Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Maternal hemoglobin and iron status in early pregnancy and risk of respiratory tract infections in childhood: A population-based prospective cohort study.

BACKGROUND: Maternal hemoglobin and iron status measures during pregnancy might affect the developing fetal respiratory system leading to adverse respiratory conditions. Our aim was to assess the associations of maternal hemoglobin and iron status measures during pregnancy with the risk of respiratory tract infections in children until 10 years of age. METHODS: In a population-based cohort study among 5134 mother-child pairs, maternal hemoglobin and iron status including ferritin, transferrin, and transferrin saturation were measured during early pregnancy. In children, physician-attended respiratory tract infections from age 6 months until 10 years were assessed by questionnaires. Confounder-adjusted generalized estimating equation modeling was applied. RESULTS: After taking multiple testing into account, high maternal ferritin concentrations and low maternal transferrin saturation during pregnancy were associated with an overall increased risk of upper, not lower, respiratory tract infections until age 10 years of the child [OR (95% CI: 1.23 (1.10, 1.38) and 1.28 (1.12, 1.47), respectively)]. High maternal transferrin saturation during pregnancy was associated with a decreased and increased risk of upper respiratory tract infections at 1 and 6 years, respectively, [OR (95% CI: 0.60 (0.44, 0.83) and 1.54 (1.17, 2.02))]. Observed associations were suggested to be U-shaped (p-values for non-linearity ≤.001). Maternal hemoglobin and iron status measures during pregnancy were not consistently associated with child's gastroenteritis and urinary tract infections, as proxies for general infection effects. CONCLUSION: High maternal ferritin and low transferrin saturation concentrations during early pregnancy were most consistently associated with an overall increased risk of child's upper, not lower, respiratory tract infections.

The influence of Epstein-Barr virus and cytomegalovirus on childhood respiratory health: A population-based prospective cohort study.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T-helper-1 and EBV infection a T-helper-2 cell response, possibly leading to disbalanced T-helper cell response, and subsequent risk of asthma or atopy. OBJECTIVE: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. METHODS: This study among 3546 children was embedded in a population-based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. RESULTS: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z-score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non-significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Associations of EBV and CMV infections in early childhood with school-age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle-related factors.

European Respiratory Society guideline on long-term management of children with bronchopulmonary dysplasia.

This document provides recommendations for monitoring and treatment of children in whom bronchopulmonary dysplasia (BPD) has been established and who have been discharged from the hospital, or who were >36 weeks of postmenstrual age. The guideline was based on predefined Population, Intervention, Comparison and Outcomes (PICO) questions relevant for clinical care, a systematic review of the literature and assessment of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. After considering the balance of desirable (benefits) and undesirable (burden, adverse effects) consequences of the intervention, the certainty of the evidence, and values, the task force made conditional recommendations for monitoring and treatment of BPD based on very low to low quality of evidence. We suggest monitoring with lung imaging using ionising radiation in a subgroup only, for example severe BPD or recurrent hospitalisations, and monitoring with lung function in all children. We suggest to give individual advice to parents regarding daycare attendance. With regards to treatment, we suggest the use of bronchodilators in a subgroup only, for example asthma-like symptoms, or reversibility in lung function; no treatment with inhaled or systemic corticosteroids; natural weaning of diuretics by the relative decrease in dose with increasing weight gain if diuretics are started in the neonatal period; and treatment with supplemental oxygen with a saturation target range of 90-95%. A multidisciplinary approach for children with established severe BPD after the neonatal period into adulthood is preferable. These recommendations should be considered until new and urgently needed evidence becomes available.

Associations of Th2, Th17, Treg cells, and IgA+ memory B cells with atopic disease in children: The Generation R Study.

BACKGROUND: New insights into immune cells could contribute to treatment and monitoring of atopic disease. Because nongenetic factors shape the human immune system, we here studied these immune cells in a large cohort with atopic children with adjustment for prenatal and postnatal confounders. METHODS: Information on atopic dermatitis, inhalant- and food-allergic sensitization, asthma lung function scores was obtained from 855 10-year-old children within the Generation R cohort. 11-color flow cytometry was performed to determine CD27+ and CD27- IgG+ , IgE+ and IgA+ memory B cells, Th1, Th2, Th17, and Treg-memory cells from venous blood. Associations between any atopic disease, the individual atopic diseases, and immune cell numbers were determined. RESULTS: Children with any atopic disease had higher Th2, Treg, Treg-memory, and CD27+ IgA+ memory B-cell numbers compared to children without atopic disease. When studying the individual diseases compared to children without the individual diseases, children with atopic dermatitis, inhalant-, and food-allergic sensitization had higher memory Treg cell numbers 12.3% (95% CI 4.2; 21.0), (11.1% (95% CI 3.0; 19.8), (23.7% (95% CI 7.9; 41.8), respectively. Children with food-allergic sensitization had higher total B and CD27+ IgA+ memory B-cell numbers (15.2% [95% CI 3.2; 28.7], 22.5% [95% CI 3.9; 44.3], respectively). No associations were observed between asthma and B- or T-cell numbers. CONCLUSION: Children with any atopic disease and children with inhalant- and food-allergic sensitization or atopic dermatitis had higher circulating memory Treg cells, but not higher IgE+ B-cell numbers. The associations of higher Treg and CD27+ IgA+ B-cell numbers in children with food-allergic sensitization are suggestive of TGF-ß-mediated compensation for chronic inflammation.