We recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 ...years of age. However, neither reached statistical significance.
To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect.
VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry.
The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ≥30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points.
This combined analysis shows that vitamin D supplementation during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ≥ 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies.
COPSAC2010: ClinicalTrials.gov NCT00856947; VDAART: ClinicalTrials.gov NCT00920621.
The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We ...hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.
To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life.
Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization.
Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 1.29-2.48; P < 0.005) independently of concurrent or later asthma.
Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.
Background Studies of children's blood lipid profiles in relation to asthma are few, and the results are ambiguous. Objective We sought to examine whether the lipid profile is associated with ...concurrent asthma, altered lung function, and allergic sensitization in children. Methods High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were measured at ages 5 to 7 years in the Copenhagen Prospective Studies on Asthma in Childhood2000 at-risk birth cohort. Asthma and allergic rhinitis were diagnosed based on predefined algorithms at age 7 years along with assessments of lung function, bronchial responsiveness, fraction of exhaled nitric oxide (F eno ), and allergic sensitization. Associations between lipid levels and clinical outcomes were adjusted for sex, passive smoking, and body mass index. Results High levels of low-density lipoprotein cholesterol were associated with concurrent asthma (adjusted odds ratio aOR, 1.93; 95% CI, 1.06-3.55; P = .03) and airway obstruction: 50% of forced expiratory flow (aβ coefficient, −0.13 L/s; 95% CI, −0.24 to −0.03 L/s; P = .01) and specific airway resistance (aβ coefficient, 0.06 kPa/s; 95% CI, 0.00-0.11 kPa/s; P = .05). High levels of high-density lipoprotein cholesterol were associated with improved specific airway resistance (aβ coefficient, −0.11 kPa/s; 95% CI, −0.21 to −0.02; P = .02), decreased bronchial responsiveness (aβ coefficient, 0.53 log-μmol; 95% CI, 0.00-1.60 log-μmol; P = .05), decreased risk of aeroallergen sensitization (aOR, 0.27; 95% CI, 0.01-0.70; P = .01), and a trend of reduced F eno levels (aβ coefficient, −0.22 log-ppb; 95% CI, −0.50 to 0.01 log-ppb; P = .06). High triglyceride levels were associated with aeroallergen sensitization (aOR, 2.01; 95% CI, 1.14-3.56; P = .02) and a trend of increased F eno levels (aβ coefficient, 0.14 log-ppb; 95% CI, −0.02 to 0.30 log-ppb; P = .08). Conclusion The blood lipid profile is associated with asthma, airway obstruction, bronchial responsiveness, and aeroallergen sensitization in 7-year-old children. These findings suggest that asthma and allergy are systemic disorders with commonalities with other chronic inflammatory disorders.
Epidemiological studies have suggested an association between maternal vitamin D dietary intake during pregnancy and risk of asthma and allergy in the offspring. However, prospective clinical studies ...on vitamin D measured in cord blood and development of clinical end-points are sparse.
To investigate the interdependence of cord blood 25-hydroxyvitamin D (25(OH)-Vitamin D) level and investigator-diagnosed asthma- and allergy-related conditions during preschool-age.
Cord blood 25(OH)-Vitamin D level was measured in 257 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) at-risk mother-child cohort. Troublesome lung symptoms (TROLS), asthma, respiratory infections, allergic rhinitis, and eczema, at age 0-7 yrs were diagnosed exclusively by the COPSAC pediatricians strictly adhering to predefined algorithms. Objective assessments of lung function and sensitization were performed repeatedly from birth.
After adjusting for season of birth, deficient cord blood 25(OH)-Vitamin D level (<50 nmol/L) was associated with a 2.7-fold increased risk of recurrent TROLS (HR = 2.65; 95% CI = 1.02-6.86), but showed no association with respiratory infections or asthma. We saw no association between cord blood 25(OH)-Vitamin D level and lung function, sensitization, rhinitis or eczema. The effects were unaffected from adjusting for multiple lifestyle factors.
Cord blood 25(OH)-Vitamin D deficiency associated with increased risk of recurrent TROLS till age 7 years. Randomized controlled trials of vitamin D supplementation during pregnancy are needed to prove causality.
Background Respiratory syncytial virus and other respiratory tract viruses lead to common colds in most infants, whereas a minority develop acute severe bronchiolitis often requiring hospitalization. ...We hypothesized that such an excessive response to respiratory tract viral infection is caused by host factors reflected in pre-existing increased bronchial responsiveness. Objective We sought to compare bronchial responsiveness and lung function in 1-month-old neonates who later develop acute severe bronchiolitis with those who do not. Methods We measured infant lung function (n = 402) and bronchial responsiveness to methacholine (n = 363) using the raised-volume rapid thoracoabdominal compression technique before any respiratory symptoms in 1-month-old neonates from the Copenhagen Prospective Study of Asthma in Childhood birth cohort born to mothers with asthma. The children were prospectively monitored for respiratory symptoms and given a diagnosis of acute severe bronchiolitis according to a fixed algorithm. Results Thirty-four (8.5%) infants had acute severe bronchiolitis before 2 years of age, 21 (62%) were hospitalized, and 23 (67%) of the cases were associated with respiratory syncytial virus. Children who later had acute severe bronchiolitis irrespective of viral species had a 2.5-fold increased responsiveness to methacholine (provocative dose of methacholine producing a 15% decrease in transcutaneous oxygen pressure PD15 ) at age 1 month compared with control subjects (median PD15 in cases vs control subjects, 0.13 vs 0.33 μmol; P = .01), whereas differences in baseline airflow were not significant for forced expiratory volume at 0.5 seconds (mean z score for cases vs control subjects, −0.18 vs −0.01; P = .36) and forced expiratory flow at 50% of forced vital capacity (mean z score for cases vs control subjects, −0.37 vs −0.09; P = .13). Conclusion Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus.
Antibiotic treatment during pregnancy and birth is very common. In this study, we describe the estimated prevalence of antibiotic administration during pregnancy and birth in the COPSAC2010 pregnancy ...cohort, and analyze dependence on social and lifestyle-related factors.
706 pregnant women from the novel unselected Copenhagen Prospective Study on Asthma in Childhood (COPSAC2010) pregnancy cohort participated in this analysis. Detailed information on oral antibiotic prescriptions during pregnancy filled at the pharmacy was obtained and verified longitudinally. Information on intrapartum antibiotics, social, and lifestyle-factors was obtained by personal interviews.
The prevalence of antibiotic use was 37% during pregnancy and 33% intrapartum. Lower maternal age at birth; adjusted odds ratio (aOR) 0.94, 95% CI, 0.90-0.98, p = 0.003 and maternal smoking; aOR 1.97, 95% CI, 1.07-3.63, p = 0.030 were associated with use of antibiotics for urinary tract infection during pregnancy. Maternal educational level (low vs. high), aOR 2.32, 95% CI, 1.24-4.35, p = 0.011, maternal asthma; aOR 1.99, 95% CI, 1.33-2.98, p < 0.001 and previous childbirth; aOR 1.80, 95% CI, 1.21-2.66, p = 0.004 were associated with use of antibiotics for respiratory tract infection during pregnancy. Lower gestational age; aOR 0.72, 95% CI, 0.61-0.85, p < 0.001, maternal smoking; aOR 2.84, 95% CI, 1.33-6.06, p = 0.007, and nulliparity; aOR 1.79, 95% CI, 1.06-3.02, p = 0.030 were associated with administration of intrapartum antibiotics in women giving birth vaginally.
Antibiotic administration during pregnancy and birth may be influenced by social and lifestyle-factors. Understanding such risk factors may guide preventive strategies in order to avoid unnecessary use of antibiotics.
The composition of the human gut microbiome matures within the first years of life. It has been hypothesized that microbial compositions in this period can cause immune dysregulations and potentially ...cause asthma. Here we show, by associating gut microbial composition from 16S rRNA gene amplicon sequencing during the first year of life with subsequent risk of asthma in 690 participants, that 1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 years. This association is only apparent among children born to asthmatic mothers, suggesting that lacking microbial stimulation during the first year of life can trigger their inherited asthma risk. Conversely, adequate maturation of the gut microbiome in this period may protect these pre-disposed children.
Asthma is believed to arise through early life aberrant immune development in response to environmental exposures that may influence the airway microbiota. Here, we examine the airway microbiota ...during the first three months of life by 16S rRNA gene amplicon sequencing in the population-based Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC
) cohort consisting of 700 children monitored for the development of asthma since birth. Microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at age one month are associated with asthma by age 6 years, both individually and with additional taxa in a multivariable model. Higher relative abundance of these bacteria is furthermore associated with an airway immune profile dominated by reduced TNF-α and IL-1β and increased CCL2 and CCL17, which itself is an independent predictor for asthma. These findings suggest a mechanism of microbiota-immune interactions in early infancy that predisposes to childhood asthma.
Supplementation with fish oil–derived fatty acids during pregnancy reduced the incidence of cases of persistent wheeze or asthma in offspring.
The incidence of asthma and wheezing disorders has more ...than doubled in westernized countries in recent decades.
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These conditions often originate in early childhood
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and currently affect one in five young children.
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Concomitantly, the increased use of vegetable oils in cooking and of grain in the feeding of livestock has resulted in an increase in the intake of n−6 polyunsaturated fatty acids and a decrease in the intake of n−3 polyunsaturated fatty acids, especially the long-chain polyunsaturated fatty acids (LCPUFAs) — eicosapentaenoic acid (20:5n–3, EPA) and docosahexaenoic acid (22:6n–3, DHA) — found in cold-water fish.
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Observational studies have suggested an . . .
Randomized trials have reported that supplementation with n–3 long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy can prolong pregnancy and thereby increase birth weight.
We aimed to ...examine the relations of n–3 LCPUFA supplementation in pregnancy with duration of pregnancy, birth weight, and size for gestational age (GA).
This was a double-blind randomized controlled trial conducted in 736 pregnant women and their offspring, from the Copenhagen Prospective Studies on Asthma in Childhood2010cohort. They were recruited between weeks 22 and 26 in pregnancy and randomly assigned to either of 2.4 g n–3 LCPUFA or control (olive oil) daily until 1 wk after birth. Exclusion criteria were endocrine, cardiovascular, or nephrologic disorders and vitamin D supplementation intake >600 IU/d. In this study we analyzed secondary outcomes, and further excluded twin pregnancies and extrauterine death. The primary outcome for the trial was persistent wheeze or asthma.
The random assignment ran between 2008 and 2010. Six hundred and ninety-nine mother-infant pairs were included in the analysis. n–3 LCPUFA compared with control was associated with a 2-d prolongation of pregnancy median (IQR): 282 (275–288) d compared with 280 (273–286) d, P = 0.02, a 97-g higher birth weight (mean ± SD: 3601 ± 534 g compared with 3504 ± 528 g, P = 0.02), and an increased size for GA according to the Norwegian population-based growth curves-Skjærven (mean ± SD: 49.9 ± 28.3 percentiles compared with 44.5 ± 27.6 percentiles, P = 0.01).
Supplementing pregnant women with n–3 LCPUFAs during the third trimester is associated with prolonged gestation and increased size for GA, leading to a higher birth weight in this randomized controlled trial. This trial was registered at clinicaltrials.gov as NCT00798226.
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