Maternal hemoglobin and iron status in early pregnancy and risk of respiratory tract infections in childhood: A population-based prospective cohort study.

BACKGROUND: Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age. METHODS: In a population-based cohort study among 5134 mother-child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied. RESULTS: After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects. CONCLUSION: High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections.

Associations of early-life pet ownership with asthma and allergic sensitization: A meta-analysis of more than 77,000 children from the EU Child Cohort Network.

BACKGROUND: Studies examining associations of early-life cat and dog ownership with childhood asthma have reported inconsistent results. Several factors could explain these inconsistencies, including type of pet, timing, and degree of exposure. OBJECTIVE: Our aim was to study associations of early-life cat and dog ownership with asthma in school-aged children, including the role of type (cat vs dog), timing (never, prenatal, or early childhood), and degree of ownership (number of pets owned), and the role of allergic sensitization. METHODS: We used harmonized data from 77,434 mother-child dyads from 9 birth cohorts in the European Union Child Cohort Network when the child was 5 to 11 years old. Associations were examined through the DataSHIELD platform by using adjusted logistic regression models, which were fitted separately for each cohort and combined by using random effects meta-analysis. RESULTS: The prevalence of early-life cat and dog ownership ranged from 12% to 45% and 7% to 47%, respectively, and the prevalence of asthma ranged from 2% to 20%. There was no overall association between either cat or dog ownership and asthma (odds ratio [OR] = 0.97 [95% CI = 0.87-1.09] and 0.92 [95% CI = 0.85-1.01], respectively). Timing and degree of ownership did not strongly influence associations. Cat and dog ownership were also not associated with cat- and dog-specific allergic sensitization (OR = 0.92 [95% CI = 0.75-1.13] and 0.93 [95% CI = 0.57-1.54], respectively). However, cat- and dog-specific allergic sensitization was strongly associated with school-age asthma (OR = 6.69 [95% CI = 4.91-9.10] and 5.98 [95% CI = 3.14-11.36], respectively). There was also some indication of an interaction between ownership and sensitization, suggesting that ownership may exacerbate the risks associated with pet-specific sensitization but offer some protection against asthma in the absence of sensitization. CONCLUSION: Our findings do not support early-life cat and dog ownership in themselves increasing the risk of school-age asthma, but they do suggest that ownership may potentially exacerbate the risks associated with cat- and dog-specific allergic sensitization.

Maternal diet in pregnancy and child's respiratory outcomes: an individual participant data meta-analysis of 18 000 children.

RATIONALE: Severe fetal malnutrition has been related to an increased risk of respiratory diseases later in life, but evidence for the association of a suboptimal diet during pregnancy with respiratory outcomes in childhood is conflicting. We aimed to examine whether a pro-inflammatory or low-quality maternal diet during pregnancy was associated with child's respiratory health. METHODS: We performed an individual participant meta-analysis among 18 326 mother-child pairs from seven European birth cohorts. Maternal pro-inflammatory and low-quality diets were estimated by energy-adjusted Dietary Inflammatory Index (E-DII) and Dietary Approaches to Stop Hypertension (DASH) scores. Preschool wheezing and school-age asthma were measured using questionnaires and lung function by spirometry. RESULTS: After adjustment for lifestyle and sociodemographic factors, we observed that a higher maternal E-DII score (a more pro-inflammatory diet) during pregnancy was associated only with a lower forced vital capacity (FVC) in children (z-score difference -0.05, 95% CI -0.08- -0.02, per interquartile range increase). No linear associations of the maternal E-DII or DASH score with child's wheezing or asthma were observed. In an exploratory examination of the extremes, a very low DASH score (<10th percentile) (a very low dietary quality) was associated with an increased risk of preschool wheezing and a low forced expiratory volume in 1 s/FVC (z-score <-1.64) (OR 1.20, 95% CI 1.06-1.36 and z-score difference 1.40, 95% CI 1.06-1.85, compared to ≥10th percentile), with corresponding population attributable risk fractions of 1.7% and 3.3%, respectively. CONCLUSION: The main results from this individual participant data meta-analysis do not support the hypothesis that maternal pro-inflammatory or low-quality diet in pregnancy are related to respiratory diseases in childhood.

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.

A population-based study on associations of stool microbiota with atopic diseases in school-age children.

BACKGROUND: Infants with less diverse gut microbiota seem to have higher risks of atopic diseases in early life, but any associations at school age are unclear. OBJECTIVES: This study sought to examine the associations of diversity, relative abundance, and functional pathways of stool microbiota with atopic diseases in school-age children. METHODS: We performed a cross-sectional study within an existing population-based prospective cohort among 1440 children 10 years of age. On stool samples, 16S ribosomal RNA gene sequencing was performed, and taxonomic and functional tables were produced. Physician-diagnosed eczema, allergy, and asthma were measured by questionnaires, allergic sensitization by skin prick tests, and lung function by spirometry. RESULTS: The α-diversity of stool microbiota was associated with a decreased risk of eczema (odds ratio [OR], 0.98; 95% CI, 0.97, 1.00), and ß-diversity was associated with physician-diagnosed inhalant allergy (R2 = 0.001; P = .047). Lachnospiraceae, Ruminococcaceae_UCG-005, and Christensenellaceae_R-7_group species were associated with decreased risks of eczema, inhalant allergic sensitization, and physician-diagnosed inhalant allergy (OR range, 0.88-0.94; 95% CI range, 0.79-0.96 to 0.88-0.98), while Agathobacter species were associated with an increased risk of physician-diagnosed inhalant allergy (OR, 1.23; 95% CI, 1.08-1.42). Functional pathways related to heme and terpenoid biosynthesis were associated with decreased risks of physician-diagnosed inhalant allergy and asthma (OR range, 0.89-0.86; 95% CI range, 0.80-0.99 to 0.73-1.02). No associations of stool microbiota with lung function were observed. CONCLUSIONS: The diversity, relative abundance and functional pathways of stool microbiota were most consistently associated with physician-diagnosed inhalant allergy in school-age children and less consistently with other atopic diseases.

Association between nasal and nasopharyngeal bacterial colonization in early life and eczema phenotypes.

BACKGROUND: An association has been reported between early life Staphylococcus aureus nasal carriage and higher risk of childhood eczema, but it is unclear whether this relationship is causal and associations with other bacterial species are unclear. OBJECTIVE: To examine the associations of early life nasal and nasopharyngeal bacterial carriage with eczema phenotypes, and the direction of any associations identified. METHODS: Among 996 subjects of a population-based prospective cohort study, nasal swabs for Staphylococcus  aureus, and nasopharyngeal swabs for Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae were collected and cultured from age 6 weeks to 6 years. Never, early, mid-, late transient and persistent eczema phenotypes were identified from parental-reported physician-diagnosed eczema from age 6 months until 10 years. Multinomial regression models and cross-lagged models were applied. RESULTS: Staphylococcus aureus nasal carriage at 6 months was associated with an increased risk of early transient and persistent eczema (OR (95% CI): 2.69 (1.34, 5.39) and 4.17 (1.12, 15.51)). The associations between Staphylococcus aureus nasal carriage and eczema were mostly cross-sectional, and not longitudinal. No associations of Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal bacterial carriage with eczema and eczema phenotypes were observed (OR range (95% CI): 0.71 (0.35, 1.44) to 1.77 (0.84, 3.73)). CONCLUSIONS: Early life Staphylococcus aureus nasal carriage, but not Staphylococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenza nasopharyngeal carriage, was associated with early transient and persistent eczema. Staphylococcus aureus nasal carriage and eczema were mostly cross-sectionally associated, and not longitudinally, making a causal relationship in either direction unlikely.

General and Organ Fat Assessed by Magnetic Resonance Imaging and Respiratory Outcomes in Childhood.

Rationale: Obesity has been implicated as a pathogenic factor in asthma, but the underlying role of general and organ fat is unclear.Objectives: We hypothesized that organ fat, rather than the total fat mass, increases the risk of asthma.Methods: In a population-based prospective cohort study among 5,421 children aged 10 years, we measured general fat including body mass index and fat mass index by dual-energy X-ray absorptiometry, and organ fat including subcutaneous fat index, visceral fat index, pericardial fat index, and liver fat fraction by magnetic resonance imaging. Lung function was measured by spirometry. Current asthma was assessed by questionnaire.Measurements and Main Results: Higher body mass index and fat mass index were associated with higher FEV1 (z-score difference [95% confidence interval (CI)], 0.16 [0.14 to 0.19] and z-score difference [95% CI], 0.06 [0.03 to 0.09] per SD score increase, respectively), higher FVC (z-score difference [95% CI], 0.19 [0.17 to 0.22] and z-score difference [95% CI], 0.07 [0.04 to 0.10]), and lower FEV1/FVC ratio (z-score difference [95% CI], -0.07 [-0.10 to -0.05] and z-score difference [95% CI], -0.03 [-0.06 to -0.00]) but not with forced expiratory flow after exhaling 75% of FVC or asthma. Higher visceral fat index, independent of fat mass index, was associated with higher FVC (z-score difference [95% CI], 0.07 [0.03 to 0.10]), lower FEV1/FVC (z-score difference [95% CI], -0.05 [-0.09 to -0.01]), and higher risk of asthma (odds ratio, 1.20; 95% CI, 1.01 to 1.43 per SD score increase). No other organ fat measures were independently associated with lung function or asthma.Conclusions: The obesity-asthma link is driven mainly by visceral fat, independent of total fat mass; therefore, abdominal fat might contribute to asthma development.

Parental psychological distress during pregnancy and the risk of childhood lower lung function and asthma: a population-based prospective cohort study.

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.

C hlamydia trachomatis during pregnancy and childhood asthma-related morbidity: a population-based prospective cohort.

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.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

The influence of Epstein-Barr virus and cytomegalovirus on childhood respiratory health: A population-based prospective cohort study.

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.

Sociodemographic factors, current asthma and lung function in an urban child population.

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. Indicators of sociodemographic factors included parental educational level, net household income, financial difficulties, parental employment status and child ethnic background. Current asthma (yes/no) was defined as ever doctor-diagnosed-asthma combined with wheezing symptoms or asthma-medication use in the past 12 months. Lung function was measured by spirometry and included forced expiratory volume in 1 second (FEV1 ), forced vital capacity (FVC), FEV1 /FVC, and forced expiratory flow after exhaling 75% of FVC (FEF75 ). Within-study sex-, height- and age-adjusted lung function measurements' z-scores were converted. RESULTS: After adjustment for all sociodemographic factors, an independent association was observed between ethnic background with current asthma and lung function. Compared with children with a Dutch background, children with a nonwestern ethnic background had a higher odds of having current asthma (OR: 1.61, 95% CI: 1.02, 2.53), lower FVC z-score (-0.25, 95% CI: -0.35, -0.14), higher FEV1 /FVC z-score (0.26, 95% CI: 0.14, 0.37) and higher FEF75% z-score (0.15, 95% CI: 0.04, 0.25). CONCLUSIONS: Among 10-year-old children, ethnic background was associated with current asthma and lung function after adjusting for a wide range of sociodemographic factors. No associations were found between socioeconomic status indicators and current asthma. Explanations for these associations such as language barriers, suboptimal care or pathophysiological differences require further investigation.

Associations of Th2, Th17, Treg cells, and IgA+ memory B cells with atopic disease in children: The Generation R Study.

BACKGROUND: New insights into immune cells could contribute to treatment and monitoring of atopic disease. Because nongenetic factors shape the human immune system, we here studied these immune cells in a large cohort with atopic children with adjustment for prenatal and postnatal confounders. METHODS: Information on atopic dermatitis, inhalant- and food-allergic sensitization, asthma lung function scores was obtained from 855 10-year-old children within the Generation R cohort. 11-color flow cytometry was performed to determine CD27+ and CD27- IgG+ , IgE+ and IgA+ memory B cells, Th1, Th2, Th17, and Treg-memory cells from venous blood. Associations between any atopic disease, the individual atopic diseases, and immune cell numbers were determined. RESULTS: Children with any atopic disease had higher Th2, Treg, Treg-memory, and CD27+ IgA+ memory B-cell numbers compared to children without atopic disease. When studying the individual diseases compared to children without the individual diseases, children with atopic dermatitis, inhalant-, and food-allergic sensitization had higher memory Treg cell numbers 12.3% (95% CI 4.2; 21.0), (11.1% (95% CI 3.0; 19.8), (23.7% (95% CI 7.9; 41.8), respectively. Children with food-allergic sensitization had higher total B and CD27+ IgA+ memory B-cell numbers (15.2% [95% CI 3.2; 28.7], 22.5% [95% CI 3.9; 44.3], respectively). No associations were observed between asthma and B- or T-cell numbers. CONCLUSION: Children with any atopic disease and children with inhalant- and food-allergic sensitization or atopic dermatitis had higher circulating memory Treg cells, but not higher IgE+ B-cell numbers. The associations of higher Treg and CD27+ IgA+ B-cell numbers in children with food-allergic sensitization are suggestive of TGF-ß-mediated compensation for chronic inflammation.

Airway bacterial carriage and childhood respiratory health: A population-based prospective cohort study.

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.

Maternal and neonatal 25-hydroxyvitamin D concentrations and school-age lung function, asthma and allergy. The Generation R Study.

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 venous 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 function 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 associated 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-gestation 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 adjustment 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 /FVC and FEF75 remained. We did not find consistent associations of 25-hydroxyvitamin D concentrations at birth with respiratory or allergy outcomes. CONCLUSION AND CLINICAL RELEVANCE: Our results suggest that maternal 25-hydroxyvitamin D concentrations in mid-gestation may influence lung development. The clinical implications of the observed associations remain unclear.

Fetal umbilical, cerebral and pulmonary blood flow patterns in relation to lung function and asthma in childhood. The Generation R Study.

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.

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.

Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.

Early life antibiotic use and the risk of asthma and asthma exacerbations in children.

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.