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Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was specifically funded by the BBSRC (BBI025751/1 and BB/I025263/1). GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. DCa is funded by the MRC (MC_UU_00011/1 and MC_UU_00011/5). GS is financially supported by the MRC [New Investigator Research Grant, MR/S009310/1] and the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, UK MRC MR/S036520/1]. AH is supported by the South-Eastern Norway Regional Health Authority (2020022) and the Research Council of Norway (274611 and 288083). The POSEIDON work was supported by the German Research Foundation [DFG; grant FOR2107; RI908/11-2 and WI3429/3-2], the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent, under the auspices of the e:Med Programme [01ZX1314G; 01ZX1614G] through grants 01EE1406C, 01EE1409C and through ERA-NET NEURON, “SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation” [01EW1810], through ERA-NET NEURON “Impact of Early life MetaBolic and psychosocial strEss on susceptibility to mental Disorders; from converging epigenetic signatures to novel targets for therapeutic intervention” [01EW1904] and by a grant of the Dietmar-Hopp Foundation. The general design of the Generation R Study is made possible by financial support from Erasmus Medical Center, Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw) and the Ministry of Health, Welfare and Sport. The EWAS data were funded by a grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA; project nr. 050-060-810), by funds from the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by a grant from the National Institute of Child and Human Development (R01HD068437). AN and HT are supported by a grant of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development). AN is also supported by a Canadian Institutes of Health Research team grant. The work of HT is further supported by a NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200). JFF has received funding from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, NutriPROGRAM project, ZonMw the Netherlands no. 529051022) and the European Union’s Horizon 2020 research and innovation programme (733206, LifeCycle; 633595, DynaHEALTH). The work of CAMC, JF and RM has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 848158 (EarlyCause Project). Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041, CP18/00018), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03-1615) Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). ISGlobal is a member of the CERCA Programme, Generalitat de Catalunya. SA is funded by a Juan de la Cierva—Incorporación Postdoctoral Contract awarded by Ministry of Economy, Industry and Competitiveness (IJCI-2017-34068). The Project Viva work was supported by the US National Institutes of Health grants R01 HD034568, UH3 OD023286 and R01 ES031259. The CHAMACOS project was supported by grants from the Environmental Protection Agency [R82670901 and RD83451301], the National Institute of Environmental Health Science (NIEHS) [P01 ES009605, R01ES021369, R01ES023067, R24ES028529, F31ES027751], the National Institute on Drug Abuse (NIDA) [R01DA035300], the National Institutes of Health (NIH) [UG3OD023356] and the National Institute of Mental Health (NIMH) [T32MH112510]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the EPA, NIEHS, or NIH. We thank all funding sources for the EDEN study (not allocated for the present study but for the cohort): Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris–Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programs (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (in collaboration with the French Association of Diabetic Patients (AFD), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale complementary health insurance (MGEN), French national agency for food security, French speaking association for the study of diabetes and metabolism (ALFEDIAM), grant # 2012/51290-6 Sao Paulo Research Foundation (FAPESP), EU funded MeDALL project. PREDO: The PREDO Study has been funded by the Academy of Finland (JL: 311617 and 269925, KR: 1312670 ja 128789 1287891), EraNet Neuron, EVO (a special state subsidy for health science research), University of Helsinki Research Funds, the Signe and Ane Gyllenberg foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Jane and Aatos Erkko Foundation, the Novo Nordisk Foundation, the Päivikki and Sakari Sohlberg Foundation, Juho Vainio foundation, Yrjö Jahnsson foundation, Jalmari and Rauha Ahokas foundation, Sigrid Juselius Foundation granted to members of the Predo study board. Methylation assays were funded by the Academy of Finland (269925). SJL is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.

SETTING: Indoor volatile organic compound (VOC) levels, which are generally correlated with each other, may have an additive or synergistic effect on health. VOC synergy with allergens is a suspected mechanism affecting respiration.OBJECTIVE: To determine the effect of exposure to interactions between VOCs and allergens on respiratory symptoms in individuals aged ≥15 years.DESIGN: A national cross‐sectional survey measured 20 VOCs and dog and cat aeroallergens in 490 main residential dwellings in France. A standardised questionnaire was used to elicit responses on respiratory conditions in 1012 inhabitants. Four VOC factor scores (linear combinations of VOCs) were generated using principal component analysis. In order to take into account the phenomenon of multi‐pollution, marginal models were used to model the relationships between exposure to VOC mixture and respiratory conditions. Stratified models were used to examine the interaction between allergens and VOCs.RESULTS: The aromatic hydrocarbon score was associated with rhinitis and wheezing, the aliphatic hydrocarbon score with asthma and cough, the halogenated hydrocarbons with asthma, wheezing and rhinitis. Aldehydes and Can f1 had a significant synergistic effect on wheezing and rhinitis. Aliphatic hydrocarbons had an antagonist effect with Can f1 on wheezing.CONCLUSION: Our data support evidence of adverse effects of exposure to VOC mixture on respiratory conditions; this effect is aggravated in the presence of pet allergens.

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels. Study-specific funding information can be found in the Supplementary Methods. JR, AH, EL, and SS were supported by the European Union’s Horizon 2020 research and innovation program [grant numbers 633595 (DynaHEALTH) and 733206 (LifeCycle)], Academy of Finland [grant number 285547 (EGEA)] and the Biocenter Oulu. ACJ was funded by the National Institute of Environmental Health Sciences [grant number R00ES023450]. AK was supported by the National Institute of Environmental Health Sciences [grant number R01ES021357]. DCa was funded by the UK Medical Research Council [grant number MC_UU_00011/7]. EKa received funding from the Horizon2020 grant for RECAP Research on Children and Adults Born Preterm [grant number 733280], Academy of Finland [grant number 315690], Foundation for Pediatric Research, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation and Sigrid Jusélius Foundation. EKe received funding from the Finnish Medical Association. MG was supported by Miguel Servet fellowship from the Institute of Health Carlos III [grant numbers MS13/00054, CP18/00018]. MVä received funding from the Research Funds of Oulu University Hospital, Juho Vainio Foundation and Signe and Ane Gyllenberg Foundation. RCH was supported by the National Health and Medical Research Council Fellowship Grants [grant number 1053384]. SJL was supported by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences. SM received funding from the University of Oulu Graduate School. SR was supported by National Health and Medical Research Council EU [grant number 1142858] and the Department of Health, Western Australia FutureHealth fund in connection with the European Union’s Horizon 2020 [grant number 733206].

Background: Allergic rhinitis (AR) is a major non-communicable disease that affects the health-related quality of life (HRQoL) of patients. AR is significantly related to asthma also affecting HRQoL. However, data on HRQoL and symptom control in AR patients with comorbid asthma are lacking. Objective: To assess the differences of symptom control and HRQoL in AR patients with and without comorbid asthma. Methods: In this multicentre, cross-sectional study, patients with AR were screened and administered questionnaires of demographic characteristics and health conditions (symptoms/diagnosis of AR and asthma, disease severity level, and allergic conditions). HRQoL was assessed using a modified version of the RHINASTHMA questionnaire and symptom control was evaluated by a modified version of the Control of Allergic Rhinitis/Asthma Test (CARAT). Results: Out of 643 patients with AR, 500 (78%) had asthma as a comorbidity, and 54% had moderate-severe intermittent AR, followed by moderate-severe persistent AR (34%). Patients with both AR and asthma had significantly higher RHINASTHMA scores than the patients with AR alone (e.g., median RHINASTHMA-total score 84 vs. 48.5, respectively). Conversely, CARAT scores were significantly lower in AR with comorbid asthma than in the patients with AR alone (median CARAT-total score 16.5 vs. 23, respectively). Upon stratifying asthma based on severity, AR patients with severe persistent asthma had worse HRQoL and control than AR patients with mild persistent asthma. Conclusions: Our observation of poorer HRQoL and symptoms control in AR patients with comorbid asthma supports the importance of a comprehensive approach for the management of AR in case of a comorbid allergic condition.

Evidence is cumulating on the adverse health effects of environmental exposures on health of the fetus and the childbearing mothers. Among mother's conditions, gestational diabetes mellitus has been considered rarely in spite of its importance for both mother and child. We determined the role of maternal exposure to lead (Pb), cadmium (Cd) and manganese (Mn) to gestational diabetes mellitus (GDM) on diagnosed GDM and impaired glucose tolerance (IGT) in diabetes-free mothers from the French EDEN mother-child cohort. 623 pregnant women without pre-existing diabetes were included in the study. GDM and IGT were diagnosed by a gynecologist during consultations after blood analysis. Pb, Cd and Mn were measured in second-trimester blood samples. Associations between ln-transformed concentrations of metals and GDM and IGT respectively were examined using multiple logistic regression analysis adjusted for potential confounders. The prevalences of GDM and IGT were 7.1% and 10.1% respectively. After adjustment for confounders, Cd was statistically related to having had a diagnosis of GDM or IGT (Adjusted Odds-Ratio (AOR): 1.61, 1.05-2.48), and Pb to GDM at borderline significance (AOR: 1.65, 0.82-3.34). Our findings add to the growing evidence supporting the role of maternal exposure to heavy toxic metals that persist longtime in the environment as a risk factor for GDM.

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Introduction: Heavy metal can affect the immune response and thus health. Birth cohort studies investigating the association between prenatal exposures to heavy metals and asthma and allergies diseases, however, are scarce. Aim: We investigated the relationship of maternal serum concentrations of lead (Pb), cadmium (Cd) and manganese to asthma and allergy in the child. Methods: Children from the French EDEN birth-cohort were followed-up with parental-standardized questionnaires administered yearly until the age of 5. Serum concentrations of lead (Pb), cadmium (Cd) and manganese (Mn) were assessed in maternal blood samples (n=706) collected during mid-pregnancy and in cord blood (n=658). Hazard ratios (HR) for the incidence of each health outcome at 5 years in relation to heavy metals were calculated using adjusted Cox models (sex, BMI, in utero and parental smoking, family allergy, education, center). Results: The incidence of asthma, allergic rhinitis, eczema and food allergy in our sample were: 27.2 [cases/person-years: 125/4,599], 38.7 [160/4,130], 95.1 [307/3,228] and 18.9 [80/4,224] per 1000, respectively. Elevated levels of Cd in cord blood were associated with a greater risk of asthma (HR [95% confidence interval] per 1 SD increase: 1.24[1.02-1.51]) and food allergy (1.44[1.13-1.83]), elevated levels of Mn in maternal serum were associated with eczema (1.14[1.04-1.26]), while cord blood Pb levels were inversely associated with allergic rhinitis (0.85[0.73-0.99]). Conclusions: Our results suggest that prenatal exposure to heavy metals may affect the development of asthma and allergic diseases in childhood.

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P − 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p

Although French farmers smoke less on average than individuals from the general population, they suffer more from COPD. Exposure to biological and chemical air pollutants in the farm may be the cause of these higher COPD rates. This study investigates the role of biocontaminants, including the relationship of exposure to volatile organic compounds (VOCs) and fine particulate matter (of diameter of 2.5 µm [PM2.5]) objectively measured in the farm settings (dwellings and workplaces) to serum cytokines involved in COPD, in a sample of 72 farmers from 50 farms in the Auvergne region, France. Mean concentrations of VOCs were highest inside the home, while levels of PM2.5 were highest in workplaces (stables and granaries). After adjusting for confounders, high exposure to PM2.5 was significantly associated with a decreased level of serum cytokines (among others, IL13: β: –0.94, CI: –1.5 to –0.2, P-value =0.004; IL8: β: –0.82, CI: –1.4 to –0.2, P-value =0.005) and high exposure to VOCs according to a VOC global score with a decreased IL13 level (β: –0.5, CI: –0.9 to –0.1, P-value =0.01). Moreover, respiratory symptoms and diseases, including COPD, were associated with a decreased level of serum cytokines significantly in the case of IL5. An alteration of immune response balance in terms of cytokine levels in relation to indoor chemical air pollution exposure may contribute to respiratory health impairment in farmers.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

Background Oral tolerance induction in early life is a promising approach for food allergy prevention. Its success requires the identification of factors necessary for its persistence. Objectives We aimed to assess in mice duration of allergy prevention by breastfeeding-induced oral tolerance and whether oral TGF-β supplementation after weaning would prolong it. Methods We quantified ovalbumin (OVA) and OVA specific immunoglobulins levels by ELISA in milk from the EDEN birth cohort. Since OVA specific Ig were found in all samples, we assessed whether OVA-immunized mice exposed to OVA during lactation could prevent allergic diarrhea in their 6 and 13-week-old progeny. In some experiments, a TGF-β enriched formula was given after weaning. Results At 6 weeks, only 13% and 34% of mice breastfed by OVA-exposed mothers exhibited diarrhea after 6 and 7 OVA challenges versus 44% and 72% in mice breastfed by naive mothers (p=0.02 and 0.01). Protection was associated with decreased levels of MMCP1 and OVA specific IgE (p

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. The BAMSE cohort was supported by The Swedish Research Council, The Swedish Heart-Lung Foundation, Freemason Child House Foundation in Stockholm, MeDALL (Mechanisms of the Development of ALLergy), a collaborative project conducted within the European Union (grant agreement No. 261357), Centre for Allergy Research, Stockholm County Council (ALF), Swedish foundation for strategic research (SSF, RBc08-0027, EpiGene project), the Strategic Research Programme (SFO) in Epidemiology at Karolinska Institutet, The Swedish Research Council Formas and the Swedish Environment Protection Agency.

International audience; The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.

The prevalence of asthma and allergies including atopy has increased during the past decades, particularly in westernized countries. The rapid rise in the prevalence of such diseases cannot be explained by genetic factors alone. Rapid urbanization and industrialization throughout the world have increased air pollution and population exposures, so that most epidemiologic studies are focusing on possible links between air pollution and respiratory diseases. Furthermore, a growing body of evidence shows that chemical air pollution may interact with airborne allergens enhancing the risk of atopic sensitization and exacerbation of symptoms in sensitized subjects. These phenomena are supported by current in vitro and animal studies showing that the combined exposure to air pollutants and allergens may have a synergistic or additive effect on asthma and allergies, although there is an insufficient evidence about this link at the population level. Further research is needed in order to elucidate the mechanisms by which pollutants and biological allergens induce damage in exposed subjects. The abatement of the main risk factors for asthma and allergic diseases may achieve huge health benefits. Thus, it is important to raise awareness of respiratory allergies as serious chronic diseases which place a heavy burden on patients and on society as a whole.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood. This work was partially supported by the Southern California Environmental Health Sciences Center (grant # P30ES007048) funded by the National Institute of Environmental Health Sciences [PI Gilliland]. Dr. Contreras was supported by a grant from the NIH T32ES013678. MEDALL and CHICOS Projects: The research leading to these results has received funding from the European Community’s Seventh Framework Program(Health–F2-grantagreements No. 261357 and 241604). Per cohort ABCD: Data of the Amsterdam Born Children and their Development cohort study used in this research was in part supported by funds from the Netherlands Organisation for Health Research and Development (ZonMw 40–00812-98–11010). The study sponsors had no role in study design, data analysis, interpretation of data, or writing of this report. BAMSE: We acknowledge all funding sources: The Swedish Research Council, The Swedish Heart and Lung Foundation, The Swedish Research Council for Working Life and Social Welfare, the Swedish Asthma and Allergy Association Research Foundation, The Swedish Research Council Formas, Stockholm County Council, and the European Commission’s Seventh Framework 29 Program Me DALL under grant agreement No.261357. We thank all the children and their parents for participating in the BAMSE cohort and the nurses and other staff members working in the BAMSE project. EDEN: We acknowledge all the funding sources for the EDEN study: Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A) and Human Nutrition National Research Programs, Paris–Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS),French National Institute for Health Education (INPES), the European Union FP7programmes (FP7/2007-2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale a complementary health insurance (MGEN),French national agency for food security, French speaking association for the study ofdiabetes and metabolism (ALFEDIAM).We acknowledge the commitment of the EDEN mother-child cohort study group: I.Annesi-Maesano, JY. Bernard, J. Botton, M.A. Charles, P. Dargent-Molina, B. de Lauzon-Guillain, P. Ducimetière, M. de Agostini, B. Foliguet, , A. Forhan, X. Fritel, A. Germa, V.Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroque†, N. Lelong, J. Lepeule, G.Magnin, L. Marchand, C. Nabet, F. Pierre, R. Slama, M.J. Saurel-Cubizolles, M.Schweitzer, O. Thiebaugeorges.The Generation R Study:The Generation R study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfareand Sport and the Ministry of Youth and Families. The project received funding from the European Union's Horizon 2020 research and innovation programme (LIFECYCLE project, grant agreement no 733206; 2016), the European Research Council (ERC-2014-CoG-648916) and from cofunded ERA-Net on Biomarkers for Nutrition and Health (ERAHDHL), Horizon 2020 (grant agreement no 696295; 2017), ZonMW The Netherlands (no529051014; 2017), Science Foundation Ireland (no SFI/16/ERA-HDHL/3360), and the European Union (ALPHABET project).The researchers are independent from the funders. The study sponsors had no role in study design, data analysis, interpretation of data, or writing of this report. INMA: Data used for this research was provided by the INMA-Environment and Childhood Project (www.proyectoinma.org). This study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041), Spanish Ministry of Health (FIS-PIO41436, PI06/0867, PI081151, and FIS-FEDER 03/1615, 04/1112,04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647), Generalitat de Catalunya-CIRIT 1999SGR00241, the Conselleria de Sanitat Generalitat Valenciana, Department of Health of the Basque Government (2005111093 and 2009111069), the ProvincialGovernment of Gipuzkoa (DFG06/004 and DFG08/001).KOALA: The collection of the data from the KOALA Birth Cohort Study used in this analysis was financially supported by Friesland Foods (now Friesland Campina),Netherlands Asthma Foundation (grant numbers 3.2.07.022 and 3.2.03.48), Netherlands Heart Foundation (grant number 2014 T037, the Netherlands Organization for Health Research and Development (Zon Mw Prevention Program number 1.210-00-090), Triodos Foundation, Phoenix Foundation, Raphaël Foundation, Iona Foundation, Foundation forthe Advancement of Heilpedagogie, all in the Netherlands. MAS:The MAS birth cohort was funded by grants from the German Federal Ministry ofEducation and Research (BMBF; reference numbers 07015633, 07 ALE 27, 01EE9405/5,01EE9406) and the German Research Foundation (DFG; reference number KE 1462/2-1).PIAMA: The PIAMA study has been funded by The Netherlands Organisation for Health Research and Development; The Netherlands Organisation for Scientific Research; The Netherlands Asthma fund; The Netherlands Ministry of Spatial Planning Housing, and the Environment; and The Netherlands Ministry of Health, Welfare and Sport. RHEA: The Rhea project was financially supported by European projects (EU FP6-003-Food-3-NewGeneris -Contract No16320, EU FP6 STREP Hiwate -Contract No36224,EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers Contract No226756, EU FP7-HEALTH-2009-single stage CHICOS Contract No241604, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU-FP7,Proposal No 264357 MeDALL, EU- FP7-HEALTH-2012 Proposal No 308333 HELIX),and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece:2011-2014; “Rhea Plus”: Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-2015).ROBBIC: Data of the Rome cohort was in part supported byfunds from the Italian Ministry of Health (Programma speciale ex art. 12, comma 2, lettera b) del D. Lgs. 502/92,2001, 2003). We thank all the fields workers and the families for their contribution to thestudy. SWS: We thank the members of the Southampton Women's Survey Study group and the many participants in the SWS for their contribution to the study. The Southampton Women’s Survey is supported by grants from the Medical Research Council, British Heart Foundation, Food Standards Agency, British Lung Foundation, Arthritis Research UK, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, and the European Union's Seventh Framework Programme (FP7/2007-2013), project Early Nutrition under grant agreement n°289346.

Background: Contradictory results exist regarding the importance of early-life exposure to phthalates for development of childhood eczema. Objectives: We evaluated the association between maternal urinary concentrations of phthalate metabolites between the 24th and 28th week of gestation and occurrence of eczema in their sons up to 5 y of age, according to allergic sensitization as assessed by total immunoglobulin E (IgE) in a subsample of individuals. Methods: Data on health outcomes and background factors were collected using five standardized annual questionnaires completed by parents at the children’s ages of 1–5 y, and their associations with phthalate metabolite urinary concentrations were assessed in 604 mother–son pairs with adjusted multiple logistic regression and Cox’s survival model. Several eczema phenotypes were considered. Atopic status was assessed at 5 y of age in 293 boys through total IgE assessment. Results: At 5 y of age, the prevalence of ever eczema was 30.4%. Metabolites of di-isobutyl phthalate (DiBP) and di-isononyl phthalate (DiNP) were positively associated with early-onset (0–24 mo of age) eczema (15.7%) and late-onset (24–60 mo of age) eczema (14.7%). Applying the Cox’s model showed a significant association of occurrence of eczema in the first 5 y of life with DiBP and DiNP metabolites. Among IgE-sensitized boys, metabolites of di-n-butyl phthalate (DBP) and DiBP were significantly associated with ever eczema {hazard ratio (HR)=1.67 [95% confidence interval (CI): 1.10, 2.54], p=0.01 and HR=1.87 (95% CI: 1.01, 3.48), p=0.04, respectively}. Conclusions: Occurrence of eczema in early childhood may be influenced by prenatal exposure to certain phthalates in boys. Further investigations are needed to confirm this observation. https://doi.org/10.1289/EHP1829

Background: Evidence on the effect of maternal complications in pregnancy on wheezing in offspring is still insufficient. Methods: A pooled analysis was performed on individual participant data from fourteen European birth cohorts to assess the relationship between several maternal pregnancy complications and wheezing symptoms in the offspring. Exposures of interest included hypertension and preeclampsia, diabetes, as well as pre-pregnancy overweight (body mass index between 25 and 29.9) and obesity (body mass index >= 30) compared with normal weight (body mass index between 18.5 and 24.9). Outcomes included both ever and recurrent wheezing from birth up to 12-24 months of age. Cohort-specific crude and adjusted risk ratios (RR) were calculated using log-binomial regression models and then pooled using a random effects model. Results: The study included 85 509 subjects. Cohort-specific prevalence of ever wheezing varied from 20.0% to 47.3%, and of recurrent wheezing from 3.0% to 14.3%. Adjusted pooled RR for ever and recurrent wheezing were: 1.02 (95% CI: 0.98-1.06) and 1.20 (95% CI: 0.98-1.47) for hypertensive disorders; 1.09 (95% CI: 1.01-1.18) and 1.23 (95% CI: 1.07-1.43) for preeclampsia; 1.04 (95% CI: 0.97-1.13) and 1.24 (95% CI: 0.86-1.79) for diabetes; 1.08 (95% CI: 1.05-1.11) and 1.19 (95% CI: 1.12-1.26) for overweight; 1.12 (95% CI: 1.08-1.17) and 1.16 (95% CI: 0.97-1.39) for obesity. No heterogeneity was found in RR estimates among the cohorts, except for diabetes and recurrent wheezing (P = 0.027). Conclusions: Preeclampsia, maternal pre-pregnancy overweight and obesity are associated with an increase risk of wheezing in the offspring.

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (

Backgroud Evidence about the relationship between prenatal maternal depression and the development of childhood asthma and allergies in early life is scarce. We aimed to examine this relationship by using data set of EDEN mother-child cohort study. A total of 1139 children were followed-up until the age of 5 years. Methods Prenatal maternal depression was self-reported by using the Centre for Epidemiological Studies-Depression scale (CES-D) questionnaire and was classified into binary variable (maternal depression [CES-D score of≥16] and no maternal depression [CES-D score of Results In our study population, 13.67 % of the mothers had clinical significant depression (the total scores for CES-D ≥16) during pregnancy. For children ages 5 years, the prevalence of wheezing, physician-diagnosed asthma, physician-diagnosed eczema and allergic rhinoconjunctivitis were 46.78, 20.99, 29.17, and 22.54%, respectively. Prenatal maternal depression was associated with ever allergic rhinoconjunctivitis (aOR 1.87 [95% confidence interval {CI}, 1.33–2.62]). No significant relationships were found between prenatal maternal depression and wheezing, physician-diagnosed asthma and physician-diagnosed eczema (aOR 1.12 [95% CI, 0.91–1.39], aOR 1.23 [95% CI, 0.81–1.85] and aOR 1.17 [95% CI, 0.86–1.61], respecitvely). Conclusion Prenatal maternal depression was related to ever allergic rhinoconjunctivitis in the first 5 years of life in children of EDEN mother-child cohort study.

Background Early-life respiratory tract infections could affect airway obstruction and increase the risk of asthma in later life. Objective We examined the associations of early-life respiratory tract infections with lung function and asthma in children. Methods We used individual participant data of 154,492 children from 37 birth cohorts to examine the associations of upper (URTI) and lower respiratory tract infections (LRTI) by the age of 6 months, 1, 2, 3, 4 and 5 years with forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC) FEV 1 /FVC, forced expiratory flow at 75% of FVC (FEF 75 ) and asthma at a mean age of 7 (SD 2) years. We used multilevel mixed effect models, to take clustering of participants within cohorts into account, and adjusted for socio-economic, lifestyle and growth factors. Results URTI were not associated with lung function. URTI at all ages were associated with an increased risk of asthma (OR (95% CI): ranging from 1.25 (1.15, 1.34) to 1.56 (1.47, 1.66)). LRTI at all ages were associated with a lower FEV 1 , FEV 1 /FVC and FEF 75 (Z-score (95% CI): ranging from -0.07 (-0.14, -0.00) to -0.24 (-0.38, -0.10)), except for LRTI at age 6 months with FEF 75 , and an increased risk of asthma (OR (95% CI): ranging from 2.00 (1.85, 2.10) to 3.72 (3.19, 3.85)). Conclusion Early-life lower respiratory tract infections are associated with lower lung function and increased risk of asthma in later life, while upper respiratory tract infections are associated with asthma only. These findings support the hypothesis that early-life respiratory tract infections might affect long term respiratory morbidity.

Background It is known that asthma is related to obesity but also to small birth weight. The objective of the present study was to clarify this issue by assessing the putative relationship between the change between birth and childhood in child's corpulence as assessed by body mass index (BMI) and asthma phenotypes. Methods The following status in corpulence were assessed in 7781 schoolchildren using quartile of BMI at birth and at around 10 (9-11years): underweight at birth and at around 10, underweight at birth and overweight at around 10, overweight at birth and underweight at around 10, overweight at birth and at around 10 and the reference group constituted by all the other children in whom corpulence changes were not extreme. Determination of asthma phenotypes (allergic, non-allergic and exercise-induced asthma) was based on a clinical examination including skin prick tests, an exercise challenge test and a questionnaire. Results The risk of allergic asthma was higher in children with persistent underweight, children with persistent overweight and children becoming markedly more corpulent. In boys, the risk of allergic asthma was significantly higher for the less corpulent children at birth, regardless of whether they remained so or become overweight. In girls, the risk of allergic asthma was significantly higher in those with persistent overweight. There were no significant associations between BMI changes and non-allergic and exercise-induced asthma. Conclusions We observed that some extreme changes in BMI, persistent underweight and persistent overweight in childhood increased the risk of allergic asthma.

Background Cow's milk allergy (CMA) is a frequent food allergy in young children. The oral food challenge is the gold standard for diagnosis, and there is currently no reliable biological test. Our aim was to evaluate the diagnostic potential of a functional assay quantifying allergen-specific Th2 cells in CMA children. Methods A total of 29 children aged 2.8–10.5 years underwent a double-blind, placebo-controlled food challenge (DBPCFC) to cow's milk. Blood was collected before performing the DBPCFC, and peripheral mononuclear cells were cultured in an 18-h ELISpot assay with casein, α-lactalbumin, or β-lactoglobulin. Numbers of antigen-specific IL-4- and IL-13-secreting lymphocytes and serum-specific IgE, IgG4, and total IgE levels were assessed. Receiver operating characteristic (ROC) curves were generated. Results A total of 17 (59%) children reacted to cow's milk and were therefore considered as allergic to cow's milk (CMA). The mean number of casein-specific IL-4- and IL-13-secreting T cells was higher in CMA than in non-CMA children (P = 0.009, 0.004, respectively). Moreover, it was inversely correlated with the cumulative dose of cow's milk tolerated (P = 0.003, 0.0009, respectively). ROC curve of combined IL-4 and IL-13 analysis showed an area under the curve of 0.98 (95% CI 0.90–1.06). For a cutoff of 10 IL-4- and 12 IL-13-secreting T cells, sensitivity and negative predictive value were 100%. Conclusions Enumeration of casein-specific IL-4- and IL-13-secreting T cells appears a promising tool to improve diagnosis and, if confirmed in larger studies, could permit less frequent use of the oral food challenge.

We investigated the relationships of behavioural problems as assessed using the standardized Strengths and Difficulties Questionnaire (SDQ) to asthma in view of improving asthma management. Six thousand eight hundred and eighty children (mean age 10.4 years, male: 49%) were recruited in the French 6 Cities Study. Children with abnormal or borderline emotional symptoms (internalizing problems) or conduct problems (externalizing problems) were more asthmatic than others (P < 0.01). Compared to being normal, abnormal emotional symptoms or conduct problems were found to be related to mild-to-moderate persistent asthma (logistic model adjusted odds ratio = 1.55 (95% CI = 1.26-1.90) and 1.42 (95% CI = 1.17-1.71), respectively) and to early-onset asthma (Cox's model Adjusted Hazard Risk = 1.60 (95% CI = 1.27-2.01) and 1.34 (95% CI = 1.05-1.70). Borderline conduct problems were found to be negatively related to parents' knowledge on how to prevent asthma attacks, compared to normal conduct problems [adjusted OR = 0.51 (95% CI = 0.31-0.85)]. Further data are needed to better understand the involvement of behavioural problems in childhood asthma according to phenotypes.

Objectives To describe the severity of asthma in schoolchildren in six cities in France in order to evaluate asthma management, observance and therapeutic education of both parents and children. Participants and methods Nine thousand six hundred and forty one schoolchildren in 401 CM1 and CM2 classrooms in 108 randomly selected primary schools participated in a multicentre epidemiological cross-sectional survey in six French cities (the 6C study). A standardized questionnaire provided information on: (1) symptoms and severity of their asthma; (2) control and management of the asthma by parents and children. Results Nine hundred and three children out of the 9641 participants were asthmatics. Of these asthmatic children, 22.3% had had no previous medical diagnosis of asthma. Among the asthmatic children, 77.3% suffered from intermittent asthma, 9.9% from mild persistent asthma and 12.8% from moderate persistent asthma. The asthmatic children were being followed mainly by pediatricians or general practitioners. Nearly a third (30%) of the parents knew how to prevent an asthma attack and more than half said that they knew how to use asthma medication in the event of severe attacks. Few parents knew the cause of the attacks. Peak flow-meters were rarely used. The positive effects of physical exercise were poorly known, especially by parents whose children suffered from mild asthma. Conclusion Guidelines for asthma control and management in France can be improved. The parents of children with mild or un-diagnosed asthma should be targeted. Guidelines for treatment and care must be adapted to the culture, the socioeconomic context and to the family's level of knowledge (or ignorance) of the disease.

Evidence on the association between mode of delivery and asthma at school age is inconclusive. We assessed the associations between specific modes of delivery and asthma in children from 9 European birth cohorts that enrolled participants between 1996 and 2006. Cohort-specific crude and adjusted risk ratios for asthma at ages 5–9 years were calculated using Poisson regression models and pooled. A sensitivity analysis was carried out in children born at term to reduce confounding due to perinatal factors. The study included 67,613 participants. Cohortspecific rates of cesarean delivery varied from 9.4% to 37.5%. Cesarean delivery, as opposed to vaginal delivery, was associated with an increased risk of asthma (adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.02, 1.46). Compared with spontaneous vaginal delivery, the adjusted risk ratio was 1.33 (95% CI: 1.02, 1.75) for elective cesarean delivery, 1.07 (95% CI: 0.94, 1.22) for emergency cesarean delivery, and 0.97 (95% CI: 0.84, 1.12) for operative vaginal delivery. In children born at term, the associations were strengthened only for elective cesarean delivery (aRR = 1.49, 95% CI: 1.13, 1.97). The large sample size allowed analysis of the associations between specific modes of delivery and asthma at school age. The increased risk of asthma associated with elective cesarean delivery, especially among children born at term, is relevant in counteracting the increasing use of this procedure, which is often performed without a clear medical indication. This work was supported by the European Community’s Seventh Framework Programme (FP7/2009–2013) under a grant agreement (grant 241604) and by the University of Turin and the San Paolo Foundation (Turin, Italy). Data collection was funded and the study teams of all participating birth cohorts were supported by local and/or national research organizations.

Background. The rate of cesarean section has continued to increase both in low-, middle-, and high-income countries largely exceeding the recommendations of World Health Organization. At least in high income countries, the increased rate is mainly due to a rise in elective caesarean, often without medical indication. Evidence on the association of modes of delivery with asthma at school age is inconclusive. We assessed the association between specific modes of delivery and asthma in children of nine prospective European birth cohorts. Methods. Cohort-specific crude and adjusted Risk Ratios (aRR) for asthma at 5-9 years were calculated using Poisson regression models and pooled. A sensitivity analysis in children born at term was carried out to reduce confounding due to perinatal factors. Results. The study included 67,613 participants. Cohort-specific rates of cesarean varied from 9.4% to 37.5%. Current asthma varied from 3.3% to 11.3%. Cesarean section, as opposed to vaginal delivery, was associated with an increased risk of asthma (aRR, 1.22; 95% CI: 1.02,1.46). Compared to spontaneous vaginal delivery, the aRR was 1.33 (95% CI: 1.02,1.75) for elective caesarean, 1.07 (95% CI: 0.94,1.22) for emergency cesarean, and 0.97 (95% CI: 0.84,1.12) for operative vaginal delivery. In children born at term, the effect estimates strengthened only for elective cesarean (aRR, 1.49; 95% CI: 1.13,1.97). Conclusions. The large sample size allowed analysis of the effect of specific modes of delivery. The increased risk of asthma associated with elective caesarean, especially in children born at term where confounding is less likely, is relevant to counteract this practice. Causal underlying mechanisms need to be explored.

Background: Preterm birth is strongly associated with increased risk of respiratory morbidity from birth until adulthood. Perinatal factors have been associated with epigenetic changes in children, and our aim was to investigate the association between gestational age (GA) and DNA methylation patterns in newborns. In addition, expression patterns of identified genes during lung development were explored. Methods: We performed an epigenome-wide analysis of DNA methylation using the Illumina 450K platform. DNA methylation was measured in cord blood of 340 newborn babies (GA 31-42 weeks) from the Mechanisms of the Development of Allergy (MeDALL) study (French EDEN and Spanish INMA cohorts). RNA expression patterns in the developing human lung during the pseudoglandular (GA 7-16 weeks) and canalicular (17-26 weeks) stages of development (GEO accession number GSE14334) were investigated. Results: In total, 202 CpG sites corresponding to 130 genes associated with GA at the genome-wide significant level (p < 1.1 x 10 -07). Sixty of the 130 identified genes were differentially expressed during human lung development (FDR p < 0.05). The greatest magnitude of effect was observed for HLA-E, YPEL3 and MAN1C1 with increased expression pattern and FKBP5 and CDK6 with decreased expression pattern across developmental stages. Conclusions: We identified 130 differentially methylated genes associated with gestational age at birth; 60 of which were differentially expressed during human lung development. We believe that our epigenetic and fetal lung transcriptomic analyses may provide important insights about mechanisms related to negative long-term respiratory health outcomes of preterm birth.

Introduction: Phthalate are endocrine disrupters widely used in our daily life (wrapping foods, cosmetics, toys, medical devices, polyvinyl chloride flooring, and building materials). Prenatal peri...

Compared to the rest of the population, the elderly are potentially highly susceptible to the effects of outdoor air pollution due to normal and pathological ageing. The purpose of the present review was to gather data on the effects on respiratory health of outdoor air pollution in the elderly, on whom data are scarce. These show statistically significant short-term and chronic adverse effects of various outdoor air pollutants on cardiopulmonary morbidity and mortality in the elderly. When exposed to air pollution, the elderly experience more hospital admissions for asthma and chronic obstructive pulmonary disease (COPD) and higher COPD mortality than others. Previous studies also indicate that research on the health effects of air pollution in the elderly has been affected by methodological problems in terms of exposure and health effect assessments. Few pollutants have been considered, and exposure assessment has been based mostly on background air pollution and more rarely on objective measurements and modelling. Significant progress needs to be made through the development of 'hybrid' models utilising the strengths of information on exposure in various environments to several air pollutants, coupled with daily activity exposure patterns. Investigations of chronic effects of air pollution and of multi-pollutant mixtures are needed to better understand the role of air pollution in the elderly. Lastly, smoking, occupation, comorbidities, treatment and the neighbourhood context should be considered as confounders or modifiers of such a role. In this context, the underlying biological, physiological and toxicological mechanisms need to be explored to better understand the phenomenon through a multidisciplinary approach.

Asthma is a phenotypically heterogeneous disorder of multifactorial origins that affects 300 million people suffering from asthma and more than 250,000 asthma-related deaths each year. Although treatment for asthma has improved, its prevalence continues to increase, particularly in low and middle income countries, or in some ethnic groups in which prevalence was previously low. Observed spatio-temporal variations in the increased prevalence of asthma depend on exposure to environmental factors. Recently, several arguments are also in favor of the involvement of host susceptibility and stress in the observed increase of asthma prevalence. Further investigations are warranted to better understand mechanisms underlying asthma increase or stagnation.

International audience; Objective:The purpose of this study was to examine the association between pre and post environmental tobacco smoke (ETS) exposure and behavioral problems in schoolchildren.Methods:In the cross-sectional 6 cities Study conducted in France, 5221 primary school children were investigated. Pre- and postnatal exposure to secondhand tobacco smoke at home was assessed using a parent questionnaire. Child’s behavioral outcomes (emotional symptoms and conduct problems) were evaluated by the Strengths and Difficulties Questionnaire (SDQ) completed by the parents.Results:ETS exposure during the postnatal period and during both pre- and postnatal periods was associated with behavioral problems in children. Abnormal emotional symptoms (internalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.72 (95% Confidence Interval (CI)= 1.36-2.17), whereas the OR was estimated to be 1.38 (95% CI= 1.12-1.69) in the case of postnatal exposure only. Abnormal conduct problems (externalizing problems) were related to ETS exposure in children who were exposed during the pre- and postnatal periods with an OR of 1.94 (95% CI= 1.51-2.50), whereas the OR was estimated to be 1.47 (95% CI=1.17-1.84) in the case of postnatal exposure only. Effect estimates were adjusted for gender, study center, ethnic origin, child age, low parental education, current physician diagnosed asthma, siblings, preterm birth and single parenthood.Conclusion:Postnatal ETS exposure, alone or in association with prenatal exposure, increases the risk of behavioral problems in school-age children.

The advent of the exposome concept, the advancement of mobile technology, sensors, and the “internet of things” bring exciting opportunities to exposure science. Smartphone apps, wireless devices, the downsizing of monitoring technologies, along with lower costs for such equipment makes it possible for various aspects of exposure to be measured more easily and frequently. We discuss possibilities and lay out several criteria for using smart technologies for external exposome studies. Smart technologies are evolving quickly, and while they provide great promise for advancing exposure science, many are still in developmental stages and their use in epidemiology and risk studies must be carefully considered. The most useable technologies for exposure studies at this time relate to gathering exposure-factor data, such as location and activities. Development of some environmental sensors (e.g., for some air pollutants, noise, UV) is moving towards making the use of these more reliable and accessible to research studies. The possibility of accessing such an unprecedented amount of personal data also comes with various limitations and challenges, which are discussed. The advantage of improving the collection of long term exposure factor data is that this can be combined with more “traditional” measurement data to model exposures to numerous environmental factors. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.

BACKGROUND: There is increasing evidence of the effect of maternal vitamin D intake during pregnancy on the risk of asthma and allergic outcomes in offspring. However, studies on the relationship between cord levels of 25-hydroxyvitamin D (25[OH]D) and asthma and allergic diseases are very few. OBJECTIVE: Our aim was to investigate the associations between cord serum 25(OH)D levels and asthma, wheezing, allergic rhinitis, and atopic dermatitis in the offspring from birth to 5 years. METHODS: Cord blood samples were collected at birth and analyzed for 25(OH)D levels in 239 newborns from the Etude des Determinants pre et post natals du developpement et de la sante de l'Enfant (EDEN) birth cohort. The children were followed up until age 5 years by using International Study of Asthma and Allergies in Childhood-based symptom questionnaires. RESULTS: The median cord serum level of 25(OH)D was 17.8 ng/mL (interquartile range, 15.1 ng/mL). By using multivariable-adjusted logistic regression models, a significant inverse association was observed between cord serum 25(OH)D levels and risk of transient early wheezing and early- and late-onset atopic dermatitis, as well as atopic dermatitis, by the ages of 1, 2, 3, and 5 years. We found no association between cord serum 25(OH)D levels and asthma and allergic rhinitis at age 5 years. CONCLUSIONS: Cord serum 25(OH)D levels were inversely associated with the risk of transient early wheezing and atopic dermatitis by the age of 5 years, but no association was found with asthma and allergic rhinitis.

Background Exercise-induced bronchospasm (EIB) is frequent among asthmatic children. However, opinions differ on the relation between EIB and rhinitis in the absence of asthma. Objectives We assessed the relationship between EIB and various phenotypes of rhinitis according to asthmatic status at the general population level in the Six Cities Study. Methods Of 7781 schoolchildren with a mean age of 10 years underwent an EIB test and skin prick test to assess allergic sensitization. Their parents completed a standardized questionnaire recording asthma-like symptoms and past-year rhinoconjunctivitis, ever hay fever (EHF), and a score for allergic rhinitis (SFAR) ≥7 as a marker of 'past-year allergic rhinitis'. Exercise-induced bronchospasm was defined as a fall in peak expiratory flow rate ≥15% after exercise. Results Of the 6813 schoolchildren retained for analysis, 227 (3.33%) experienced EIB after exercise. Odds ratios [95% confidence intervals] between EIB and allergic rhinitis phenotypes in the absence of asthma were 1.56 [0.92-2.63] for EHF, 1.97 [1.16-3.35] for past-year rhinoconjunctivitis, and 1.84 [1.16-2.91] for a SFAR ≥7. Results were unchanged after adjustment for confounders. Multiple correspondence analysis showed that EIB, although related to asthma, constitutes a separate entity. Exercise-induced bronchospasm was not significantly related to familial history of asthma. Conclusion In our large population-based sample of children, different phenotypes of atopic rhinitis were associated with EIB, independently of asthma. Exercise-induced bronchospasm, although related to asthma, seems to constitute a separate entity. Clinical relevance In this large (6813) sample of 10-year children drawn from the general population, EIB is associated with rhinitis phenotypes in the absence of asthma. Furthermore, it constitutes an entity independent from asthma and is not related to a familial history of asthma. Thus, investigating these symptoms could be important in this disease, as a specific nasal treatment might improve EIB in these children.

Benzene is a ubiquitous pollutant of both indoor and outdoor environments which impacts on respiratory health. Our aim was to relate urinary S-phenylmercapturic acid (S-PMA), a biomarker of benzene exposure, to benzene concentrations and related sources at home and asthma in a population-based sample of children.Exposure to benzene was assessed in the dwellings of 63 children (32 asthmatics and 31 controls) through the identification of sources of benzene and in situ assessments with passive samplers. The determination of urinary S-PMA was obtained by liquid chromatography-mass spectrometry.At home, asthmatics were significantly more polluted by benzene levels from ambient sampling than controls (p ≤ 0.05). Benzene exposure significantly aggravated asthma symptoms overall in non-atopic children (OR = 10.10; 95% confidence interval: 10.10). Urinary S-PMA was significantly associated with benzene concentrations in the entire population (regression coefficient = 0.28, 95% CI: 0.07-0.49; p0.05) and asthma (OR = 7.69; 95% CI: 1.37-42.52 for an increase of 1 µg/g creatinine of urinary S-PMA). However, after adjustment for environmental tobacco smoking exposure, familial allergy, age and sex, the latter relationship was no more significant (OR = 4.95; 95% CI: 0.91-27.4, p0.10). Both benzene concentrations and urinary S-PMA concentrations were higher in dwelling built after 1948 and in flats.Our study suggests a relationship between childhood asthma and benzene concentrations at home, even at low levels of this pollutant. This was confirmed when considering urinary S-PMA, which was related to both benzene concentrations and asthma. Further epidemiological and toxicological studies are needed to confirm our results.

Summary The purpose of this study was to explore respiratory health effects of indoor exposures to aldehydes and volatile organic compounds (VOCs) in elderly living in a population-based representative sample of French dwellings and to compare them to the rest of the occupants of the dwellings. Twenty VOCs were objectively measured in 490 main dwellings. The respiratory conditions were assessed through a standardized questionnaire in 1012 inhabitants aged over 15 years, 144 of whom were aged over 65 years. Generalized estimating equations (GEE) were used to model the relationship between respiratory health outcomes and air pollutants concentrations using the median value of the distribution to define elevated exposure. Similar levels of indoor air pollutants were found in elderly and others. However, associations between breathlessness and living in dwellings with elevated concentrations of toluene and o -xylene respectively were statistically significant in elderly but not in the rest of the population (adjusted odds ratios (AOR(95% confidence interval) = 3.36(1.13, 9.98) and 2.85(1.06, 7.68) in elderly vs. 0.91(0.59, 1.39) and 0.79 ( 0.47, 1.34 ) in the others respectively). A more pronounced effect of n-decane on past year breathlessness was observed in case of poor ventilation in the dwellings. Our results showed a higher risk of breathlessness in elderly exposed to indoor air pollution than in the rest of the exposed population. Further investigations are needed to confirm whether this is related to frailty in elderly.

Vitamin D deficiency has been implicated in the increased risk of several diseases. Exposure to air pollution has been suggested as a contributor to vitamin D deficiency. However, studies that have examined the effects of air pollution on vitamin D status are few and have never focused on prenatal life as an exposure window.Our aim was to investigate the associations between gestational exposure to urban air pollutants and 25-hydroxyvitamin D [25(OH)D] cord blood serum level in 375 mother-child pairs of the EDEN birth cohort.The Atmospheric Dispersion Modelling System (ADMS-Urban) pollution model, a validated dispersion model combining data on traffic conditions, topography, meteorology, and background pollution, was used to assess the concentrations of two major urban pollutants, particulate matter less than 10 μm in diameter (PM(10)) and nitrogen dioxide (NO(2)), at the mother's home address during pregnancy. Cord blood samples were collected at birth and were analyzed for levels of 25(OH)D.Maternal exposure to ambient urban levels of NO(2) and PM(10) during the whole pregnancy was a strong predictor of low vitamin D status in newborns. After adjustment, log-transformed 25(OH)D decreased by 0.15 U (P = 0.05) and 0.41 U (P = 0.04) for a 10-μg/m(3) increase in NO(2) and PM(10) pregnancy levels, respectively. The association was strongest for third-trimester exposures (P = 0.0003 and P = 0.004 for NO(2) and PM(10), respectively).Gestational exposure to ambient urban air pollution, especially during late pregnancy, may contribute to lower vitamin D levels in offspring. This could affect the child's risk of developing diseases later in life.