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Background: High body mass index (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 BMI and asthma, infections and other asthma traits during childhood., Methods: Data were obtained from the two ongoing Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts. Polygenic risk scores for adult BMI were calculated for each child. Replication was done in the large-scale register-based Integrative Psychiatric Research (iPSYCH) cohort using data on hospitalisation for asthma and infections., Results: In the COPSAC cohorts (n=974), the adult BMI polygenic risk score was significantly associated with lower respiratory tract infections (incidence rate ratio (IRR) 1.20, 95% CI 1.08-1.33, false discovery rate p-value (pFDR)=0.005) at age 0-3 years and episodes of severe wheeze (IRR 1.30, 95% CI 1.06-1.60, pFDR=0.04) at age 0-6 years. Lower respiratory tract infections partly mediated the association between the adult BMI polygenic risk score and severe wheeze (proportion mediated: 0.59, 95% CI 0.28-2.24, p-value associated with the average causal mediation effect (pACME)=2e -16 ). In contrast, these associations were not mediated through the child's current BMI and the polygenic risk score was not associated with an asthma diagnosis or reduced lung function up to age 18 years. The associations were replicated in iPSYCH (n=114 283), where the adult BMI polygenic risk score significantly increased the risk of hospitalisations for lower respiratory tract infections and wheeze or asthma throughout childhood to age 18 years., Conclusion: Children with genetic predisposition to higher BMI had increased risk of lower respiratory tract infections and severe wheeze, independent of the child's current BMI. These results shed further light on the complex relationship between body mass BMI and asthma., Competing Interests: Conflict of interest: The authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease., Methods: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC 2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (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 false discovery rate of 5% (FDR5%) multiple testing correction., Results: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA 2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE 2 and PGI 2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC 2010 showed that lower isoprostanes and PGF 2 eicosanoids and higher PGD 2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE 2 and higher TXA 2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%)., Conclusions: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases., Competing Interests: Disclosure Statement COPSAC is funded by private and public research funds, which are all listed on www.copsac.com. The Lundbeck Foundation, Danish State Budget, Danish Council for Strategic Research, Danish Council for Independent Research, and The Capital Region Research Foundation have provided core support for COPSAC. The study is further supported by the following National Institutes of Health grants: R01HL129735, R01HL141826, and UH3OD023268. C.E.W. acknowledges support from the Swedish Heart Lung Foundation (HLF 20200693 and HLF 20210519) and the Swedish Research Council (2022-00796). This project has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 946228). R.S.K. was supported by the National Heart, Lung, and Blood Institute (HKL146980). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic diseases, obesity and neuropsychiatric disorders are lifestyle-related and environmental-related chronic inflammatory disorders, and the incidences have increased in the last years., Objective: To outline the design of the 18-year follow-up of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC 2000 ) birth cohort, where risk factors of atopic diseases, obesity and neuropsychiatric disorders are identified through extensive characterisation of the environment, along with deep clinical phenotyping and biosampling for omics profiling., Methods: COPSAC 2000 is a Danish prospective clinical birth cohort study of 411 children born to mothers with asthma who were enrolled at 1 month of age and closely followed at the COPSAC clinical research unit through childhood for the development of atopic diseases. At the 18-year follow-up visit, biomaterial (hair, blood, urine, faeces, throat, and skin swabs, nasal lining fluid and scraping, and hypopharyngeal aspirates) and extensive information on environmental exposures and risk behaviours were collected along with deep metabolic characterisation and multiorgan investigations including anthropometrics, heart, lungs, kidneys, intestines, bones, muscles and skin. Neuropsychiatric diagnoses were captured from medical records and registers accompanied by electronic questionnaires on behavioural traits and psychopathology., Results: A total of 370 (90%) of the 411 cohort participants completed the 18-year visit. Of these, 25.1% had asthma, 23.4% had a body mass index >25 kg/m 2 and 16.8% had a psychiatric diagnosis in childhood. Of the 62 probands with a neuropsychiatric diagnosis in childhood, a total of 68.7% drank alcohol monthly, and when drinking, 22.2% drank >10 units. Of the participants, 31.4% were currently smoking, and of these, 24.1% smoked daily. A total of 23.8% had tried taking drugs, and 19.7% reported having done self-destructive behaviour. The mean screen time per day was 6.0 hours., Conclusion: This huge dataset on health and habits, exposures, metabolism, multiorgan assessments and biosamples from COPSAC 2000 by age 18 provides a unique opportunity to explore risk factors and underlying mechanisms of atopic disease and other lifestyle-related, non-communicable diseases such as obesity and neuropsychiatric disorders, which are highly prevalent in the community and our cohort., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Importance: Eicosanoids have a pathophysiological role in atopic dermatitis (AD), but it is unknown whether this is affected by prenatal ω-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA; ie, fish oil) supplementation and genetic variations in the cyclooxygenase-1 (COX1) pathway., Objective: To explore the association of n-3 LCPUFA supplementation during pregnancy with risk of childhood AD overall and by maternal COX1 genotype., Design, Setting, and Participants: This prespecified secondary analysis of a randomized clinical trial included mother-child pairs from the Danish Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort, with prospective follow-up until children were aged 10 years. In the trial, maternal and child COX1 genotypes were determined, and urinary eicosanoids were quantified when the child was 1 year of age. The present study was conducted from January 2019 to December 2021, and data were analyzed from January to September 2023., Intervention: A total of 736 pregnant women at 24 weeks' gestation were randomized 1:1 to 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day until 1 week post partum., Main Outcomes and Measures: Risk of childhood AD until age 10 years overall and by maternal COX1 genotype., Results: At age 10 years, 635 children (91%; 363 [57%] female) completed the clinical follow-up, and these mother-child pairs were included in this study; 321 (51%) were in the intervention group and 314 (49%) in the control group. Pregnancy n-3 LCPUFA supplementation was associated with lower urinary thromboxane A2 metabolites at age 1 year (β, -0.46; 95% CI, -0.80 to -0.13; P = .006), which was also associated with COX1 rs1330344 genotype (β per C allele, 0.47; 95% CI, 0.20-0.73; P = .001). Although neither n-3 LCPUFA supplementation (hazard ratio [HR], 1.00; 95% CI, 0.76-1.33; P = .97) nor maternal COX1 genotype (HR, 0.94; 95% CI, 0.74-1.19; P = .60) was associated with risk of childhood AD until age 10 years, there was evidence of an interaction between these variables (P < .001 for interaction). Among mothers with the TT genotype, risk of AD was reduced in the n-3 LCPUFA group compared with the placebo group (390 mother-child pairs [61%]; HR, 0.70; 95% CI, 0.50-0.98; P = .04); there was no association for mothers with the CT genotype (209 [33%]; HR, 1.29; 95% CI, 0.79-2.10; P = .31), and risk was increased among offspring of mothers with the CC genotype (37 [6%]; HR, 5.77; 95% CI, 1.63-20.47; P = .007). There was a significant interaction between n-3 LCPUFA supplementation and child COX1 genotype and development of AD (P = .002 for interaction)., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, the association of prenatal n-3 LCPUFA supplementation with risk of childhood AD varied by maternal COX1 genotype. The findings could be used to inform a personalized prevention strategy of providing supplementation only to pregnant individuals with the TT genotype., Trial Registration: ClinicalTrials.gov: NCT00798226.

Background: Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts., Methods: Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC 2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms., Findings: Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections., Conclusions: Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes., Funding: The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was supported by R01HL091528 from the NHLBI, UG3OD023268 from Office of The Director, National Institute of Health, and P01HL132825 from the NHLBI., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Infections in childhood remain a leading global cause of child mortality and environmental exposures seem crucial. We investigated whether urbanicity at birth was associated with the risk of infections and explored underlying mechanisms., Methods: Children (n=633) from the COPSAC 2010 mother-child cohort were monitored daily with symptom diaries of infection episodes during the first 3 years and prospectively diagnosed with asthma until age 6 years. Rural and urban environments were based on the CORINE land cover database. Child airway immune profile was measured at age 4 weeks. Maternal and child metabolomics profiling were assessed at pregnancy week 24 and at birth, respectively., Results: We observed a mean (SD) total number of infections of 16.3 (8.4) consisting mainly of upper respiratory infections until age 3 years. Urban versus rural living increased infection risk (17.1 (8.7) vs 15.2 (7.9), adjusted incidence rate ratio; 1.15 (1.05-1.26), p=0.002) and altered the child airway immune profile, which increased infection risk (principal component 1 (PC1): 1.03 (1.00-1.06), p=0.038 and PC2: 1.04 (1.01-1.07), p=0.022). Urban living also altered the maternal and child metabolomic profiles, which also increased infection risk. The association between urbanicity and infection risk was partly mediated through the maternal metabolomic and child airway immune profiles. Finally, urbanicity increased the risk of asthma by age 6 years, which was mediated through early infection load (p ACME <0.001)., Conclusion: This study suggests urbanicity as an independent risk factor for early infections partly explained by changes in the early metabolic and immunological development with implications for later risk of asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early life respiratory tract infections have been linked to the development of asthma, but studies on the burden and subtypes of common infections in asthma development are sparse., Objective: To examine the association between burden of early life infections, including subtypes, with the risk of asthma from age 3 to 10 years and lung function at age 10 years., Methods: We included 662 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort, for whom infections such as colds, acute tonsillitis, acute otitis media, pneumonia, gastroenteritis, and fever were registered prospectively in daily diaries at age 0 to 3 years and asthma was diagnosed longitudinally from age 3 to 10 years. The association between the burden of infection and subtypes and risk of asthma was analyzed by generalized estimating equations., Results: The children experienced a median of 16 infections (interquartile range, 12-23 infections) at age 0 to 3 years. Children with a high burden of infections (above the median) had an increased risk of asthma at age 3 to 10 years (adjusted odds ratio = 3.61; 95% CI, 2.39-5.45; P < .001), which was driven by colds, pneumonia, gastroenteritis, and fever episodes (P < .05) but not by acute otitis media and tonsillitis. Lower lung function measures at age 10 years were associated with the burden of pneumonia but not the overall infection burden. The association between colds and the risk of asthma was significantly higher in children with allergic rhinitis at age 6 years (P interaction = .032)., Conclusion: A high burden of early life infections in terms of colds, pneumonia, gastroenteritis, and fever is associated with an increased risk of developing asthma, particularly in children with respiratory allergy. Strategies to diminish these early life infections may offer a path for the primary prevention of childhood asthma., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nonattendance at scheduled outpatient visits among children with asthma has been associated with an increased risk of acute asthma events and increased health care expenses. Specific risk factors for nonattendance have been suggested, but a comprehensive overview is lacking., Objective: To investigate risk factors for nonattendance among children with asthma and assess whether nonattendance associates with acute events through a systematic review and meta-analysis., Methods: The study (PROSPERO: CRD42023471893) was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the PubMed, Ovid MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases and search terms "asthma/wheeze," "child," and "nonattendance." Original peer-reviewed studies in English were included and evaluated for risk of bias using the Newcastle Ottawa scale. A meta-analysis was performed for all risk factors. Finally, we analyzed whether nonattendance was associated with the risk of acute events., Results: A total of 17 studies encompassing 27,023 children with asthma were included. The meta-analysis was performed on 11 eligible studies, with 25,948 children, and identified the following risk factors for nonattendance; teenage versus preteen (odds ratio [OR] 1.26; 95% confidence interval [95% CI] 1.06-1.49; P < .01), non-White versus White ethnicity (OR 1.51; 95% CI 1.04-2.18; P = .03) and lower disease severity (OR 1.41; 95% CI 1.13-1.77; P < .01). There were no significant findings in the meta-analysis for insurance status, atopy, sex, or rural residence. Nonattendance associated with an increased risk of acute asthma events (OR 1.11; 95% CI 1.07-1.16; P < .01)., Conclusions: This systematic review and meta-analysis identified specific risk factors to facilitate the development of a strategy against nonattendance for pediatric patients with asthma. This is particularly important given nonattendance being associated with an increased risk of acute asthma., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Asthma is the most common chronic disease in childhood affecting the daily lives of many patients despite current treatment regimens. Therefore, the need for new therapeutic approaches is evident, where a primary prevention strategy is the ultimate goal. Studies of children born to mothers in farming environments have shown a lower risk of respiratory infections and asthma development. Already at birth, these newborns have demonstrated accelerated maturation and upregulation of host defense immune functions suggesting a prenatal transplacental training of the innate immune system through maternal microbial exposure. This mechanism could possibly be utilized to help prevent both respiratory infections and asthma in young children. Human studies exploring the potential preventative effects of pregnancy bacterial lysate treatment on asthma and respiratory infections are lacking, however, this has been studied in experimental studies using mice through administrations of the bacterial lysate OM-85. This review will present the current literature on the immunomodulatory effects relevant for respiratory infections and asthma in the offspring of mice treated with OM-85 throughout pregnancy. Further, the review will discuss the cellular and molecular mechanisms behind these effects. In conclusion, we found promising results of an accelerated immune competence and improved resistance to airway challenges as a result of prenatal bacterial lysate treatment that may pave the way for implementing this in human trials to prevent asthma and respiratory infections., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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 (P ACME  < .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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

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 [β 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 COPSAC 2010 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/cm 2 (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.

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 Childhood 2010 (COPSAC 2010 ) 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 COPSAC 2010 , 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 COPSAC 2010 , 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 D 3 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., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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 (COPSAC 2000 ) 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., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

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., (© 2023 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

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 Childhood 20 1 0 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., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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 COPSAC 2010 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 COPSAC 2000 cohort with 387 newborn metabolomics profiles., Results: The newborn metabolomics profiles differed between children in the fish-oil vs. placebo group in COPSAC 2010 (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 COPSAC 2000 , 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., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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 COPSAC 2010 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., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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 (n cases / n total  = 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 (P interaction  = .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., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Importance: Several health benefits of vitamin D have been suggested; however, the safety of high-dose supplementation in early childhood is not well described., Objective: To systematically assess the risk of adverse events after high-dose supplementation with vitamin D reported in published randomized clinical trials., Data Sources: PubMed and ClinicalTrials.gov were searched through August 24, 2021., Study Selection: Randomized clinical trials of high-dose vitamin D supplementation in children aged 0 to 6 years, defined as greater than 1000 IU/d for infants (aged 0-1 year) and greater than 2000 IU/d for children aged 1 to 6 years., Data Extraction and Synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 reviewers independently extracted the data from the eligible studies. Summary risk ratio (RR), 95% CI, and P values were derived from random-effects meta-analysis., Main Outcomes and Measures: Adverse events, serious adverse events (SAEs), and/or levels of 25-hydroxyvitamin D, calcium, alkaline phosphatase, phosphate, parathyroid hormone, and/or the ratio of urine calcium to creatinine levels., Results: A total of 32 randomized clinical trials with 8400 unique participants were included. Different clinical outcomes of children receiving high-dose vitamin D supplements ranging from 1200 to 10 000 IU/d and bolus doses from 30 000 IU/week to a single dose of 600 000 IU were evaluated. Eight studies with 4612 participants were eligible for meta-analysis using a control group receiving either low-dose vitamin D supplementation (≤400 IU/d) or placebo when investigating the risk of SAEs such as hospitalization or death. No overall increased risk of SAEs in the high-dose vitamin D vs control groups was found (RR, 1.01 [95% CI, 0.73-1.39]; P = .89, I2 = 0%). In addition, risk of hypercalcemia (n = 726) was not increased (RR, 1.18 [95% CI, 0.72-1.93]; P = .51). Clinical adverse events potentially related to the vitamin D supplementation reported in the studies were rare., Conclusions and Relevance: This meta-analysis and systematic review found that high-dose vitamin D supplementation was not associated with an increased risk of SAEs in children aged 0 to 6 years, and that clinical adverse events potentially related to the supplementation were rare. These findings suggest that vitamin D supplementation in the dose ranges of 1200 to 10 000 IU/d and bolus doses to 600 000 IU to young children may be well tolerated.

The pregnancy period and first days of a newborn's life is an important time window to ensure a healthy development of the baby. This is also the time when the mother and her baby are exposed to the same environmental conditions and intake of nutrients, which can be determined by assessing the blood metabolome. For this purpose, dried blood spots (DBS) of newborns are a valuable sampling technique to characterize what happens during this important mother-child time window. We used metabolomics profiles from DBS of newborns (age 2-3 days) and maternal plasma samples at gestation week 24 and postpartum week 1 from n=664 mother-child pairs of the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort, to study the vertical mother-child transfer of metabolites. Further, we investigated how persistent the metabolites are from the newborn and up to 6 months, 18 months, and 6 years of age. Two hundred seventy two metabolites from UPLC-MS (Ultra Performance Liquid Chromatography-Mass Spectrometry) analysis of DBS and maternal plasma were analyzed using correlation analysis. A total of 11 metabolites exhibited evidence of transfer (R>0.3), including tryptophan betaine, ergothioneine, cotinine, theobromine, paraxanthine, and N6-methyllysine. Of these, 7 were also found to show persistence in their levels in the child from birth to age 6 years. In conclusion, this study documents vertical transfer of environmental and food-derived metabolites from mother to child and tracking of those metabolites through childhood, which may be of importance for the child's later health and disease.

Background: Exposure to vitamin D in early life has been associated with improved bone mineralization, but no studies have investigated the combined effect of pregnancy supplementation and childhood 25(OH)D concentrations on bone health., Methods: We analyzed the effect of serum 25(OH)D concentrations at age 6 months and 6 years and the combined effect with prenatal high-dose vitamin D (2800 vs. 400 IU/day) on bone mineral density (BMD) and content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) scans at age 3 and 6 years and longitudinal risk of fractures in a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 ) mother-child cohort with enrollment from March 4, 2009, to November 17, 2010, and clinical follow-up until January 31, 2019 (NCT00856947). All participants randomized to intervention and with complete data were included in the analyses., Findings: At age 6 months, serum 25(OH)D concentration was measured in 93% ( n  = 541) of 584 children. Children with sufficient (≥ 75 nmol/l) vs. insufficient (< 75 nmol/l) concentrations did not have lower risk of fractures: incidence rate ratio (95% CI); 0.64 (0.37;1.11), p  = 0.11. However, vitamin D sufficient children from mothers receiving high-dose supplementation during pregnancy had a 60% reduced incidence of fractures compared with vitamin D insufficient children from mothers receiving standard-dose: 0.40 (0.19;0.84), p  = 0.02.At age 6 years, serum 25(OH)D concentration was measured in 83% ( n  = 318) of 383 children with available DXA data. Whole-body bone mineralization was higher in vitamin D sufficient children at age 6 years; BMD, adjusted mean difference (aMD) (95% CI): 0.011 g/cm 2 (0.001;0.021), p  = 0.03, and BMC, aMD: 12.3 g (-0.8;25.4), p  = 0.07, with the largest effect in vitamin D sufficient children from mothers receiving high-dose vitamin D supplementation; BMD, aMD: 0.016 g/cm 2 (0.002;0.030), p  = 0.03, and BMC, aMD: 23.5 g (5.5;41.5), p  = 0.01., Interpretation: Childhood vitamin D sufficiency improved bone mineralization and in combination with prenatal high-dose vitamin D supplementation reduced the risk of fractures., Funding: The study was supported by The Lundbeck Foundation R16-A1694, The Danish Ministry of Health 903,516, The Danish Council for Strategic Research 0603-00280B and The European Research Council 946,228., Competing Interests: All authors declare no conflict of interest regarding the content of this manuscript. The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. JL reports receiving grants from the NIH and the Simons Foundation for Autism and a leadership role in the Metabolomics Society outside of the submitted work. SW reports receiving a grant UH3 OD023268 from the NIH and honoraria from UPTODATE outside of the submitted work. JS reports receiving grants from the NNF and DFF outside of the submitted work. KB reports receiving consulting fees from Sanofi and Astra Zeneca, honoraria from Boehringer Ingelheim and participation in an advisory board from ALK-Abelló Nordic outside of the submitted work., (© 2021 The Author(s).)

Vitamin D deficiency and elevated high sensitivity C-reactive protein (hs-CRP) have been associated with several health outcomes, but knowledge on early life trajectories and association between 25 hydroxyvitamin D (25(OH)D) and hs-CRP is lacking. We investigated the association between longitudinal measurements of 25(OH)D and hs-CRP, respectively, from pregnancy to childhood and throughout childhood in two Danish mother-child cohorts-the COPSAC 2010 and COPSAC 2000 . In COPSAC 2010 , there was an association between 25(OH)D concentrations at week 24 in pregnancy and at age 6 months in childhood ( n = 633): estimate (95% CI); 0.114 (0.041;0.187), p = 0.002, and between 25(OH)D at age 6 months and 6 years ( n = 475): 0.155 (0.083;0.228), p < 0.001. This was also demonstrated in the COPSAC 2000 cohort between 25(OH)D concentrations in cord blood and at age 4 years ( n = 188): 0.294 (0.127;0.461), p < 0.001 and at age 6 months and 4 years ( n = 264): 0.260 (0.133;0.388), p < 0.001. In COPSAC 2000 , we also found an association between hs-CRP at age 6 months and 12 years in childhood ( n = 232): 0.183 (0.076;0.289), p < 0.001. Finally, we found a negative association between the cross-sectional measurements of 25(OH)D and hs-CRP at age 6 months ( n = 613) in COPSAC 2010 : -0.004 (-0.008;-0.0004), p = 0.030, but this was not replicated in COPSAC 2000 . In this study, we found evidence of associations across timepoints of 25(OH)D concentrations from mid-pregnancy to infancy and through childhood and associations between hs-CRP levels during childhood, although with weak correlations. We also found a negative cross-sectional association between 25(OH)D and hs-CRP concentrations in COPSAC 2010 proposing a role of vitamin D in systemic low-grade inflammation, though this association was not present in COPSAC 2000 .

Background: Prenatal vitamin D 3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D 3 supplementation against offspring asthma/recurrent wheeze., Methods: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 , n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D 3 supplementation versus placebo., Results: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D 3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC 2010 ), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC 2010 )., Conclusion: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D 3 supplementation against offspring asthma/recurrent wheeze., Competing Interests: Conflict of interest: H.M. Knihtilä has nothing to disclose. Conflict of interest: R.S. Kelly has nothing to disclose. Conflict of interest: N. Brustad has nothing to disclose. Conflict of interest: M. Huang has nothing to disclose. Conflict of interest: P. Kachroo has nothing to disclose. Conflict of interest: B.L. Chawes has nothing to disclose. Conflict of interest: J. Stokholm has nothing to disclose. Conflict of interest: K. Bønnelykke has nothing to disclose. Conflict of interest: C-E.T. Pedersen has nothing to disclose. Conflict of interest: H. Bisgaard has nothing to disclose. Conflict of interest: A.A. Litonjua reports author royalties from UpToDate, Inc., outside the submitted work. Conflict of interest: J.A. Lasky-Su has nothing to disclose. Conflict of interest: S.T. Weiss has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs., Methods: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC 2010 ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART)., Results: In COPSAC 2010 , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal P interaction  = .049 and child P interaction  = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC 2010 or VDAART: all P interaction  ≥ .17., Conclusions: We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC 2010 RCT, but not VDAART, which may be due to population differences., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated. Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data. Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC 2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort. Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05. Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.

Importance: 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., Objective: 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., Design, Setting, and Participants: 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., Interventions: Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth., Main Outcomes and Measures: 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., Results: 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., Conclusions and Relevance: 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., Trial Registration: ClinicalTrials.gov Identifier: NCT00856947.

Vitamin D insufficiency has become a common health problem worldwide, particularly among pregnant women and young children. Therefore, we sought to identify environmental, dietary, and genetic determinants of serum 25(OH)-vitamin D (25(OH)D) levels during pregnancy and early childhood. 25(OH)D was measured in women at 24-weeks of gestation ( n = 738) and one-week postpartum ( n = 284) in the population-based Danish COPSAC 2010 mother-child cohort; and in cord blood ( n = 257) and age 4 years ( n = 298) in children from the at-risk COPSAC 2000 mother-child cohort. Environmental, dietary, and genetic variables were tested for association with 25(OH)D using linear regression analyses. After adjusting for season of blood sampling, determinants of lower 25(OH)D levels during pregnancy in the women were higher pre-pregnancy BMI, lower age at birth, lower genetic vitamin D score, lower dietary vitamin D intake, and lower social circumstances. In children, the determinants were lower maternal age at birth, higher pre-pregnancy BMI, lower genetic vitamin D score, older siblings, exposure to tobacco smoking, and female sex. Genetics was an important determinant at all time points, alone explaining 2%-11% of the variance in 25(OH)D. Important determinants of circulating 25(OH)D levels during pregnancy and early childhood include environmental factors, diet, and to a large extent genetics.