Rebecca K. Vinding

Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.

IMPORTANCE 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. OBJECTIVE To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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]. CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00856947.

Fish Oil–Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring

BACKGROUND 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. METHODS 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 Childhood2010 (COPSAC2010) 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 childrens 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. RESULTS 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. CONCLUSIONS 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 .).

Azithromycin for episodes with asthma-like symptoms in young children aged 1–3 years: a randomised, double-blind, placebo-controlled trial

Summary Background 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. Methods 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. Findings 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. Interpretation 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. Funding Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation.

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. We conducted a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 was associated with gestational duration; the association was replicated in 9,291 additional infants (combined P = 3.96 × 10−14). Analysis of 15,536 mother-child pairs showed that the association was driven by fetal rather than maternal genotype. Functional experiments showed that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Publisher Correction: Maturation of the gut microbiome and risk of asthma in childhood

The originally published version of this Article contained an incorrect version of Figure 3 that was introduced following peer review and inadvertently not corrected during the production process. Both versions contain the same set of abundance data, but the incorrect version has the children’s asthma status erroneously disconnected from the abundance data, thereby producing the non-representative p values and graphic presentations. These errors have now been rectified, with the correct version of Figure 3 replaced in both the PDF and HTML versions of the Article.

Effect of fish oil supplementation in pregnancy on bone, lean, and fat mass at six years: randomised clinical trial

Abstract Objective To examine the effect of supplementation with n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) in pregnancy on anthropometry and body composition in offspring. Design Double blinded, randomised controlled trial. Setting Copenhagen Prospective Studies on Asthma in Childhood2010 cohort. Participants 736 pregnant women and their offspring. Intervention n-3 LCPUFA (fish oil) or control (olive oil) daily from pregnancy week 24 until one week after birth. Main outcome measures Height/length, weight, head, and waist measurements and body composition from dual energy x ray absorptiometry (all pre-specified secondary endpoints of the n-3 LCPUFA trial; the primary outcome for the trial was persistent wheeze/asthma). Results The mean body mass index (BMI) z score was increased between age 0 and 6 years in the fish oil supplementation group compared with the control group (0.14 (95% confidence interval 0.04 to 0.23); P=0.006). At 6 years, supplementation was associated with a higher BMI z score (0.19 (0.06 to 0.32); P=0.004), a higher weight/height (3.48 (0.38 to 6.57) g/cm; P=0.03), and a larger waist circumference (0.6 (0.0 to 1.2) cm; P=0.04) but not a higher proportion of obese children, using International Obesity Task Force grades. The dual energy x ray absorptiometry scan at age 6 years showed a higher total mass (395.4 (86.6 to 704.3) g; P=0.01) in the supplementation versus the control group, explained by a higher lean mass (280.7 (98.9 to 462.4) g; P=0.002), a higher bone mineral content (10.3 (2.3 to 18.1) g; P=0.01), and a non-significantly higher fat mass (116.3 (−92.9 to 325.5) g; P=0.28), but no differences were seen in total body fat or lean mass percentage. Conclusion Fish oil supplementation from the 24th week of pregnancy led to a higher BMI in the offspring from 0 to 6 years of age but not an increased risk of obesity at age 6. The body composition at age 6 years in children given fish oil supplementation was characterised by a proportional increase in lean, bone, and fat mass suggesting a general growth stimulating effect of n-3 LCPUFA. Trial registration Clinicaltrials.gov NCT00798226

Cesarean Delivery and Body Mass Index at 6 Months and Into Childhood

Children born by CD had a higher mean BMI at 6 months of age, but this difference did not track into later childhood. BACKGROUND AND OBJECTIVES: The prevalence of cesarean delivery (CD) is rising worldwide, and so is childhood obesity. Studies have shown associations between these factors. We examined the development of BMI from birth through childhood to determine whether CDs were associated with differences in growth and obesity. METHODS: Term children from the birth cohorts Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and COPSAC2010 were included. Height, length, and weight measurements were collected prospectively until 5 years in COPSAC2010 and until 13 years in COPSAC2000. Dual-energy x-ray absorptiometry (DXA) scans were performed at 3.5 and 7 years. Information on relevant covariates were verified during clinical visits. Analyses were adjusted for covariates associating with CD. RESULTS: In COPSAC2010, 20% (N = 138/673) of the children were delivered by CD; 49% were girls. In COPSAC2000, 19% (N = 76/393) were delivered by CD; 51% were girls. Children delivered by CD had a higher mean BMI at 6 months compared with those delivered vaginally: COPSAC2010 β-coefficient, .41 (95% confidence interval [CI], .12 to .69), P = .01; COPSAC2000 β-coefficient, .16 (95% CI, −.11 to .68), P = .16; and meta-analysis β-coefficient, .37 (95% CI, .14 to .60), P = .002. There were no differences in BMI trajectory between the 2 groups by 5 and 13 years, nor cross-sectional BMI at 5 and 13 years, nor in fat percentages from DXA scans. CONCLUSIONS: Children delivered by CD had a higher BMI at 6 months of age, but this difference did not track into later childhood. Our study does not support the hypothesis that CD leads to later overweight.