Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Dimensional profiling of psychopathology in children and adolescents based on the K-SADS-PL and an analysis of the construct validity of two ADHD symptom dimensions.

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.

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.

Height and bone mineral content after inhaled corticosteroid use in the first 6 years of life.

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.

Associations between Inhaled Corticosteroid Use in the First 6 Years of Life and Obesity-related Traits.

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 (-0.18 [95% confidence interval, -0.28 to -0.08] 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.

Asthma-like symptoms in young children increase the risk of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) may originate in early life and share disease mechanisms with asthma-like symptoms in early childhood. This possibility remains unexplored on account of the lack of long-term prospective studies from infancy to the onset of COPD. OBJECTIVE: We aimed to investigate the relationship between asthma-like symptoms in young children and development of COPD. METHODS: In a population-based cohort of women who gave birth at the central hospital in Copenhagen during period from 1959 to 1961, we investigated data from 3290 mother-child pairs who attended examinations during pregnancy and when the children were aged 1, 3, and 6 years. COPD was assessed from the Danish national registries on hospitalizations and prescription medication since 1994. A subgroup of 930 individuals underwent spirometry testing at age 50 years. RESULTS: Of the 3290 children, 1 in 4 had a history of asthma-like symptoms in early childhood. The adjusted hazard ratio for hospitalization for COPD was 1.88 (95% CI = 1.32-2.68), and the odds ratio for prescription of long-acting muscarinic antagonists was 2.27 (95% CI = 1.38-3.70). Asthma-like symptoms in early childhood were also associated with a reduced FEV1 percent predicted and an FEV1-to-forced vital capacity ratio at age 50 years (-3.36% [95% CI = -5.47 to -1.24] and -1.28 [95% CI = -2.17 to -0.38], respectively) and with COPD defined according to Global Initiative for Chronic Obstructive Lung Disease stage higher than 1 (odds ratio = 1.96 [95% CI = 1.13-3.34]). CONCLUSION: This 60-year prospective follow-up of a mother-child cohort demonstrated a doubled risk for COPD from childhood asthma-like symptoms.

Time trends of chronic immune diseases by year of birth in Danish registries.

Chronic immune diseases are often reported to be on the rise and are speculated to share early life risk factors. Here, we investigated year of birth as a common denominator for time trends using the consistent data source of the Danish National Patient Registry with 35 years nationwide coverage. Observational nationwide birth cohort registry study, where persons born in Denmark since 1953 were investigated for chronic immune diseases per person years at risk. Outcomes were defined by inpatient hospitalizations in pre-chosen age bins by year of birth in 5 year bins. A population of 3.8 million persons born in Denmark since 1953 was investigated for a total sum of 68 million person years in the ages 5-34 years. We found increasing trends by year of birth for juvenile arthritis age 10-14, adult asthma age 20-24, inflammatory bowel diseases age 20-24, and multiple sclerosis age 25-29, whereas type 1 diabetes age 15-19 was declining until birth year mid 1980s followed by a subsequent increase. Childhood asthma age 5-9 inpatient hospitalizations were relatively stable over time. Nationwide introduction of measles, mumps, rubella vaccine in 1987 did not alter the trends. Hospitalization for the chronic immune diseases adult asthma, juvenile arthritis, inflammatory bowel diseases and multiple sclerosis showed a general increasing trend by birth year in recent 35 years while diabetes 1 and childhood asthma seemed stable in this period. These results were not affected by the introduction of vaccinations against the major childhood viral infections.

Fish Oil Supplementation in Pregnancy Increases Gestational Age, Size for Gestational Age, and Birth Weight in Infants: A Randomized Controlled Trial.

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.

Preeclampsia Associates with Asthma, Allergy, and Eczema in Childhood.

RATIONALE: Preeclampsia reflects an unusual increase in systemic inflammation during pregnancy. OBJECTIVES: We studied associations between preeclampsia and asthma, allergy, and eczema in Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and in national registries. METHODS: COPSAC2000 is a high-risk birth cohort of 411 Danish children. Asthma, allergy, and eczema were diagnosed prospectively, and lung function measured at age 1 month and 7 years. Sensitization was evaluated at age 6 months, 18 months, 4 years, and 6 years by skin prick tests and IgE measurements. The register-based cohort included 1.7 million children from Danish national registries in the 35-year period 1977-2012. Children born to mothers with preeclampsia were analyzed regarding risk of asthma, allergy, and eczema. MEASUREMENTS AND MAIN RESULTS: In the COPSAC2000 cohort, 5.6% (n = 23) were diagnosed with preeclampsia. Preeclampsia was associated with increased risk of treatment with inhaled corticosteroids at age 7 years (adjusted odds ratio, 4.01 [95% confidence interval (CI), 1.11-14.43]; P = 0.0337), increased bronchial responsiveness to methacholine (adjusted ß-coefficient log-µmol, -0.80 [95% CI, -1.55 to -0.06]; P = 0.0348), and allergic rhinitis (adjusted odds ratio, 4.83 [95% CI, 1.58-14.78]; P = 0.0057) in the 7-year-old children. Furthermore, the children had an increased risk of sensitization to both aeroallergens and food allergens, and increased amount of total IgE during childhood. In the registry-based cohort, 3.7% (n = 62,728) were born to mothers with preeclampsia. Preeclampsia was associated with increased risk of asthma, eczema, and aeroallergen and food allergy, especially pronounced after a duration of preeclampsia of 14 days or more. Maternal asthma increased the risk of preeclampsia. CONCLUSIONS: Preeclampsia is a shared prenatal risk factor for asthma, eczema, and allergy in childhood pointing toward in utero immune programming of the child.

A novel common variant in DCST2 is associated with length in early life and height in adulthood.

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ß = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Risk of Asthma from Cesarean Delivery Depends on Membrane Rupture.

OBJECTIVE: To assess our prospective mother-child cohort and the national registry data to analyze the risk of asthma by delivery mode and whether cesarean delivery before or after membrane rupture affects this risk differently. STUDY DESIGN: The Copenhagen Prospective Studies on Asthma in Childhood2000 is a high-risk birth cohort of 411 Danish children. Asthma was diagnosed prospectively by physicians at the research site, and associations with cesarean delivery were investigated using Cox proportional hazard models. From the Danish national prospective registry we included data from 1997-2010. Childhood asthma was defined from recurrent use of inhaled corticosteroids filled at pharmacies. Cesarean delivery was classified as either before or after rupture of membranes, and the risk of asthma was compared with vaginal delivery. Results were adjusted stepwise for age and calendar year, sex, birth weight, gestational age, multiple births, parity, and maternal factors (age, smoking/antibiotics during pregnancy, employment status, and asthma). RESULTS: In the Copenhagen Prospective Studies on Asthma in Childhood2000 cohort, the adjusted hazard ratio for asthma was increased by cesarean delivery relative to vaginal birth 2.18 (1.27-3.73). Registry data replicated these findings. Cesarean delivery performed before rupture of membranes carried significantly higher risk of asthma, (incidence rate ratio to vaginal delivery 1.20 [1.16-1.23]) than cesarean delivery after rupture of membranes (incidence rate ratio to vaginal delivery 1.12 [1.09-1.16]). CONCLUSIONS: We confirmed cesarean delivery to be a risk factor for childhood asthma. This effect was more pronounced for cesarean delivery performed before rupture of membranes.

Stable admission rate for acute asthma in Danish children since 1977.

Childhood asthma is consistently reported to have increased in recent decades in most westernized countries, but it is unknown if this increase is similar across severities. We aimed to study the time-trend of acute hospital admission and readmission for asthma of school-aged children in the recent 35 years in Denmark. We analyzed time-trends in the national incidence rate of hospitalization for acute severe asthma in children aged 5-15 in Denmark during the 35-year period 1977-2012 in the Danish national registry. Only in-patient admissions with a principal diagnosis of asthma (ICD-8: 493** or ICD-10: J45** or J46**) were included. Among children with asthma hospitalizations, we investigated the risk of readmission beyond 1 month of first admission. Admissions were summarized as rates per thousand person years at risk. The overall time-trend is stable with a rate of one admission per year per thousand children at risk and a per-year incidence rate ratio 0.999 [95 % CI 0.997-1.001]. The rate of any readmission decreased from approximately 20 per thousand children in the eighties to less than 10 in the early nineties before stabilizing at around 10 per thousand children from mid-nineties and onwards. During 35 years of nation-wide follow-up, we find a highly stable incidence rate of first hospital admission for acute severe asthma in children. Moreover, rates of readmission halved during the seventies and stabilized in the last twenty years. In conclusion, our data suggest that the reported increase in childhood asthma is mainly due to less severe cases.

Association between respiratory infections in early life and later asthma is independent of virus type.

BACKGROUND: Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent. OBJECTIVE: We sought to study the association between specific infections in early life and development of asthma later in childhood. METHODS: Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years. RESULTS: In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma. CONCLUSION: The number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent.

Duration of wheezy episodes in early childhood is independent of the microbial trigger.

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.

Fish oil supplementation during pregnancy, anthropometrics, and metabolic health at age ten: A randomized clinical trial.

BACKGROUND: We previously reported that children of mothers who received fish oil supplementation during pregnancy had higher body mass index [BMI (in kg/m2)] at 6 y of age as well as a concomitant increase in fat-, muscle, and bone mass, but no difference in fat percentage. OBJECTIVES: Here, we report follow-up at age 10 y including assessment of metabolic health. METHODS: This is a follow-up analysis of a randomized clinical trial conducted among 736 pregnant females and their offspring participating in the Copenhagen Prospective Studies on Asthma in Childhood mother-child cohort. The intervention was 2.4 g n-3 (ω-3) Long-Chain PolyUnsaturated Fatty Acid (n-3 LCPUFA) or control daily from pregnancy week 24 until 1 wk after birth. Outcomes were anthropometric measurements, body composition from Bioelectrical Impedance Analysis, blood pressure, concentrations of triglycerides, cholesterol, glucose, and C-peptide from fasting blood samples, and a metabolic syndrome score was calculated. Anthropometric measurements and body composition were prespecified secondary endpoints of the n-3 LCPUFA trial, and others were exploratory. RESULTS: Children in the n-3 LCPUFA group had a higher mean BMI at age 10 year compared to the control group: 17.4 (SD: 2.44) compared with 16.9 (2.28); P = 0.020 and a higher odds ratio of having overweight (odds ratio: 1.53; 95% CI: 1.01, 2.33; P = 0.047). This corresponded to differences in body composition in terms of increased lean mass (0.49 kg; 95% CI: -0.20, 1.14; P = 0.17), fat mass (0.49 kg; 95% CI: -0.03, 1.01; P = 0.06), and fat percent (0.74%; 95% CI: -0.01, 1.49; P = 0.053) compared to the control group. Children in the n-3 LCPUFA group had a higher metabolic syndrome score compared to the control (mean difference: 0.19; 95% CI: -0.02, 0.39; P = 0.053). CONCLUSIONS: In this randomized clinical trial, children of mothers receiving n-3 LCPUFA supplementation had increased BMI at age 10 y, increased risk of being overweight, and a tendency of increased fat percentage and higher metabolic syndrome score. These findings suggest potential adverse health effects from n-3 LCPUFA supplementation during pregnancy and need to be replicated in future independent studies. This trial was registered at clinicaltrials.gov as NCT00798226.

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.

A Western Dietary Pattern during Pregnancy is Associated with Neurodevelopmental Disorders in Childhood and Adolescence.

Despite the high prevalence of neurodevelopmental disorders, there is a notable gap in clinical studies exploring the impact of maternal diet during pregnancy on child neurodevelopment. This observational clinical study examined the association between pregnancy dietary patterns and neurodevelopmental disorders, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. A Western dietary pattern in pregnancy (per SD change) was significantly associated with attention-deficit / hyperactivity disorder (ADHD) (OR 1.66 [1.21 - 2.27], p=0.002) and autism diagnosis (OR 2.22 [1.33 - 3.74], p=0.002) and associated symptoms (p<0.001). Findings for ADHD were validated in three large (n=59725, n=656, n=348), independent mother-child cohorts. Objective blood metabolome modelling at 24 weeks gestation identified 15 causally mediating metabolites which significantly improved ADHD prediction in external validation. Temporal analyses across five blood metabolome timepoints in two independent mother-child cohorts revealed that the association of Western dietary pattern metabolite scores with neurodevelopmental outcomes was consistently significant in early to mid-pregnancy, independent of later child timepoints. These findings underscore the importance of early intervention and provide robust evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.

Exposures to perfluoroalkyl substances and asthma phenotypes in childhood: an investigation of the COPSAC2010 cohort.

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 (SciLifeLab, Sweden) for supporting calibration of the untargeted metabolomics PFAS data. BC and AS has received funding for this project from the European Union's Horizon 2020 research and innovation programme (BC: grant agreement No. 946228 DEFEND; AS: grant agreement No. 864764 HEDIMED).

COVID-19 lockdown, genetic ADHD susceptibility, and mental health in 10- year-old children.

Previous studies report that the COVID-19 lockdown had an impact on the mental health of the pediatric population. In this study, we harness the deep neuropsychiatric phenotyping of the population-based COPSAC2010 (n = 700) cohort at age 10 to study the impact of the COVID-19 lockdown on mental health outcomes with focus on the role of the genetic vulnerability to attention-deficit/hyperactivity disorder (ADHD), in the form of polygenic risk scores (PRS). A total of 593 children were examined between 2019 and 2021, resulting in two groups of different children, those evaluated before the lockdown (n = 230) and those evaluated after (n = 363). Children assessed after the lockdown presented higher odds of being diagnosed with ADHD and had significantly higher scores in most neuropsychiatric scales, particularly in subscales pertaining to behavior and attention problems. We observed a significant interaction between the lockdown and ADHD PRS on several neuropsychiatric dimensions, with a large post-lockdown increase in children with a high PRS, while there was little to no pre-post difference in children with low PRS. These results indicate mental health consequences of the lockdown in children and suggest that genetically susceptible individuals are more affected by such stressors in childhood.