). C. trachomatis infection during pregnancy was associated with an increased odds of asthma (OR 2.29 (95% CI 1.02-5.13)), and with a lower forced expiratory volume in 1 s/forced vital capacity and forced expiratory flow at 75% of forced vital capacity (z-score difference -0.28 (95% CI -0.52- -0.04) and -0.24 (95% CI -0.46- -0.01), respectively) in children at age 10 years. The observed associations were only partly explained by mode of delivery, gestational age at birth or birthweight. CONCLUSIONS: C. trachomatis infection during pregnancy is associated with increased odds of wheezing, asthma and impaired lung function. The causality of the observed associations and potential underlying mechanisms need to be explored.

Background: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T-helper-1 and EBV infection a T-helper-2 cell response, possibly leading to disbalanced T-helper cell response, and subsequent risk of asthma or atopy. Objective: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. Methods: This study among 3546 children was embedded in a population-based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. Results: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z-score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non-significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. Conclusions and Clinical Relevance: Associations of EBV and CMV infections in early childhood with school-age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle-related factors.

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.

Background: Adrenal suppression is a side effect of long-term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long-term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children. Methods: A cross-sectional observation

Background: Adrenal suppression is a side effect of long-term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long-term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children. Methods: A cross-sectional observation

Background: Eczema phenotypes and emotional and behavioural problems are highly prevalent in childhood, but their mutual relationship is not fully clear. Objectives: To examine the associations of eczema phenotypes with school-age emotional and behavioural problems, and the bidirectional associations of eczema and emotional and behavioural problems from birth until 10 years. Methods: This study among 5265 individuals was embedded in a prospective population-based cohort study. Never, early transient, mid-transient, late transient and persistent eczema phenotypes were identified based on parent-reported, physician-diagnosed eczema from age 6 months until 10 years. Emotional (internalizing) and behavioural (externalizing) problems were measured repeatedly using the Child Behavior Checklist from age 1·5 to 10 years. Cross-lagged models were applied for bidirectional analyses. Results: All eczema phenotypes were associated with more internalizing problems and attention problems at age 10 years, compared with never having eczema: range of Z-score differences 0·14 [95% confidence interval (CI) 0·01–0·27] to 0·39 (9

Introduction: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. Objective: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. Methods: Spontaneous reports concerni

Background: Childhood asthma is a common condition. Currently there is no validated objective test which can be used to guide asthma treatment in children. This study tests the hypothesis that the addition of fractional exhaled nitric oxide (FENO) monitoring in addition to standard care reduces the number of exacerbations (or attacks) in children with asthma. Methods: This is a multi-centre, randomised controlled study. Children will be included of age 6–16 years who have a diagnosis of asthma, currently use inhaled corticosteroids (ICSs) and have had an exacerbation in the previous 12 months. Exclusion criteria in

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization and

Background: Vitamin D deficiency in early life might affect the developing lung and immune system, and subsequently influence the risk of asthma and allergy in later life. Objective: We examined the associations of 25‐hydroxyvitamin D concentrations in mid‐gestation and at birth with lung function, asthma, inhalant allergic sensitization and inhalant allergy at school‐age. Methods: This study among 4951 children and their mothers was embedded in a population‐based prospective cohort in Rotterdam, the Netherlands. Maternal ve‐ nous blood samples in mid‐gestation and umbilical cord blood samples at birth were used to determine 25‐hydroxyvitamin D concentrations. At age 10 years, lung func‐ tion was measured by spirometry, current asthma and physician‐diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. We used multivariable regression models to examine associations. Results: Higher 25‐hydroxyvitamin D concentrations in mid‐gestation were associ‐ ated with a higher forced vital capacity (FVC), but a lower forced expiratory volume in 1 second/FVC (FEV1/FVC) and a lower forced expiratory flow after exhaling 75% of FVC (FEF75) (Z‐score differences [95% CI] 0.02 [0.00, 0.03], −0.02 [−0.03, −0.01] and −0.01 [‐0.03, −0.00], respectively, per 10 nmol/L 25‐hydroxyvitamin D), but not with asthma. Furthermore, higher 25‐hydroxyvitamin D concentrations in mid‐gesta‐ tion were associated with an increased risk of inhalant allergy (Odds Ratio [95% CI] 1.07 [1.02, 1.12]), but not with inhalant allergic sensitization. After additional adjust‐ ment for child's 25‐hydroxyvitamin D concentrations at the age of 6 years, only the associations of 25‐hydroxyvitamin D concentrations in mid‐gestation with FEV1

Background: Childhood eczema is variable in onset and persistence. Objectives: To identify eczema phenotypes during childhood, and their associations with early-life environmental and genetic factors. Methods: In this study of 5297 children from a multiethnic population-based prospective cohort study, phenotypes based on parent-reported physician-diagnosed ec

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.

Objective: Children with congenital diaphragmatic hernia (CDH) suffer from long-term pulmonary morbidity. Longitudinal data of exercise capacity in these children are lacking. We hypothesized that exercise capacity would be impaired in children with CDH and deteriorates over time. We evaluated exercise capacity and its determinants in CDH patients longitudinally until 12 years of age. Design: Prospective longitudinal follow-up study in tertiary university hospital. Patients: One hundred and fourteen children with CDH born between 1999 and 2012. Methods: Exercise capacity was evaluated using the Bruce treadmill-protocol at the ages of 5, 8, and 12 years. Primary outcome parameter was standard deviation score (SDS) of maximal endurance time. Data were analyzed by using linear mixed models. Results:A total of 107 children (30 treated with extracorporeal membrane oxygenation [ECMO]) performed 191 reliable exercise tests. At ages 5, 8, and 12 years, the mean (95%CI) SDS endurance time was −0.44 (−0.65 to −0.24); −1.01 (−1.23 to −0.78); −1.10 (−1.40 to −0.80), respectively, all less than zero (P < 0.001). Exercise capacity declined significantly over time irrespective of ECMO-treatment (5-12 years: non-ECMO P = 0.015; ECMO P = 0.006). Duration of initial hospital stay and diffusion capacity corrected for alveolar volume were associated with SDS endurance time (P < 0.001 and P = 0.039). Conclusions: In CDH patients exercise capacity deteriorates between 5 and 12 years of age, irrespective of ECMO-treatment. CDH patients may benefit from long-term assessments of exercise capacity with timely intervention.

Introduction As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. Objective Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. Methods Spontaneous reports concerning asthma drugs were obtained from EudraVigilance, the European Medicine Agency's database for suspected adverse drug reactions. For each drug-event combination, we calculated the proportional reporting ratio (PRR) in the study period 2011-2017. Signals in children (aged 0-17 years) were compared with signals in the whole population. Analyses were repeated for diferent age categories, by sex and by therapeutic area. Results In total, 372,345 reports in children resulted in 385 diferent signals concerning asthma therapy. The largest group consisted of psychiatric events (65 signals). Only 30 signals were new, with seven, including herpes viral infections, associated with omalizumab. Stratification by age, sex and therapeutic area provided additional new signals, such as hypertrichoses with budesonide and encephalopathies with theophylline. Of all signals in children, 60 (16%) did not appear in the whole population. Conclusions The majority of signals regarding asthma therapy in children were already known, but we also identifed new signals. We showed that signals can be masked if age stratifcation is not conducted. Further exploration is needed to investigate the risk and causality of the newly found signals.

OBJECTIVES: To compare the rate, indications and type of antibiotic prescriptions in children with and without asthma. DESIGN: A retrospective cohort study. SETTING: Two population-based primary care databases: Integrated Primary Care Information database (IPCI; the Netherlands) and The Health Improvement Network (THIN; the UK). PARTICIPANTS: Children aged 5-18 years were included from January 2000 to December 2014. A child was categorised as having asthma if there were ≥2 prescriptions of respiratory drugs in the year following a code for asthma. Children were labelled as non-asthmatic if no asthma code was recorded in the patient file. MAIN OUTCOME MEASURES: Rate of antibiotic prescriptions, related indications and type of antibiotic drugs. RESULTS: The cohorts in IPCI and THIN consisted of 946 143 and 7 241 271 person years (PY), respectively. In both cohorts, antibiotic use was significantly higher in asthmatic children (IPCI: 197vs126 users/1000 PY, THIN: 374vs250 users/1000 PY). In children with asthma, part of antibiotic prescriptions were for an asthma exacerbation only (IPCI: 14%, THIN: 4%) and prescriptions were more often due to lower respiratory tract infections then in non-asthmatic children (IPCI: 18%vs13%, THIN: 21%vs12%). Drug type and quality indicators depended more on age, gender and database than on asthma status. CONCLUSIONS: Use of antibiotics was higher in asthmatic children compared with non-asthmatic children. This was mostly due to diseases for which antibiotics are normally not indicated according to guidelines. Further awareness among physicians and patients is needed to minimise antibiotic overuse and limit antibiotic resistance.

Objective: To examine the associations of maternal hemoglobin and hematocrit levels during pregnancy with childhood lung function and asthma, and whether adverse pregnancy outcomes and atopic predisposition modify the associations. Methods: In a population-based prospective cohort study among 3672 subjects, we measured maternal hemoglobin and hematocrit levels in early pregnancy, and lung function by spirometry and current asthma by questionnaire at age 10 years. Results: Higher maternal hematocrit levels, both continuously and categorized into clinical cut-offs, were associated with lower forced expiratory flow at 75% of forced vital capacity (FEF75) in children (Z-score (95%CI): −0.04 (−0.07, −0.01), per increase of 1 SDS in hematocrit level; Z-score (95%CI) difference: −0.11 (−0.20, −0.03) compared with normal hematocrit levels, respectively), taking lifestyle and socio-economic factors into account. Adverse pregnancy outcomes and atopic predisposition did not modify the results. No associations of maternal hemoglobin and hematocrit with current asthma were observed. Conclusion: Higher maternal hematocrit levels during pregnancy are associated with lower childhood lung function but not with risk of asthma. Adverse pregnancy outcomes and atopic predisposition do not modify these associations. Underlying mechanisms need to be further studied.

The number of children requiring pediatric intensive care unit (PICU) admission for severe acute asthma (SAA) around the world has increased. Objectives: We investigated whether this trend in SAA PICU admissions is present in the Netherlands. Methods: A multicenter retrospective cohort study across all tertiary care PICUs in the Netherlands. Inclusion criteria were children (2-18 years) hospitalized for SAA between 2003 and 2013. Data included demographic data, asthma diagnosis, treatment, and mortality. Results: In the 11-year study period 590 children (660 admissions) were admitted to a PICU with a threefold increase in the number of admissions per year over time. The severity of SAA seemed unchanged, based on the first blood gas, length of stay and mortality rate (0.6%). More children received highflow nasal cannula (P<0.001) and fewer children needed invasive ventilation (P<0.001). In 58% of the patients the maximal intravenous (IV) salbutamol infusion rate during PICU admission was 1mcg/kg/min. However, the number of patients treated with IV salbutamol in the referring hospitals increased significantly over time (P=0.005). The proportion of steroid-naïve patients increased from 35% to 54% (P=0.004), with a significant increase in both age groups (2-4 years [P=0.026] and 5-17 years [P=0.036]). Conclusions: The number of children requiring PICU admission for SAA in the Netherlands has increased. We speculate that this threefold increase is explained by an increasing number of steroid-naïve children, in conjunction with a lowered threshold for PICU admission, possibly caused by earlier use of salbutamol IV in the referring hospitals.

Background: The use of antibiotic therapy early in life might influence the risk of developing asthma. Studies assessing the influence of early life antibiotic use on the risk of asthma exacerbations are limited, and the results are inconsistent. Therefore, the aim of this study was to assess the association between use of antibiotic during the first 3 years of life and the risk of developing childhood asthma and the occurrence of asthma exacerbations. Methods: Data from four large childhood cohorts were used; two population-based cohorts to study the risk of developing asthma: Generation R (n=7393, The Netherlands) and SEATON (n=891, Scotland, UK), and two asthma cohorts to assess the risk of asthma exacerbations: PACMAN (n=668, The Netherlands) and BREATHE (n=806, Scotland, UK). Odds ratios (ORs) were derived from logistic regression analysis within each database followed by pooling the results using a fixed- or random-effect model. Results: Antibiotic use in early life was associated with an increased risk of asthma in a meta-analysis of the Generation R and SEATON data (OR: 2.18, 95% CI: 1.04-4.60; I2: 76.3%). There was no association between antibiotic use in early life and risk of asthma exacerbations later in life in a meta-analysis of the PACMAN and BREATHE data (OR: 0.93, 95% CI: 0.65-1.32; I2: 0.0%). Conclusion: Children treated with antibiotic in the first 3 years of life are more likely to develop asthma, but there is no evidence that the exposure to antibiotic is associated with increased risk of asthma exacerbations.

Early-life nutrition is an important modifiable determinant in the development of a child’s immune system, and may thereby influence the risk of allergic sensitization and atopic diseases. However, associations between overall dietary patterns and atopic diseases in childhood remain unclear. We examined associations of diet quality in early life with allergic sensitization, self-reported physician-diagnosed inhalant and food allergies, eczema, and asthma among 5225 children participating in a population-based cohort in the Netherlands. Diet was assessed during pregnancy, infancy, and childhood using validated food-frequency questionnaires. We calculated food-based diet quality scores (0–10 or 0–15), reflecting adherence to dietary guidelines. At age 10 years, allergic sensitization was assessed with skin prick tests. Information on physician-diagnosed inhalant and food allergies, eczema, and asthma was obtained with questionnaires. We observed no associations between diet quality during pregnancy and allergic sensitization (odds ratio (OR) = 1.05 per point in the diet score, 95% confidence interval (CI): 0.99, 1.13), allergies (0.96, 95% CI: 0.88, 1.04), eczema (0.99, 95% CI: 0.93, 1.06), or asthma (0.93, 95% CI: 0.85, 1.03) in childhood. Also, diet quality in infancy or childhood were not associated with atopic outcomes in childhood. Our findings do not support our hypothesis that a healthy dietary pattern in early life is associated with a lower risk of allergic sensitization or atopic diseases in childhood.

Background The protection of breastfeeding against respiratory tract infections in the first year of life has o

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).

Background: The expiration of patents of brand inhalation medications and the ongoing pressure on healthcare budgets resulted in a growing market for generics. Aim: To study the use of brand and generic inhalation medication and the frequency of switching between brand and generic and between devices. In addition, we investigated whether switching affected adherence. Methods: From dispensing data from the Dutch PHARMO Database Network a cohort aged ≥ 5 years, using ≥ 1 year of inhalation medication between 2003 and 2012 was selected. Switching was defined as changing from brand to generic or vice versa. In addition, we studied change in aerosol delivery device type (e.g., DPI, pMDI, and nebulizers). Adherence was calculated using the medication possession ratio (MPR). Results: The total cohort comprised 70,053 patients with 1,604,488 dispensations. Per calendar year, 5% switched between brand and generic inhalation medication and 5% switched between devices. Median MPRs over the first 12 months ranged between 33 and 55%. Median MPR over the total period was lower after switch from brand to generic and vice versa for formoterol (44.5 vs. 42.1 and 63.5 vs. 53.8) and beclomethasone (93.8 vs. 59.8 and 81.3 vs. 55.9). Conclusion: Per year, switching between brand and generic inhalation medication was limited to 5% of the patients, switching between device types was observed in 5% as well. Adherence to both generic and brand inhalation medication was low. Effect of switching on adherence was contradictory; depending on time period, medication and type, and direction of switching. Further research on reasons for switching and potential impact on clinical outcomes is warranted.

Background: The role of timing and diversity of allergenic food introduction in the development of childhood allergic sensitization and atopic diseases is controversial. Objective: To examine whether timing and diversity of allergenic food introduction are associated with allergic sensitization, allergy and eczema in children until age 10 years. Materials and methods: This study among 5,202 children was performed in a population-based prospective cohort. Timing (age 6 months vs. >6 months) and diversity (0, 1, 2 and 3 foods) of allergenic food (cow’s milk, hen’s egg, peanut, tree nuts, soy and gluten) introduction were assessed by questionnaires at ages 6 and 12 months. At age 10 years, inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy by questionnaire. Data on parental-reported physician-diagnosed eczema were obtained from birth until age 10 years. Results: Children introduced to gluten at age 6 months had a decreased risk of eczema (aOR (95% CI): 0.84 (0.72, 0.99)), compared with children introduced to gluten at age >6 months. However, timing of allergenic food introduction was not associated with allergic sensitization or physician-diagnosed allergy. Children introduced to 3 allergenic foods at age 6 months had a decreased risk of physician-diagnosed inhalant allergy (0.64 (0.42, 0.98)), compared with children not introduced to any allergenic food at age 6 months. However, diversity of allergenic food introduction was not associated with allergic sensitization, physician-diagnosed food allergy or eczema. Conclusion: Neither timing nor diversity of allergenic food introduction was consistently associated

Background Helicobacter pylori prevalence in Western countries has been declining simultaneously with increases in childhood asthma and allergic diseases; prior studies have linked these phenomena. Aims To examine the association between H. pylori colonisation in children and risk of asthma and related conditions at school age. We secondly examined additional effects of maternal H. pylori status by pairing with children's status. Methods This study was embedded in a multi-ethnic population-based cohort in Rotterdam, The Netherlands. We measured anti-H. pylori and anti-CagA antibodies in serum of children obtained at age 6 years, and of their mothers obtained during midpregnancy. Asthma or related conditions were reported for children at age 6 years. We used multivariate logistic regression analyses among 3797 subjects. Results In children, the H. pylori positivity rate was 8.7%, and 29.2% of these were CagA-positive. A child's colonisation with a CagA-negative-H. pylori strain was associated with an increased risk of asthma (Odds ratio 2.11; 95% CI 1.23-3.60), but this differed for European (3.64; 1.97-6.73) and non-European (0.52; 0.14-1.89) children. When taking into account maternal H. pylori status, only H. pylori-positive children with an H. pylori-negative mother had increased risk of asthma (2.42; 1.11-5.27), accounting for 3.4% of the asthma risk. Conclusions Colonisation of a European child with a CagA-negative-H. pylori strain at age 6 was associated with an increased prevalence of asthma, but there was no association for non-European children. The underlying mechanisms for the observed risk differences require further research.

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 epigenom

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina" s HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

Asthma is a highly prevalent chronic condition associated with considerable morbidity, reduced health-related quality of life (HRQOL) and significant costs for public health [1], [2]. Interventions aimed at preventing childhood asthma are being developed and evaluated [3]-[9]. While the majority of asthma management education for parents occurs in the clinical setting, increasingly, multifaceted environmental interventions to decrease asthma-like symptoms are delivered by community health workers [7]. Previous studies identified positive outcomes associated with community health worker-delivered interventions, including decreased asthmalike symptoms [7].

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified a

Background: In adults, overweight is associated with reduced lung function, in children evidence on this association is conflicting. We examined the association of body mass index (BMI) and waist circumference (WC) at age 12, and of persistently (at ages 8 and 12 years) high BMI and large WC, with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at age 12. Methods: Height, weight, WC and FVC and FEV1 were measured during a medical examination in 1288 12-year-olds participating in the PIAMA birth cohort study. 1090 children also had BMI and WC measured at age 8. The associations between BMI and WC and FVC, FEV1, and FEV1/FVC ratio were studied using local and linear regression analyses, separately for girls and boys. The regression models were adjusted for age, height, and pubertal development and maternal educational level. Results: High BMI and large WC (sd-score >90th percentile) were associated with higher FVC; in girls these associations were statistically significant (4.6% (95% CI: 1.5, 7.9) and 3

Objective: HbA1c is associated with cardiovascular risk in persons without diabetes and cardiovascular risk accumulates over the life course. Therefore, insight in factors determining HbA1c from childhood onwards is important. We investigated (lifestyle) determinants of HbA1c at age 12 years and the effects of growth on change in HbA1c and the tracking of HbA1c between the age of 8 and 12 years. Study Design and Methods: Anthropometric measurements were taken and HbA1c levels were assessed in 955 children without diabetes aged around 12 years participating in the PIAMA birth cohort study. In 363 of these children HbA1c was also measured at age 8 years. Data on parents and children were collected prospectively by questionnaires. Results: We found no significant association between known risk factors for diabetes and HbA1c at age 12 years. Mean(SD) change in HbA1c between ages 8 and 12 years was 0.6(0.7) mmol/mol per year (or 0.1(0.1) %/yr). Anthropometric measures at age 8 and their change between age 8 and 12 years were not associated with the change in HbA1c. 68.9% of the children remained in the same quintile or had an HbA1c one quintile higher or lower at age 8 years compared to age 12 years. Conclusion: The lack of association between known risk factors for diabetes and HbA1c suggest that HbA1c in children without diabetes is relatively unaffected by factors associated with glycaemia. HbA1c at age 8 years is by far the most important predictor of HbA1c at age 12. Therefore, the ranking of HbA1c levels

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 ch

Low birth weight is associated with lower bone accrual in children and peak bone mass in adults. We assessed how different patterns of longitudinal fetal and early childhood growth influence bone properties at school age. In 5431 children participating in a population-based prospec

Objectives: This study aimed to evaluate the effectiveness of systematic assessment of asthma-like symptoms and environmental tobacco smoke (ETS) exposure during regular preventive well-child visits between age 1 and 4 years by wellchild professionals. Methods: Sixteen well-child centres in Rotterdam, the Netherlands, were randomised into 8 centres where the brief assessment form regarding asthma-like symptoms and ETS exposure was used and 8 centres that applied usual care. 3596 and 4179 children (born between April 2002 and January 2006) and their parents visited the intervention and control centres, respectively. At child's age 6 years, physician-diagnosed asthma ever, wheezing, fractional exhaled nitric oxide (FeNO), airway resistance (Rint), health-related quality of life (HRQOL) and ETS exposure at home ever were measured. Linear mixed models were applied. Results: No differences in asthma, wheezing, FeNO, Rint or HRQOL measurements between intervention and control group were found using multilevel regression in an intention-to-treat analysis (p>0.05). Children of whom the parents were interviewed by using the brief assessment form at the intervention well-child centres had a decreased risk on ETS exposure at home ever, compared to children who v

Background: Fetal growth characteristics are used to identify influences of several maternal characteristics and to identify individuals at increased risk of adverse outcomes. The extent to which fetal growth characteristics track in different trimesters is not known. Methods: In a population-based prospective cohort study among 8636 pregnant women, we examined the extent to which fetal growth characteristics track, are influenced by maternal socio-demographic and lifestyle related determinants and are associated with birth outcomes. Fetal growth was assessed in each trimester and at birth. Results: Correlation coefficient between first-trimester crown-rump length and birthweight was r=0.12 (P-value<0.05). Correlation coefficients for fetal-head circumference, (femur) length and (estimated) fetal weight ranged from r=0.16 to r=0.30 (all P-values<0.05) between second trimester and birth and from r=0.36 to r=0.58 (all P-values<0.05) between third trimester and birth, and were highest for (estimated) fetal weight. Correlation coefficients for (estimated) fetal weight tended to be lower among overweight mothers, as compared with normal weight mothers, but were not influenced by other maternal characteristics. First, second and third-trimester fetal growth characteristics were associated with risks of preterm birth and small size for gestational age at birth,with the strongest associations present in third trimester. Conclusion: Fetal growth characteristics track moderately throughout gestation, with stronger tracking coefficients present in later pregnancy. Tracking coefficients were not materially influenced by maternal socio-demographic and lifestyle characteristics. First, second and third trimester fetal growth characteristics were associated with the risk of adverse birth outcomes.

Background Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. Objectives We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. Results Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P <.05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). Conclusion Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were lar

Sphingolipids comprise a class of bioactive lipids that are involved in a variety of pathophysiologic processes, including cell death and survival. Ceramide and sphingosine-1-phosphate (S1P) form the center of sphingolipid metabolism and determine proapoptotic and antiapoptotic balance. Findings in animal models suggest a possible pathophysiologic role of ceramide and S1P in COPD, cystic fibrosis, and asthma. Sphingolipid research is now focusing on the role of ceramides during lung inflammation and its regulation by sphingomyelinases. Recently, sphingolipids have been shown to play a role in the pathogenesis of bronchopulmonary dysplasia (BPD). Ceramide upregulation was linked with vascular endothelial growth factor suppression and decreased surfactant protein B levels, pathways important for the development of BPD. In a murine model of BPD, intervention with an S1P analog had a favorable effect on histologic abnormalities and ceramide levels. Ceramides and S1P also regulate endothelial permeability through cortical actin cytoskeletal rearrangement, which is relevant for the pathogenesis of ARDS. On the basis of these observations, the feasibility of pharmacologic intervention in the sphingolipid pathway to influence disease development and progression is presently explored, with promising early results. The prospect of new strategies to prevent and repair lung disease by interfering with sphingolipid metabolism is exciting and could potentially reduce morbidity and mortality in patients with severe lung disorders.

Rationale: Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied. Methods: The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models. Results: At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18-2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24-2.15, aOR = 1.85, 95% CI:1.11-3.09, aOR = 1.58, 95% CI:1.24-2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained. Conclusions: This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6 y

We assessed whether dynamic preschool wheezing patterns affect health-related quality of life (HRQOL) at age 4 years. The study included 3878 children participating a prospective cohort study. Information on preschool wheezing was obtained by questionnaire and children were categorised into: never, early, late and persistent wheezing. At age 4 years HRQOL was measured using the Child Health Questionnaire (CHQ). Persistent wheezing was associated with reduced scores for nine out of 13 CHQ scales. No differences in psychosocial CHQ scores (p.0.05), but lower physical CHQ scores were found in children with late and persistent wheezing, compared to children who never wheezed (p,0.001). Mean scores on general health perceptions were, respectively, eight and 12 points lower (on a 0– 100 scale) in children with late and persistent wheezing (p,0.001), and children with one to three episodes and four or more episodes of wheezing in the fourth year respectively scored seven and 24 points lower (p,0.001), compared to children who never wheezed. Persistent wheezing during preschool age independently affects a child’s HRQOL, particularly general health perceptions and physical domains at age 4 years. HRQOL was more affected by frequent wheezing episodes in the fourth year of life, rather than by the duration of wheezing at age 0–4 years.

We studied the associations of maternal pre-pregnancy body mass index and gestational weight gain with risks of preschool wheezing in offspring and explored the role of growth, infectious and atopic mechanisms. This substudy of 4656 children was embedded in a population-based birth cohort. Information about maternal pre-pregnancy weight, gestational weight gain and wheezing at the ages of 1-4 years was obtained by either physical measurements or questionnaires. Among mothers with a history of asthma or atopy, maternal pre-pregnancy obesity was associated with an overall increased risk of preschool wheezing (odds ratio 1.47, 95% confidence interval 1.12-1.95). Also, each standard deviation increase of gestational weight gain was associated with an increased overall risk of preschool wheezing (1.09, 1.04-1.14), was independent of pre-pregnancy body mass index and was not different between mothers with and without a history of asthma or atopy. Child's growth, respiratory tract infections or eczema did not alter the results. Mothers with pre-pregnancy obesity and a history of asthma or atopy, and mothers with higher gestational weight gain showed higher risks of wheezing in their offspring. These associations could not be explained by growth, infectious or atopic mechanisms. Further research is needed to identify underlying mechanisms and long-term consequences. Copyright