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Objectives: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification.Methods: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia – Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls).Results: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale.Conclusions: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.

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.

Background Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown. Methods In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics. Findings Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes. Interpretations Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. Funding All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764); 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. COPSAC acknowle, Background: Exposure to perfluoroalkyl substances may affect offspring immune development and thereby increase risk of childhood asthma, but the underlying mechanisms and asthma phenotype affected by such exposure is unknown. Methods: In the Danish COPSAC2010 cohort of 738 unselected pregnant women and their children plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics analyses and calibrated using a targeted pipeline in mothers (gestation week 24 and 1 week postpartum) and children (age ½, 1½ and 6 years). We examined associations between pregnancy and childhood PFOS and PFOA exposure and childhood infections, asthma, allergic sensitization, atopic dermatitis, and lung function measures, and studied potential mechanisms by integrating data on systemic low-grade inflammation (hs-CRP), functional immune responses, and epigenetics. Findings: Higher maternal PFOS and PFOA exposure during pregnancy showed association with a non-atopic asthma phenotype by age 6, a protection against sensitization, and no association with atopic asthma or lung function, or atopic dermatitis. The effect was primarily driven by prenatal exposure. There was no association with infection proneness, low-grade inflammation, altered immune responses or epigenetic changes. Interpretations: Prenatal exposure to PFOS and PFOA, but not childhood exposure, specifically increased the risk of low prevalent non-atopic asthma, whereas there was no effect on atopic asthma, lung function, or atopic dermatitis. Funding: All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764); 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. COPSAC acknowledges the National Facility for Exposomics (SciLi

Asthma and autoimmune disorders might be affected by opposing immune mechanisms, T helper cells type 2 (Th2) and T helper cells type 1 (Th1) immunity, respectively. Knowledge on comorbidity can increase understanding of the underlying etiologies. We aim to examine the association between childhood asthma and subsequent risk of type 1 diabetes (T1D) and inflammatory bowel diseases (IBD) in Danish children. Children of Danish origin born during 1991–1996 were included and childhood asthma, defined as a minimum of two collected prescriptions of inhalation corticosteroids age 5–7 years, was linked to hospitalisations with either T1D or IBD after age 8. Associations between childhood asthma and incidence of T1D and IBD were analysed using sex- and year stratified Cox regression. A total of 366,200 children were included in the study, 4.9% had asthma, which increased the risk of both T1D and IBD, hazard ratios of 1.32 (1.08–1.61) and 1.27 (1.09–1.48). In this large nationwide Danish study, we found that children with asthma have increased risk of developing immune diseases T1D and IBD. This contradicts the Th1 vs Th2 paradigm and points towards shared disease mechanisms and risk factors.

BACKGROUND: Infants and young children might be particularly susceptible to the potential side effects from inhaled corticosteroid (ICS) on height and bone mineral content (BMC), but this has rarely been studied in long-term prospective studies.METHODS: Children from two Copenhagen Prospective Studies on Asthma in Childhood cohorts were included. ICS use was registered prospectively from birth to age 6 and the cumulative dose was calculated. Primary outcomes were height and BMC from dual-energy X-ray absorptiometry (DXA) scans at age 6.RESULTS: At age 6, a total of 930 children (84%) from the cohorts had a valid height measurement and 792 (71%) had a DXA scan. 291 children (31%) received a cumulated ICS dose equivalent to or above 10 weeks of standard treatment before age 6. We found an inverse association between ICS use and height, -0.26 cm (95% CI: -0.45 to -0.07) per 1 year standard treatment from 0 to 6 years of age, p=0.006. This effect was mainly driven by children with ongoing treatment between age 5 and 6 years (-0.31 cm (95% CI: -0.52 to -0.1), p=0.004), while there was no significant association in children who stopped treatment at least 1 year before age 6 (-0.09 cm (95% CI: -0.46 to 0.28), p=0.64). There was no association between ICS use and BMC at age 6.CONCLUSIONS: ICS use in early childhood was associated with reduced height at age 6 years but only in children with continued treatment in the sixth year of life.

Rationale: Infants and young children might be particularly likely to experience the potential clinical side effects of inhaled corticosteroids (ICSs) on body mass index (BMI), adiposity rebound (AR), and body composition, but this has rarely been studied in long-term studies in this age group. Objectives: To determine the association between ICS exposure in the first 6 years of life and the BMI, AR, body composition, and blood lipid concentrations. Methods: Children from the two mother-child cohorts of the COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) were included. ICS use was registered prospectively to age 6 years, and the cumulative dose was calculated. Multiple linear regression models were used for analysis. Measurements and Main Results: A total of 932 (84%) of the 1,111 children from the COPSAC cohorts had BMI data, 786 (71%) had dual-energy X-ray absorptiometry scan data at the age of 6 years, and 815 (73%) had an AR age calculated. Two hundred ninety-one children (31%) received a cumulative ICS dose higher than that from 10 weeks of standard treatment before the age of 6. ICS treatment during 0-6 years of age was associated with an increased BMI z-score (0.05 [95% confidence interval, 0.005 to 0.09] SDs per each year of standard treatment; P = 0.03) an earlier age at AR (20.18 [95% confidence interval, 20.28 to 20.08] yr; P = 0.0006), and a 2% increased geometric mean android fat percentage (P = 0.05). ICS exposure and dual-energy X-ray absorptiometry scan data were not associated. Conclusions: ICS use in early childhood was associated with an increased BMI z-score at age 6, an earlier AR, and a trend of association with an increased android body fat percentage.

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

BACKGROUND: Randomized trials have reported that supplementation with n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in pregnancy can prolong pregnancy and thereby increase birth weight.OBJECTIVE: We aimed to examine the relations of n-3 LCPUFA supplementation in pregnancy with duration of pregnancy, birth weight, and size for gestational age (GA).METHODS: This was a double-blind randomized controlled trial conducted in 736 pregnant women and their offspring, from the Copenhagen Prospective Studies on Asthma in Childhood2010cohort. They were recruited between weeks 22 and 26 in pregnancy and randomly assigned to either of 2.4 g n-3 LCPUFA or control (olive oil) daily until 1 wk after birth. Exclusion criteria were endocrine, cardiovascular, or nephrologic disorders and vitamin D supplementation intake >600 IU/d. In this study we analyzed secondary outcomes, and further excluded twin pregnancies and extrauterine death. The primary outcome for the trial was persistent wheeze or asthma.RESULTS: The random assignment ran between 2008 and 2010. Six hundred and ninety-nine mother-infant pairs were included in the analysis. n-3 LCPUFA compared with control was associated with a 2-d prolongation of pregnancy [median (IQR): 282 (275-288) d compared with 280 (273-286) d, P = 0.02], a 97-g higher birth weight (mean ± SD: 3601 ± 534 g compared with 3504 ± 528 g, P = 0.02), and an increased size for GA according to the Norwegian population-based growth curves-Skjærven (mean ± SD: 49.9 ± 28.3 percentiles compared with 44.5 ± 27.6 percentiles, P = 0.01).CONCLUSION: Supplementing pregnant women with n-3 LCPUFAs during the third trimester is associated with prolonged gestation and increased size for GA, leading to a higher birth weight in this randomized controlled trial. This trial was registered at clinicaltrials.gov as NCT00798226.

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

BACKGROUND: Wheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger.OBJECTIVE: We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger.METHODS: Two hundred eighty-three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth.RESULTS: Eight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species.CONCLUSIONS: The duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes.

OBJECTIVES: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases.METHODS: Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977-2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses.RESULTS: Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease.CONCLUSIONS: Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention.