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.
Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with ...n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring.
We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood
(COPSAC
) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization.
A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval CI, 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization.
Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .).
Studies suggest an association between maternal vitamin D status during pregnancy and offspring anthropometry and bone mineralization, but investigations are few and with mixed results.
To ...investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring.
A prespecified analysis of a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort that included 623 pregnant mothers and their 584 children. Data were analyzed between January 2019 and September 2019.
Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth.
Longitudinal anthropometry assessments including length/height, weight, and body mass index until age 6 years and bone mineral content (BMC) and bone mineral density (BMD) at age 3 years and 6 years from dual-energy radiography absorptiometry scans.
At age 6 years, 517 children (89%) completed the clinical follow-up. All participants were Danish and white; 261 were boys and 256 were girls. A mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that children in the vitamin D vs placebo group had higher whole-body BMC: mean difference adjusted (aMD) for age, sex, height, and weight was 11.5 g (95% CI, 2.3-20.7; P = .01); higher whole-body-less-head BMC aMD was 7.5 g (95% CI, 1.5-13.5; P = .01); and higher head BMD aMD was 0.023 g/cm2 (95% CI, 0.003-0.004; P = .03). The largest effect was in children from vitamin D-insufficient mothers (<30 ng/mL; to convert to nanomoles per liter, multiply by 2.496) and among winter births. In a post hoc analysis, we found borderline lower incidence of fractures in the vitamin D group (n = 23 vs n = 36; incidence rate ratio, 0.62 95% CI, 0.37-1.05; P = .08), but no differences in any anthropometric outcomes. Adjustment for a concomitant ω-3 polyunsaturated fatty acids intervention did not change the results.
High-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose, suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. We found no supplementation effect on anthropometric outcomes.
ClinicalTrials.gov Identifier: NCT00856947.
Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to ...pregnant women is unknown.
To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring.
A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014.
Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care.
Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed.
Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group. table: see text.
The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect.
clinicaltrials.gov Identifier: NCT00856947.
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.
Background
Children with asthma are at risk of depression and anxiety and growing evidence suggest they may also be at risk of attention deficit hyperreactivity disorder (ADHD) and autism spectrum ...disorder (ASD). Here, we conducted a systematic review with meta‐analysis of studies investigating association between asthma and ADHD or ASD in children.
Methods
A comprehensive search using PubMed, EMBASE and Cochrane Library databases was completed in March 2019. Observational human studies published in English, clinic‐based or population‐based with a healthy comparator group, evaluating asthma‐ADHD or asthma‐ASD overlap in children 18 years or younger using categorical diagnoses (yes/no) were considered for inclusion. Random effects meta‐analysis models were used to analyse data. The Newcastle Ottawa Scale was used to evaluate risk of bias.
Results
A total of 25 asthma‐ADHD studies were included of which 17 showed significant positive associations and one a negative association: 17/25 studies were population‐based, 19/25 were cross‐sectional or cohort studies and 7/25 had a low risk of bias. We performed a meta‐analysis of 23 of the studies, which showed a significant association between asthma and ADHD: odds ratio (OR) 1.52 (1.42‐1.63), P < .001, I2 = 60%. All studies were adjusted for age and sex and a large proportion; that is, 19/23 were further adjusted for relevant confounders. Seventeen asthma‐ASD studies were included, whereof 7 showed a positive association and 3 a negative association; 8/17 were population‐based with a cross‐sectional study design and 4/17 had a low risk of bias. We performed a meta‐analysis of 14 of the studies, which did not show a significant association between asthma and ASD: OR 1.12 (0.93‐1.34), P = .24, I2 = 89%. All studies were adjusted for age and sex and 10/14 were further adjusted for relevant confounders.
Conclusions
This systematic review with meta‐analyses shows a significant overlap between asthma and ADHD, but not between asthma and ASD in children. Clinicians taking care of children with asthma or ADHD should be aware of such association to aid an early diagnosis and treatment of such comorbidity.
Bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. We aimed to ...assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period.
In this randomised, double-blind, placebo-controlled trial, we recruited children aged 1-3 years, who were diagnosed with recurrent asthma-like symptoms from the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort; a birth cohort consisting of the general Danish population of Zealand, including Copenhagen. Exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°C; C-reactive protein concentration of ≥476·20 nmol/L ≥50 mg/L). Each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the Copenhagen Prospective Studies on Asthma research unit. Each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the Pharmacy of Glostrup). Investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. The primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with Poisson regression. Analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). This trial is registered with ClinicalTrials.gov, number NCT01233297.
Between Nov 17, 2010, and Jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 50% to azithromycin and 79 50% to placebo). The mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. Azithromycin caused a significant shortening of the episode of 63·3% (95% CI 56·0-69·3; p<0·0001). The effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). We noted no differences in clinical adverse events between the azithromycin (18 23% of 78 episodes included in final analysis) and placebo (24 30% of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment.
Azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. Further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation.
Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.
We previously reported that children of mothers who received fish oil supplementation during pregnancy had higher body mass index BMI (in kg/m2) at 6 y of age as well as a concomitant increase in ...fat-, muscle, and bone mass, but no difference in fat percentage.
Here, we report follow-up at age 10 y including assessment of metabolic health.
This is a follow-up analysis of a randomized clinical trial conducted among 736 pregnant females and their offspring participating in the Copenhagen Prospective Studies on Asthma in Childhood mother-child cohort. The intervention was 2.4 g n–3 (ω–3) Long-Chain PolyUnsaturated Fatty Acid (n–3 LCPUFA) or control daily from pregnancy week 24 until 1 wk after birth. Outcomes were anthropometric measurements, body composition from Bioelectrical Impedance Analysis, blood pressure, concentrations of triglycerides, cholesterol, glucose, and C-peptide from fasting blood samples, and a metabolic syndrome score was calculated. Anthropometric measurements and body composition were prespecified secondary endpoints of the n–3 LCPUFA trial, and others were exploratory.
Children in the n–3 LCPUFA group had a higher mean BMI at age 10 year compared to the control group: 17.4 (SD: 2.44) compared with 16.9 (2.28); P = 0.020 and a higher odds ratio of having overweight (odds ratio: 1.53; 95% CI: 1.01, 2.33; P = 0.047). This corresponded to differences in body composition in terms of increased lean mass (0.49 kg; 95% CI: –0.20, 1.14; P = 0.17), fat mass (0.49 kg; 95% CI: –0.03, 1.01; P = 0.06), and fat percent (0.74%; 95% CI: –0.01, 1.49; P = 0.053) compared to the control group. Children in the n–3 LCPUFA group had a higher metabolic syndrome score compared to the control (mean difference: 0.19; 95% CI: –0.02, 0.39; P = 0.053).
In this randomized clinical trial, children of mothers receiving n–3 LCPUFA supplementation had increased BMI at age 10 y, increased risk of being overweight, and a tendency of increased fat percentage and higher metabolic syndrome score. These findings suggest potential adverse health effects from n–3 LCPUFA supplementation during pregnancy and need to be replicated in future independent studies.
This trial was registered at clinicaltrials.gov as NCT00798226.
A double‐blind randomized controlled trial of n‐3 long‐chain polyunsaturated fatty acid (n‐3 LCPUFA) supplementation or matching placebo during third trimester of pregnancy was conducted within the ...COPSAC2010 mother‐child cohort consisting of 736 women and their children. The objective was to determine if maternal n‐3 LCPUFA pregnancy supplementation affects offspring neurodevelopment until 6 years. Neurodevelopment was evaluated in 654 children assessing age of motor milestone achievement, language development, cognitive development, general neurodevelopment, and emotional and behavioral problems. Maternal n‐3 LCPUFA supplementation during pregnancy improved early language development and reduced the impact of emotional and behavioral problems. The n‐3 LCPUFA supplementation was in boys associated with the earlier achievement of gross motor milestones, improved cognitive development, and a reduced impact of emotional and behavioral problems.
Purpose
It is controversial whether a higher intake of n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) through breastfeeding is associated or not to a lower blood pressure (BP) during ...childhood. We aimed to clarify this point by undertaking a meta-analysis involving the data from seven European birth cohorts.
Methods
We searched
https://www.birthcohort.net
for studies that had collected breast milk samples, and had at least one BP measurement in childhood. Principal investigators were contacted, and all agreed to share data. One additional study was identified by contacts with the principal investigators. For each cohort, we analyzed the association of breast milk n-3 LC PUFAs with systolic and diastolic BP with linear mixed effects models or linear regression, and pooled the estimates with a random effects model. We also investigated age-specific and sex-specific associations.
Results
A total of 2188 participants from 7 cohorts were included. Overall, no associations between breast milk n-3 LC PUFAs and BP were observed. In the pooled analysis, each 0.1 wt% increment in breast milk docosahexaenoic acid (DHA) was associated with a 1.19 (95% CI − 3.31, 0.94) mmHg lower systolic BP. Associations were similar for boys and girls and at different ages.
Conclusion
In this individual participant meta-analysis, we found no evidence for an association between breast milk n-3 LC PUFAs and BP.
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