Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

INTRODUCTION: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs) and leukotrienes (LTs) with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. We aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: We quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (age 1 year, n=450) and VDAART (age 3 years, n=575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of Type-2 inflammation, applying FDR5% multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P

Genetic predisposition to high BMI increases risk of early life respiratory infections and episodes of severe wheeze and asthma.

BACKGROUND: High BMI is an established risk factor for asthma, but the underlying mechanisms remain unclear.Objective: To increase understanding of the BMI-asthma relationship by studying the association between genetic predisposition to higher body mass index (BMI) and asthma, infections, and other asthma-traits during childhood. METHODS: Data was obtained from the two ongoing COPSAC mother-child cohorts. Polygenic risk score (PRS) for adult BMI were calculated for each child. Replication was done in the large-scale iPSYCH cohort using data on hospitalization for asthma and infections. RESULTS: In the COPSAC cohorts (n=974), the adult BMI PRS was significantly associated with lower respiratory tract infections (LRTI) (IRR 1.20 95% CI 1.08-1.33, FDR=0.005) age 0-3 years and episodes of severe wheeze (IRR 1.30, 1.06-1.60, FDR=0.04) age 0-6 years. LRTI partly mediated the association between the adult BMI PRS and severe wheeze (proportion mediated: 0.59, 0.28-2.24, pACME 2E-16). In contrast, these associations were not mediated through the child's current BMI and the PRS was not associated with an asthma diagnosis or reduced lung function up to age 18. The associations were replicated in iPSYCH (n=114 283), where the adult BMI PRS significantly increased the risk of hospitalizations for LRTI and wheeze or asthma during childhood to age 18 years. CONCLUSION: Children with genetic predisposition to higher BMI had increased risk of LRTI and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between BMI and asthma.

BURDEN AND SUBTYPES OF EARLY-LIFE INFECTIONS INCREASE THE RISK OF ASTHMA.

BACKGROUND: Early-life respiratory tract infections have been linked to the development of asthma, but studies on burden and subtypes of common infections in asthma development are sparse. OBJECTIVE: The study aimed to examine the association between burden of early-life infections, including subtypes, with risk of asthma from ages 3-10 years and lung function at age 10 years. METHODS: We included 662 children from the COPSAC2010 birth cohort, where infections, i.e., colds, acute tonsillitis, acute otitis media (AOM), pneumonia, gastroenteritis, and fever were registered prospectively in daily diaries at age 0-3 years, and asthma was diagnosed longitudinally from ages 3-10 years. The association between infection burden and subtypes and risk of asthma was analysed by generalized estimating equations. RESULTS: The children experienced a median of 16 [IQR=12-23] infections age 0-3 years. Children with a high burden of infections (above median) had an increased risk of asthma age 3-10: aOR=3.61 (2.39-5.45), p<0.001, which was driven by colds, pneumonia, gastroenteritis, and fever episodes (p-values<0.05), but not by AOM and tonsillitis. Lower lung function measures age 10 were associated with burden of pneumonia, but not the overall infection burden. The association between colds and risk of asthma was significantly higher in children with allergic rhinitis at age 6 (p-interaction=0.032). CONCLUSION: High burden of early-life infections in terms of colds, pneumonia, gastroenteritis, and fever is associated with increased risk of developing asthma, particularly in children with respiratory allergy. Strategies to diminish these early-life infections could potentially offer a path for primary prevention of childhood asthma.

Vertical Metabolome Transfer from Mother to Child: An Explainable Machine Learning Method for Detecting Metabolomic Heritability.

Vertical transmission of metabolic constituents from mother to child contributes to the manifestation of disease phenotypes in early life. This study probes the vertical transmission of metabolites from mothers to offspring by utilizing machine learning techniques to differentiate between true mother-child dyads and randomly paired non-dyads. Employing random forests (RF), light gradient boosting machine (LGBM), and logistic regression (Elasticnet) models, we analyzed metabolite concentration discrepancies in mother-child pairs, with maternal plasma sampled at 24 weeks of gestation and children's plasma at 6 months. The propensity of vertical transfer was quantified, reflecting the likelihood of accurate mother-child matching. Our findings were substantiated against an external test set and further verified through statistical tests, while the models were explained using permutation importance and SHapley Additive exPlanations (SHAP). The best model was achieved using RF, while xenobiotics were shown to be highly relevant in transfer. The study reaffirms the transmission of certain metabolites, such as perfluorooctanoic acid (PFOA), but also reveals additional insights into the maternal influence on the child's metabolome. We also discuss the multifaceted nature of vertical transfer. These machine learning-driven insights complement conventional epidemiological findings and offer a novel perspective on using machine learning as a methodology for understanding metabolic interactions.

Maternal Diet Associates with Offspring Bone Mineralization, Fracture Risk and Enamel Defects in Childhood and Influences the Prenatal Effect of High-Dose Vitamin D Supplementation.

We previously demonstrated a beneficial effect of high-dose vitamin D in pregnancy on offspring bone and dental health. Here, we investigated the effect of maternal dietary patterns during pregnancy on the risk of bone fractures, bone mineralization and enamel defects until age 6 years in the offspring. Further, the influence of diet on the effect of high-dose vitamin D was analyzed in the COPSAC2010 mother-child cohort including 623 mother-child pairs. A weighted network analysis on FFQs revealed three specific maternal dietary patterns that associated (Bonferroni p < 0.05) with both offspring bone and dental health. The effect of prenatal high-dose (2800 IU/day) vs. standard-dose (400 IU/day) vitamin D on offspring bone mineral content (adjusted mean difference (aMD): 33.29 g, 95% CI: 14.48-52.09, p < 0.001), bone mineral density (aMD: 0.02 g/cm2 (0.01-0.04), p < 0.001), fracture risk (adjusted incidence rate ratio: 0.36 (0.16-0.84), p = 0.02), and enamel defects in primary (adjusted odds ratio (aOR): 0.13 (0.03-0.58), p < 0.01) and permanent molars (aOR: 0.25; (0.10-0.63), p < 0.01) was most pronounced when mothers had lower intake of fruit, vegetables, meat, eggs, sweets, whole grain, offal and fish. This study suggests that prenatal dietary patterns influence offspring bone and dental development, and should be considered in order to obtain the full benefits of vitamin D to enhance personalized supplementation strategy.

Vitamin D Primary Prevention of Respiratory Infections and Asthma in Early Childhood: Evidence and Mechanisms.

Respiratory infections are a leading cause of child morbidity worldwide, and asthma is the most common chronic disorder in childhood. Both conditions associate with high socioeconomic costs and are major reasons for medication prescriptions and hospitalizations in children. Vitamin D deficiency has concomitantly increased with asthma prevalence and is hypothesized to play a key role in the development. Current evidence suggests that high prenatal and early childhood vitamin D could be protective against respiratory infections and asthma in some studies where several mechanisms are proposed. However, other studies have reported no effects on these outcomes. Therefore, future large intervention studies on this topic are warranted. Mechanistic studies have shown that vitamin D holds antimicrobial properties by inducing production of several peptides through altered gene expression. Others have shown a complex interplay between asthma risk genotypes, the sphingolipid pathway, and prenatal vitamin D in early childhood asthma. Vitamin D has also been suggested to change both airway immune and microbiota profiles, which are directly related to asthma risk. Finally, systemic low-grade inflammation seems to be regulated by vitamin D exposure. This review presents the current literature of the primary preventive effect of vitamin D on early childhood asthma and respiratory infections. Mechanisms of actions are discussed, and gaps in knowledge are highlighted to facilitate planning of future intervention trials.

Key risk factors of asthma-like symptoms are mediated through infection burden in early childhood.

BACKGROUND: Risk factors of asthma-like symptoms in childhood may act through an increased infection burden because infections often trigger these symptoms. OBJECTIVE: We sought to investigate whether the effect of established risk factors of asthma-like episodes in early childhood is mediated through burden and subtypes of common infections. METHODS: The study included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, in which infections were registered prospectively in daily diaries from age 0 to 3 years. The association between established risk factors of asthma-like episodes and infection burden was analyzed by quasi-Poisson regressions, and mediation analyses were performed for significant risk factors. RESULTS: In the first 3 years of life, the children experienced a median of 16 (interquartile range, 12-23) infectious episodes. We found that the infection burden significantly (PACME < .05) mediated the association of maternal asthma (36.6% mediated), antibiotics during pregnancy (47.3%), siblings at birth (57.7%), an asthma exacerbation polygenic risk score (30.6%), and a bacterial airway immune score (80.2%) with number of asthma-like episodes, whereas the higher number of episodes from male sex, low birth weight, low gestational age, and maternal antibiotic use after birth was not mediated through an increased infection burden. Subtypes of infections driving the mediation were primarily colds, pneumonia, gastroenteritis, and fever, but not acute otitis media or acute tonsillitis. CONCLUSIONS: Several risk factors of asthma-like symptoms in early childhood act through an increased infection burden in the first 3 years of life. Prevention of infectious episodes may therefore be beneficial to reduce the burden of asthma-like symptoms in early childhood.

High-dose vitamin D3 supplementation in pregnancy and risk of neurodevelopmental disorders in the children at age 10: A randomized clinical trial.

BACKGROUND: Vitamin D deficiency in pregnancy may increase the risk of autism and attention deficit hyperactivity disorder (ADHD). OBJECTIVE: The objective of this study was to estimate the effect of vitamin D3 supplementation in pregnancy on risk of autism and ADHD. DESIGN: This randomized clinical trial was part of the COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPYCH) project nested within the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising a population-based sample of 700 healthy mother-child pairs enrolled at week 24 of pregnancy. Maternal 25-hydroxy-vitamin D (25(OH)D) was measured at inclusion and 623 mothers were randomized 1:1 to either high-dose (2800 IU/d) or standard dose (400 IU/d) vitamin D3 until 1 wk postpartum (315 received high-dose, 308 standard dose). At age 10, diagnoses and symptom load of autism and ADHD, respectively, were established using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. RESULTS: The psychopathologic evaluation was completed by 591 children aged 10 y, and 16 children (2.7%) were diagnosed with autism and 65 (11.0%) with ADHD. Hereof, 496 children participated in the vitamin D3 trial (246 received high-dose, 250 standard dose). Of these, 12 children (2.4%) were diagnosed with autism and 58 (11.7%) with ADHD. Higher maternal preintervention 25(OH)D levels were associated with a decreased risk of autism [odd ratio (OR) per 10 nmol/L: 0.76 (0.59,0.97); P = 0.034], lower autistic symptom load [ß per 10 nmol/L: -0.03 (-0.05,0.00); P = 0.024), and decreased risk of ADHD diagnosis (OR per 10 nmol/L: 0.88 (0.78,0.99); P = 0.033]. High-dose vitamin D3 supplementation was not associated with risk of autism or ADHD. CONCLUSIONS: Higher maternal preintervention 25(OH)D was associated with a decreased risk of autism, lower autistic symptom load, and decreased risk of ADHD diagnosis, but high-dose vitamin D3 supplementation in pregnancy had no effect on risk of autism and ADHD. This trial was registered at clinicaltrials.gov as NCT00856947.

Atopic and non-atopic effects of fish oil supplementation during pregnancy.

BACKGROUND: We recently conducted a double-blinded randomised controlled trial showing that fish-oil supplementation during pregnancy reduced the risk of persistent wheeze or asthma in the child by 30%. Here, we explore the mechanisms of the intervention. METHODS: 736 pregnant women were given either placebo or n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the third trimester in a randomised controlled trial. Deep clinical follow-up of the 695 children in the trial was done at 12 visits until age 6 years, including assessment of genotype at the fatty acid desaturase (FADS) locus, plasma fatty acids, airway DNA methylation, gene expression, microbiome and metabolomics. RESULTS: Supplementation with n-3 LCPUFA reduced the overall risk of non-atopic asthma by 73% at age 6 (relative risk (RR) 0.27 (95% CI 0.06 to 0.85), p=0.042). In contrast, there was no overall effect on asthma with atopic traits (RR 1.42 (95% CI 0.63 to 3.38), p=0.40), but this was significantly modified by maternal FADS genotype and LCPUFA blood levels (interaction p<0.05), and supplementation did reduce the risk of atopic asthma in the subgroup of mothers with FADS risk variants and/or low blood levels of n-3 LCPUFA before the intervention (RR 0.31 (95% CI 0.11 to 0.75), p=0.016). Furthermore, n-3 LCPUFA significantly reduced the number of infections (croup, gastroenteritis, tonsillitis, otitis media and pneumonia) by 16% (incidence rate ratio 0.84 (95% CI 0.74 to 0.96), p=0.009). CONCLUSIONS: n-3 LCPUFA supplementation in pregnancy showed protective effects on non-atopic asthma and infections. Protective effects on atopic asthma depended on maternal FADS genotype and n-3 LCPUFA levels. This indicates that the fatty acid pathway is involved in multiple mechanisms affecting the risk of asthma subtypes and infections. TRIAL REGISTRATION NUMBER: NCT00798226.

Maternal vitamin D-related metabolome and offspring risk of asthma outcomes.

BACKGROUND: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS: In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

Dietary prevention strategies for childhood asthma.

Asthma is the most common chronic disease in childhood and a rise in prevalence has been observed concomitantly with changing dietary habits in the Western world. This change has favored a more Westernized diet characterized by high intake of processed food and fat in contrast to a Mediterranean diet high in fruit, vegetable and fish intake. This has resulted in a decreased intake of several antioxidants and micronutrients including n-3 long-chained polyunsaturated fatty acids and vitamin D that are speculated to have anti-inflammatory effects and hold immunoregulatory properties. Several observational studies have investigated associations between dietary intake and wheeze and asthma but only few large well-conducted randomized controlled trials (RCTs) have been performed investigating the primary preventive effect of micronutrient supplementations. Currently, the recommendations from the Global Initiative for Asthma (GINA) for primary prevention of asthma in children do not include maternal dietary changes or supplementations during pregnancy, although the most recent report mentions both specific dietary patterns and micronutrients as potential protective supplementation regimes. This review will present the current literature and future research needs focusing on primary and secondary prevention of both early and late childhood asthma from dietary intake during pregnancy and early childhood to highlight potential preventive effects of specific dietary patterns and micronutrient supplements, which may facilitate the planning of future clinical trials in search of a preemptive strategy.

The Impact of Baseline 25-Hydroxyvitamin D Level and Gestational Age on Prenatal Vitamin D Supplementation to Prevent Offspring Asthma or Recurrent Wheezing.

BACKGROUND: Prenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive. OBJECTIVES: We aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing. METHODS: We conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10-18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation. RESULTS: An inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32-38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D-deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9-12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82). CONCLUSIONS: Pregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy. This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621.

Associations of pre- and postnatal exposures with optic nerve status in young adults.

PURPOSE: We aimed to explore the effect of multiple pre- and postnatal exposures on optic nerve status in young adults due to this critical period for development. METHODS: We analysed peripapillary retinal nerve fibre layer (RNFL) status and macular thickness at age 18 years in the Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000 ) cohort in relation to several exposures. RESULTS: Of the 269 participants (median (IQR) age, 17.6 (0.6) years; 124 boys), 60 participants whose mothers had smoked during pregnancy had a thinner RNFL: adjusted mean difference -4.6 µm (95% CI -7.7; -1.5 µm, p = 0.004) compared with participants whose mothers had not smoked during pregnancy. A total of 30 participants who were exposed to tobacco smoke both during foetal life and childhood had thinner RNFL: -9.6 µm (-13.4; -5.8 µm, p < 0.001). Smoking during pregnancy was also associated with a macular thickness deficit: -4.7 µm (-9.0; -0.4 µm, p = 0.03). Higher indoor concentrations of particulate matter 2.5 (PM2.5) was associated with thinner RNFL: -3.6 µm (-5.6; -1.6 µm, p < 0.001) and a macular deficit: -2.7 µm (-5.3; -0.1 µm, p = 0.04) in the crude analyses, but not in the adjusted analyses. No difference was found among participants who smoked at age 18 years compared with non-smokers on RNFL or macular thickness. CONCLUSIONS: We found that exposure to smoking during early life was associated with a thinner RNFL and macula at age 18 years. The absence of an association between active smoking at 18 years suggests that the vulnerability of the optic nerve is highest during prenatal life and early childhood.

Risk Factors and Age-Related Patterns of Asthma-Like Symptoms in Early Childhood.

BACKGROUND: Episodes of asthma-like symptoms in young children are common, but little is known about risk factors and their patterns for the daily symptom burden. OBJECTIVE: We investigated a variety of possible risk factors and their age-related impact on the number of asthma-like episodes during age 0 to 3 years. METHODS: The study population included 700 children from the Copenhagen Prospective Studies on Asthma in Childhood2010 mother-child cohort followed prospectively from birth. Asthma-like symptoms were recorded until age 3 by daily diaries. Risk factors were analyzed by quasi-Poisson regressions, and interaction with age was explored. RESULTS: Diary data were available in 662 children. Male sex, maternal asthma, low birth weight, maternal antibiotic use, high asthma exacerbation polygenic risk score, and high airway immune score were associated with a higher number of episodes in a multivariable analysis. Maternal asthma, preterm birth, caesarean section, and low birth weight showed an increasing impact with age, whereas sibling(s) at birth showed a decreased association with age. The remaining risk factors had a stable pattern during age 0 to 3 years. For every additional clinical risk factor (male sex, low birth weight, and maternal asthma) a child had, we found 34% more episodes (incidence rate ratio: 1.34, 95% confidence interval: 1.21-1.48; P < .001). CONCLUSION: Using unique day-to-day diary recordings, we identified risk factors for the burden of asthma-like symptoms in the first 3 years of life and described their unique age-related patterns. This provides novel insight into the origin of asthma-like symptoms in early childhood that potentially pave a path for personalized prognostics and treatment.

Diet-associated vertically transferred metabolites and risk of asthma, allergy, eczema, and infections in early childhood.

BACKGROUND: Evidence suggests maternal pregnancy dietary intake and nutrition in the early postnatal period to be of importance for the newborn child's health. However, studies investigating diet-related metabolites transferred from mother to child on disease risk in childhood are lacking. We sought to investigate the influence of vertically transferred metabolites on risk of atopic diseases and infections during preschool age. METHODS: In the Danish population-based COPSAC2010 mother-child cohort, information on 10 diet-related vertically transferred metabolites from metabolomics profiles of dried blood spots (DBS) at age 2-3 days was analyzed in relation to the risk of childhood asthma, allergy, eczema, and infections using principal component and single metabolite analyses. RESULTS: In 678 children with DBS measurements, a coffee-related metabolite profile reflected by principal component 1 was inversely associated with risk of asthma (odds ratio (95% CI) 0.78 (0.64; 0.95), p = .014) and eczema at age 6 years (0.79 (0.65; 0.97), p = .022). Furthermore, increasing stachydrine (fruit-related), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (fish-related), and ergothioneine (fruit-, green vegetables-, and fish-related) levels were all significantly associated with reduced risks of infections at age 0-3 years (p < .05). CONCLUSION: This study demonstrates associations between pregnancy diet-related vertically transferred metabolites measured in children in early life and risk of atopic diseases and infections in childhood. The specific metabolites associated with a reduced disease risk in children may contribute to the characterization of a healthy nutritional profile in pregnancy using a metabolomics-based unbiased tool for predicting childhood health.

Supplementation With Fish Oil in Pregnancy Reduces Gastroenteritis in Early Childhood.

BACKGROUND: We hypothesized that insufficient intake of fish oil-derived omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) during pregnancy is a contributing factor to gastroenteritis in early childhood. We examined the effect of n-3 LCPUFA supplementation on gastroenteritis symptoms in the offspring's first 3 years of life. METHODS: This was a double-blinded, randomized controlled trial whereby 736 mothers were administered n-3 LCPUFA or control from pregnancy week 24 until 1 week after birth. We measured the number of days with gastroenteritis, number of episodes with gastroenteritis, and the risk of having a gastroenteritis episode in the first 3 years of life. RESULTS: A median reduction of 2.5 days with gastroenteritis (P = .018) was shown, corresponding to a 14% reduction in the n-3 LCPUFA group compared with controls in the first 3 years of life (P = .037). A reduction in the number of gastroenteritis episodes (P = .027) and a reduced risk of having an episode (hazard ratio, 0.80 [95% confidence interval, .66-.97]; P = .023) were also shown. CONCLUSIONS: Fish oil supplementation from the 24th week of pregnancy led to a reduction in the number of days and episodes with gastroenteritis symptoms in the first 3 years of life. The findings suggest n-3 LCPUFA supplementation as a preventive measure against gastrointestinal infections in early childhood. CLINICAL TRIALS REGISTRATION: NCT00798226.

Furan fatty acid metabolite in newborns predicts risk of asthma.

BACKGROUND: Intake of fish-oil and fatty fish during pregnancy has been shown to reduce the risk of childhood asthma but biomarkers of such intake are lacking. OBJECTIVE: To establish biomarkers of prenatal fish-oil exposure from newborn dry blood spot metabolomics profiles and assess their relevance for childhood asthma risk stratification. METHODS: The Danish COPSAC2010 mother-child cohort was utilized to investigate the effect of a double-blinded randomized controlled trial of fish-oil supplementation during pregnancy on dry blood spot liquid-chromatography mass spectrometry-based metabolomics profiles of 677 newborns. We thereafter investigated the association between fish-oil associated biomarkers in the newborn and development of asthma-related outcomes. Replication was sought in the independent observational COPSAC2000 cohort with 387 newborn metabolomics profiles. RESULTS: The newborn metabolomics profiles differed between children in the fish-oil vs. placebo group in COPSAC2010 (area under the receiver operator curve = 0.94 ± 0.03, p < .001). The fish-oil metabolomics profile and the top biomarker, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) were both associated with a decreased risk of asthma by age 6 years (HR = 0.89, p = .002 and HR = 0.67, p = .005, respectively). In COPSAC2000 , newborn CMPF level was also inversely associated with asthma risk by age 6 years (HR = 0.69, p = .01). Troublesome lung symptoms and common infections in the first 3 years were also inversely associated with newborn CMPF levels in both cohorts. CONCLUSIONS: Newborn children's blood levels of the furan fatty acid metabolite CMPF reflect fish-oil and fatty fish intake during pregnancy and are associated with a lower risk of asthma across two cohorts, which could aid newborn screening for childhood asthma.

Fish Oil and Vitamin D Supplementations in Pregnancy Protect Against Childhood Croup.

BACKGROUND: Croup is a prevalent respiratory disorder in early childhood most often caused by parainfluenza virus infections. There are no preventive strategies; therefore, we investigated the potential effects of prenatal micronutrient supplementations. OBJECTIVE: To investigate the supplementation effects of (1) 2.4-g n-3 long-chained polyunsaturated fatty acid (n-3 LCPUFA) (fish oil) versus olive oil and (2) high-dose (2800 IU/d) versus standard-dose (400 IU/d) of vitamin D from pregnancy week 24 until 1 week after birth on the risk for offspring croup during the double-blinded first 3 years of life in a secondary analysis of a 2 × 2 factorial designed randomized controlled trial. METHODS: The study was completed in the Danish population-based single-center Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, which included 736 pregnant women. Croup was diagnosed by physicians' clinical examinations and medical record checks. Potential mediating mechanisms were investigated using blood metabolomics, airway cytokines, and airway microbiome. RESULTS: Of 695 children, 97 had croup before age 3 years (14%). The risk of croup was reduced in the n-3 LCPUFA (ncases / ntotal = 38/346; 11%) versus olive oil group (59 of 349 children; 17%) (hazard ratio = 0.62; 95% CI, 0.41-0.93; P = .02) and in the high-dose vitamin D group (32 of 295 children; 11%) versus the standard-dose group (51 of 286 children; 18%) (hazard ratio = 0.60; 95% CI, 0.38-0.93; P = .02). There was no evidence of interaction or additive effects between the supplements (Pinteraction = .56). Furthermore, the results did not change when they were adjusted for each other, persistent wheeze, and lower respiratory tract infection. CONCLUSIONS: This analysis of the double-blinded period of the Copenhagen Prospective Studies on Asthma in Childhood 2010 randomized controlled trial of n-3 LCPUFA and high-dose vitamin D supplementation during pregnancy demonstrated a reduced risk of croup in early childhood.