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Purpose: The Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) cohort was established to (1) investigate how exposures before conception and in previous generations influence health and disease, particularly allergies and respiratory health, (2) identify susceptible time windows and (3) explore underlying mechanisms. The ultimate aim is to facilitate efficient intervention strategies targeting multiple generations., Participants: RHINESSA includes study participants of multiple generations from ten study centres in Norway (1), Denmark (1), Sweden (3), Iceland (1), Estonia (1), Spain (2) and Australia (1). The RHINESSA core cohort, adult offspring generation 3 (G3), was first investigated in 2014-17 in a questionnaire study (N=8818, age 18-53 years) and a clinical study (subsample, n=1405). Their G2 parents participated in the population-based cohorts, European Community Respiratory Heath Survey and Respiratory Health In Northern Europe, followed since the early 1990s when they were 20-44 years old, at 8-10 years intervals. Study protocols are harmonised across generations., Findings to Date: Collected data include spirometry, skin prick tests, exhaled nitric oxide, anthropometrics, bioimpedance, blood pressure; questionnaire/interview data on respiratory/general/reproductive health, indoor/outdoor environment, smoking, occupation, general characteristics and lifestyle; biobanked blood, urine, gingival fluid, skin swabs; measured specific and total IgE, DNA methylation, sex hormones and oral microbiome. Research results suggest that parental environment years before conception, in particular, father's exposures such as smoking and overweight, may be of key importance for asthma and lung function, and that there is an important susceptibility window in male prepuberty. Statistical analyses developed to approach causal inference suggest that these associations may be causal. DNA methylation studies suggest a mechanism for transfer of father's exposures to offspring health and disease through impact on offspring DNA methylation., Future Plans: Follow-up is planned at 5-8 years intervals, first in 2021-2023. Linkage with health registries contributes to follow-up of the cohort., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Asthma is a complex, heterogeneous disease and one of the most common chronic diseases among children. Exposure to ambient air pollution in early life and childhood may influence asthma aetiology, but it is uncertain which specific components of air pollution and exposure windows are of importance. The role of socio-economic status (SES) is also unclear. The aims of the present study are, therefore, to investigate how various exposure windows of different pollutants affect risk-induced asthma in early life and to explore the possible effect SES has on that relationship., Methods: The study population was constructed using register data on all singleton births in the greater Stockholm area between 2006 and 2013. Exposure to ambient black carbon (BC), fine particulate matter (PM 2.5 ), primary organic carbon (pOC) secondary organic aerosols (SOA), secondary inorganic aerosols, and oxidative potential at the residential address was modelled as mean values for the entire pregnancy period, the first year of life and the first three years of life. Swedish national registers were used to define the outcome: asthma diagnosis assessed at hospital during the first six years of life. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were modelled with Cox proportional hazards model with age as the underlying time-scale, adjusting for relevant potential confounding variables., Results: An increased risk for developing childhood asthma was observed in association with exposure to PM 2.5 , pOC and SOA during the first three years of life. With an interquartile range increase in exposure, the HRs were 1.06 (95% CI: 1.01-1.10), 1.05 (95% CI: 1.02-1.09) and 1.02 (95% CI: 1.00-1.04), for PM 2.5 , pOC and SOA, respectively, in the fully adjusted models. Exposure during foetal life or the first year of life was not associated with asthma risk, and the other pollutants were not statistically significantly associated with increased risk. Furthermore, the increase in risk associated with PM 2.5 and the components BC, pOC and SOA were stronger in areas with lower SES., Conclusion: Our results suggest that exposure to air pollution during the first three years of life may increase the risk for asthma in early childhood. The findings further imply a possible increased vulnerability to air pollution-attributed asthma among low SES children., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: While direct effects of occupational exposures on an individual's respiratory health are evident, a new paradigm is emerging on the possible effects of pre-conception occupational exposure on respiratory health in offspring. We aimed to study the association between parental occupational exposure starting before conception and asthma in their offspring (at 0-15 years of age)., Methods: We studied 3985 offspring participating in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Their mothers or fathers (n = 2931) previously participated in the European Community Respiratory Health Survey (ECRHS). Information was obtained from questionnaires on parental job history pre- and post-conception which was linked to an asthma-specific job-exposure matrix (JEM). We assessed the association between parental occupational exposure and offspring asthma, applying logistic regression models, clustered by family and adjusted for study centre, offspring sex, parental characteristics (age, asthma onset, place of upbringing, smoking) and grandparents' level of education., Results: Parental occupational exposure to microorganisms, pesticides, allergens or reactive chemicals pre-conception or both pre- and post-conception was not related to offspring asthma; in general, subgroup analyses confirmed this result. However, maternal exposure both pre- and post-conception to allergens and reactive chemicals was associated with increased odds for early-onset asthma in offspring (0-3 years of age); odds ratio 1.70 (95% CI: 1.02-2.84) and 1.65 (95% CI: 0.98-2.77), respectively., Conclusions: This study did not find evidence that parental occupational exposure, defined by an asthma JEM before conception only or during pre- and post-conception vs non-exposed, was associated with offspring asthma., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: A farm upbringing has been associated with lower risk of asthma and methylation of asthma-related genes. As such, a farm upbringing has the potential to transfer asthma risk across generations, but this has never been investigated. We aimed to study the generational effects from a parental farm upbringing on offspring asthma., Methods: Our study involved three generations: 5759 participants from the European Community Respiratory Health Survey (ECRHS) study (born 1945-1971, denoted G1), their 9991 parents (G0) and their 8260 offspring (G2) participating in RHINESSA (Respiratory Health In Northern Europe, Spain and Australia). Questionnaire data were collected on G0 and G1 from G1 in 2010 and on G2 from themselves in 2013. The parental/grandparental place of upbringing was categorized: (i) both parents from farm; (ii) mother from farm, father from village/city; (iii) father from farm, mother from village/city; (iv) both parents from village or one parent from village and one from city; (v) both parents from city (reference group). Grandparental upbringing was equivalently categorized. Offspring asthma was self-reported and data were analysed using Cox-regression models with G2 age as the time scale., Results: A parental farm upbringing was not associated with offspring asthma when compared with city upbringing [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.74-1.69]. Findings remained similar when stratified by offspring upbringing and asthma phenotypes. Quantitative bias analyses showed similar estimates for alternative data sources. A grandparental farm upbringing was not associated with offspring asthma in either the maternal (HR 1.05, 95% CI 0.67-1.65) or paternal line (HR 1.02, 95% CI 0.62-1.68)., Conclusions: This multigenerational analysis suggests no evidence of an association between parental/grandparental farm upbringing and offspring asthma., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objectives: To investigate if air pollution and greenness exposure from birth till adulthood affects adult asthma, rhinitis and lung function., Methods: We analysed data from 3428 participants (mean age 28) in the RHINESSA study in Norway and Sweden. Individual mean annual residential exposures to nitrogen dioxide (NO 2 ), particulate matter (PM 10 and PM 2.5 ), black carbon (BC), ozone (O 3 ) and greenness (normalized difference vegetation index (NDVI)) were averaged across susceptibility windows (0-10 years, 10-18 years, lifetime, adulthood (year before study participation)) and analysed in relation to physician diagnosed asthma (ever/allergic/non-allergic), asthma attack last 12 months, current rhinitis and low lung function (lower limit of normal (LLN), z-scores of forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC below 1.64). We performed logistic regression for asthma attack, rhinitis and LLN lung function (clustered with family and study centre), and conditional logistic regression with a matched case-control design for ever/allergic/non-allergic asthma. Multivariable models were adjusted for parental asthma and education., Results: Childhood, adolescence and adult exposure to NO 2 , PM 10 and O 3 were associated with an increased risk of asthma attacks (ORs between 1.29 and 2.25), but not with physician diagnosed asthma. For rhinitis, adulthood exposures seemed to be most important. Childhood and adolescence exposures to PM 2.5 and O 3 were associated with lower lung function, in particular FEV 1 (range ORs 2.65 to 4.21). No associations between NDVI and asthma or rhinitis were revealed, but increased NDVI was associated with lower FEV 1 and FVC in all susceptibility windows (range ORs 1.39 to 1.74)., Conclusions: Air pollution exposures in childhood, adolescence and adulthood were associated with increased risk of asthma attacks, rhinitis and low lung function in adulthood. Greenness was not associated with asthma or rhinitis, but was a risk factor for low lung function., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We investigated if greenness and air pollution exposure in parents' childhood affect offspring asthma and hay fever, and if effects were mediated through parental asthma, pregnancy greenness/pollution exposure, and offspring exposure. We analysed 1106 parents with 1949 offspring (mean age 35 and 6) from the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Mean particulate matter (PM 2.5 and PM 10 ), nitrogen dioxide (NO 2 ), black carbon (BC), ozone (O 3 ) (µg/m 3 ) and greenness (normalized difference vegetation index (NDVI)) were calculated for parents 0-18 years old and offspring 0-10 years old, and were categorised in tertiles. We performed logistic regression and mediation analyses for two-pollutant models (clustered by family and centre, stratified by parental lines, and adjusted for grandparental asthma and education). Maternal medium PM 2.5 and PM 10 exposure was associated with higher offspring asthma risk (odds ratio (OR) 2.23, 95%CI 1.32-3.78, OR 2.27, 95%CI 1.36-3.80), and paternal high BC exposure with lower asthma risk (OR 0.31, 95%CI 0.11-0.87). Hay fever risk increased for offspring of fathers with medium O 3 exposure (OR 4.15, 95%CI 1.28-13.50) and mothers with high PM 10 exposure (OR 2.66, 95%CI 1.19-5.91). The effect of maternal PM 10 exposure on offspring asthma was direct, while for hay fever, it was mediated through exposures in pregnancy and offspring's own exposures. Paternal O 3 exposure had a direct effect on offspring hay fever. To conclude, parental exposure to air pollution appears to influence the risk of asthma and allergies in future offspring.

Background: Overweight status and asthma have increased during the last decades. Being overweight is a known risk factor for asthma, but it is not known whether it might also increase asthma risk in the next generation., Objective: We aimed to examine whether parents being overweight in childhood, adolescence, or adulthood is associated with asthma in their offspring., Methods: We included 6347 adult offspring (age, 18-52 years) investigated in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) multigeneration study of 2044 fathers and 2549 mothers (age, 37-66 years) investigated in the European Community Respiratory Health Survey (ECRHS) study. Associations of parental overweight status at age 8 years, puberty, and age 30 years with offspring's childhood overweight status (potential mediator) and offspring's asthma with or without nasal allergies (outcomes) was analyzed by using 2-level logistic regression and 2-level multinomial logistic regression, respectively. Counterfactual-based mediation analysis was performed to establish whether observed associations were direct or indirect effects mediated through the offspring's own overweight status., Results: We found statistically significant associations between both fathers' and mothers' childhood overweight status and offspring's childhood overweight status (odds ratio, 2.23 [95% CI, 1.45-3.42] and 2.45 [95% CI, 1.86-3.22], respectively). We also found a statistically significant effect of fathers' onset of being overweight in puberty on offspring's asthma without nasal allergies (relative risk ratio, 2.31 [95% CI, 1.23-4.33]). This effect was direct and not mediated through the offspring's own overweight status. No effect on offspring's asthma with nasal allergies was found., Conclusion: Our findings suggest that metabolic factors long before conception can increase asthma risk and that male puberty is a time window of particular importance for offspring's health., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Individuals raised on a farm appear to have less asthma than individual raised elsewhere. However, selective migration might contribute to this as may also the suggested protection from farm environment. This study investigated if parents with asthma are less likely to raise their children on a farm. This study involved three generations: 6045 participants in ECRHS/RHINE cohorts (born 1945-1973, denoted G1), their 10,121 parents (denoted G0) and their 8260 offspring participating in RHINESSA (born 1963-1998, denoted G2). G2-offspring provided information on parents not participating in ECRHS/RHINE. Asthma status and place of upbringing for all three generations were reported in questionnaires by G1 in 2010-2012 and by G2 in 2013-2016. Binary regressions with farm upbringing as outcome were performed to explore associations between parental asthma and offspring farm upbringing in G0-G1 and G1-G2. Having at least one parent with asthma was not associated with offspring farm upbringing, either in G1-G2 (RR 1.11, 95% CI 0.81-1.52) or in G0-G1 (RR 0.99, 0.85-1.15). G1 parents with asthma born in a city tended to move and raise their G2 offspring on a farm (RR 2.00, 1.12-3.55), while G1 parents with asthma born on a farm were less likely to raise their G2 offspring on a farm (RR 0.34, 0.11-1.06). This pattern was not observed in analyses of G0-G1. This study suggests that the protective effect from farm upbringing on subsequent asthma development could not be explained by selective migration. Intriguingly, asthmatic parents appeared to change environment when having children.

Background: Mothers' smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers' smoking may have a similar effect, and biological plausibility that fathers' smoking during adolescence may influence offspring's health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma., Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents' (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines., Results: Fathers' smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01-2.01] and mothers' smoking during pregnancy (RRR = 1.27, 95% CI: 1.01-1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers' smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55)., Conclusions: Fathers' smoking during early adolescence and grandmothers' and mothers' smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception., Funding: European Union (Horizon 2020, GA-633212).

Background: Self-report questionnaires are commonly used in epidemiology, but may be susceptible to misclassification, especially if answers are given on behalf of others, e.g. children or parents. The aim was to determine agreement and analyse predictors of disagreement in parents' reports of offspring asthma, and in offspring reports of parents' asthma., Methods: In the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study, 6752 offspring (age range 18-51 years) and their parents (age range 39-66 years) reported their own and each other's asthma status. Agreement between asthma reports from offspring and parents was determined by calculating sensitivity, specificity, positive and negative predictive value and Cohen's kappa. The participants' own answers regarding themselves were defined as the gold standard. To investigate predictors for disagreement logistic regression analyses were performed to obtain odds ratios (OR) with 95% confidence intervals (CI) for sex, smoking status, education, comorbidity and severity of asthma., Results: Agreement was good for parental report of offspring early onset asthma (< 10 years, Cohen's kappa 0.72) and moderate for offspring later onset asthma (Cohen's kappa 0.46). Specificity was 0.99 for both, and sensitivity was 0.68 and 0.36, respectively. For offspring report of maternal and paternal asthma the agreement was good (Cohen's kappa 0.69 and 0.68), specificity was 0.96 and 0.97, and sensitivity was 0.72 and 0.68, respectively. The positive predictive value (PPV) was lowest for offspring report of maternal asthma (0.75), and highest for parents' report of early onset asthma in the offspring (0.83). The negative predictive value (NPV) was high for all four groups (0.94-0.97). In multivariate analyses current smokers (OR = 1.46 [95% CI 1.05, 2.02]) and fathers (OR = 1.31 [95% CI 1.08, 1.59]) were more likely to report offspring asthma incorrectly. Offspring wheeze was associated with reporting parental asthma incorrectly (OR = 1.60 [95% CI 1.21, 2.11]), both under- and over reporting., Conclusions: Asthma reports across generations show moderate to good agreement, making information from other generations a useful tool in the absence of direct reports.

Background: Some human and animal studies have recently shown that maternal grandmother's smoking during pregnancy increases the risk of asthma in the grandchildren. We have investigated whether sex of the exposed parent and/or grandchild modifies the association between grandmaternal smoking and grandchild asthma., Methods: We formed a cohort study based on linkage of national registries with prospectively collected data over three generations. Smoking habits in early pregnancy were registered since 1982 and purchases of prescribed medication since 2005. In all, 10 329 children born since 2005 had information on maternal and grandmaternal smoking on both sides and were followed from birth up to 6 years of age. Ages when medication was purchased were used to classify the cohort into never, early transient (0-3 years), early persistent (0-3 and 4-6 years), and late-onset (4-6 years) phenotypes of childhood asthma., Results: Maternal grandmother's smoking was associated with an increased odds of early persistent asthma after adjustment for maternal smoking and other confounders (odds ratio 1.29, 95% confidence interval 1.10-1.51). Grandchild sex did not modify the association. Paternal grandmother's smoking was not associated with any of the asthma phenotypes., Conclusion: Maternal but not paternal exposure to nicotine before conception was related to an increased risk of early persistent childhood asthma, but not other asthma phenotypes. Our findings are possibly consistent with a sex-specific mode of epigenetic transfer., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

It has been suggested that children that are exposed to a stressful environment at home have an increased susceptibility for air pollution-related asthma. The aim here was to investigate the association between air pollution exposure and asthma, and effect modification by mental health and by socio-economic status (as markers of a stressful environment). All individuals under 18 years of age in four Swedish counties during 2007 to 2010 (1.2 million people) were included. The outcome was defined as dispensing at least two asthma medications during follow up. We linked data on NO₂ from an empirical land use regression to data from national registers on outcome and potential confounders. Data was analyzed with logistic regression. There was an odds ratio (OR) of 1.02 (95% Confidence Interval (CI: 1.01-1.03) for asthma associated with a 10 µg·m -3 increase in NO₂. The association only seemed to be present in areas where NO₂ was higher than 15 µg·m -3 with an OR of 1.09 (95% CI: 1.07-1.12), and the association seemed stronger in children with parents with a high education, OR = 1.05 (95% CI: 1.02-1.09) and OR = 1.04 (95% CI: 1.01-1.07) in children to mothers and father with a high education, respectively. The association did not seem to depend on medication history of psychiatric disorders. There was weak evidence for the association between air pollution and asthma to be stronger in neighborhoods with higher education levels. In conclusion, air pollution was associated with dispensed asthma medications, especially in areas with comparatively higher levels of air pollution, and in children to parents with high education. We did not observe support for our hypothesis that stressors linked to socio-economy or mental health problems would increase susceptibility to the effects of air pollution on the development of asthma., Competing Interests: The authors declare no conflict of interest.

Background: Whereas it is generally accepted that maternal environment plays a key role in child health, emerging evidence suggests that paternal environment before conception also impacts child health. We aimed to investigate the association between children's asthma risk and parental smoking and welding exposures prior to conception., Methods: In a longitudinal, multi-country study, parents of 24 168 offspring aged 2-51 years provided information on their life-course smoking habits, occupational exposure to welding and metal fumes, and offspring's asthma before/after age 10 years and hay fever. Logistic regressions investigated the relevant associations controlled for age, study centre, parental characteristics (age, asthma, education) and clustering by family., Results: Non-allergic early-onset asthma (asthma without hay fever, present in 5.8%) was more common in the offspring with fathers who smoked before conception {odds ratio [OR] = 1.68 [95% confidence interval (CI) = 1.18-2.41]}, whereas mothers' smoking before conception did not predict offspring asthma. The risk was highest if father started smoking before age 15 years [3.24 (1.67-6.27)], even if he stopped more than 5 years before conception [2.68 (1.17-6.13)]. Fathers' pre-conception welding was independently associated with non-allergic asthma in his offspring [1.80 (1.29-2.50)]. There was no effect if the father started welding or smoking after birth. The associations were consistent across countries., Conclusions: Environmental exposures in young men appear to influence the respiratory health of their offspring born many years later. Influences during susceptible stages of spermatocyte development might be important and needs further investigation in humans. We hypothesize that protecting young men from harmful exposures may lead to improved respiratory health in future generations., (© The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association)

Background and Objectives: Childhood immunization may influence the development of asthma, possibly due to lack of infections or a shift in the T-helper cell type 1/T-helper cell type 2/regulatory T cells balance. We therefore investigated whether pertussis immunization in infancy is associated with asthma medication in adolescence., Methods: After 14 years of no general pertussis vaccination, almost 82,000 Swedish children were immunized for pertussis in a vaccination trial between June 1, 1993, and June 30, 1994. In a follow-up analysis of almost 80,000 children, their data were compared with those of ∼100,000 nonvaccinated children, born during a 5-month period before and a 7-month period after the vaccination trial. Data for the main outcome variable (ie, dispensed prescribed asthma medication for each individual in the cohort during 2008-2010) were obtained from the national prescription database. Multivariate regression models were used to calculate the effect size of vaccination on dispensed asthma medication (odds ratios [OR], 95% confidence intervals [CI]). Approaches similar to intention-to-treat and per-protocol methods were used., Results: The prevalence rates of various asthma medications for study patients at 15 years of age differed between 4.6% and 7.0%. The crude ORs for any asthma medication and antiinflammatory treatment in pertussis-vaccinated children after intention-to-treat analysis were 0.97 (95% CI: 0.93-1.00) and 0.94 (95% CI: 0.90-0.98), respectively. Corresponding adjusted ORs were 0.99 (95% CI: 0.95-1.03) and 0.97 (95% CI: 0.92-1.01). Similar ORs were found after per-protocol analysis., Conclusions: Pertussis immunization in infancy does not increase the risk of asthma medication use in adolescents. Our study presents evidence that pertussis immunization in early childhood can be considered safe with respect to long-term development of asthma., (Copyright © 2014 by the American Academy of Pediatrics.)

Background: It has been proposed that maternal obesity during pregnancy may increase the risk that the child develops allergic disease and asthma, although the mechanisms underpinning this relationship are currently unclear. We sought to assess if this association may be due to confounding by genetic or environmental risk factors that are common to maternal obesity and childhood asthma, using a sibling pair analysis., Methods: The study population comprised a Swedish national cohort of term children born between 1992 and 2008 to native Swedish parents. Maternal body mass index (BMI) was measured at 8-10 weeks gestation. Unconditional logistic regression models were used to determine if maternal obesity was associated with increased risk of inhaled corticosteroid (ICS) in 431,718 first-born children, while adjusting for potential confounders. An age-matched discordant sib-pair analysis was performed, taking into account shared genetic and environmental risk factors., Results: Maternal over-weight and obesity were associated with increased risk that the child would require ICS (for BMI≥35 kg/m(2), aOR = 1.30, 95%CI = 1.10-1.52 compared with normal weight mothers) in children aged 6-12 years. Similar effects were seen in younger children, but in children aged 13-16 years, maternal obesity (BMI≥30) was related to increased risk of ICS use in girls (aOR = 1.28, 95%CI = 1.07-1.53) but not boys (OR = 1.05, 95%CI = 0.87-1.26). The sib-pair analysis, which included 2,034 sib-pairs older than six years who were discordant for both ICS use and maternal BMI category, failed to find any evidence that increasing maternal weight was related to increased risk of ICS use., Conclusion: Maternal obesity is associated with increased risk of childhood ICS use up to approximately 12 years of age, but only in girls after this age. These effects could not be confirmed in a sib pair analysis, suggesting either limited statistical power, or the effects of maternal BMI may be due to shared genetic or environmental risk factors.

Cord blood IgE has previously been studied as a possible predictor of asthma and allergic diseases. Results from different studies have been contradictory, and most have focused on high-risk infants and early infancy. Few studies have followed their study population into adulthood. This study assessed whether cord blood IgE levels and a family history of asthma were associated with, and could predict, asthma medication and allergy-related respiratory symptoms in adults. A follow-up was carried out in a Swedish birth cohort comprising 1,701 consecutively born children. In all, 1,661 individuals could be linked to the Swedish Prescribed Drug Register and the Medical Birth Register, and 1,227 responded to a postal questionnaire. Cord blood IgE and family history of asthma were correlated with reported respiratory symptoms and dispensed asthma medication at 32-34 years. Elevated cord blood IgE was associated with a two- to threefold increased risk of pollen-induced respiratory symptoms and dispensed anti-inflammatory asthma medication. Similarly, a family history of asthma was associated with an increased risk of pollen-induced respiratory symptoms and anti-inflammatory medication. However, only 8% of the individuals with elevated cord blood IgE or a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication at follow-up. In all, 49 out of 60 individuals with dispensed anti-inflammatory asthma medication at 32-34 years of age had not been reported having asthma at previous check-ups of the cohort during childhood. Among those, only 5% with elevated cord blood IgE and 6% with a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication as adults. Elevated cord blood IgE and a positive family history of asthma were associated with reported respiratory symptoms and dispensed asthma medication in adulthood, but their predictive power was poor in this long-time follow-up.

Objective: Preterm birth is associated with respiratory morbidity later in life, including asthma. Previous studies have mainly focused on asthma in early childhood in children born extremely preterm. In this study, we examined the risk of asthma in a national cohort of schoolchildren grouped according to degree of immaturity expressed as completed gestational weeks at birth., Methods: This was a register study in a Swedish national cohort of 1 100 826 children 6 to 19 years old. Retrieval of at least 1 prescription of inhaled corticosteroids (ICS) during 2006 was used as the main indicator for asthma. Logistic regression was used to test hypotheses, with adjustment for multiple socioeconomic and perinatal indicators., Results: Degree of immaturity, expressed as completed gestational weeks at birth, had an inverse dose-response relationship with ICS use. Compared with children born between 39 and 41 weeks' gestation, the odds ratio for ICS use increased with the degree of prematurity, from 1.10 (95% confidence interval: 1.08-1.13) for children born in weeks 37 to 38, to 2.28 (95% confidence interval: 1.96-2.64) for children born in weeks 23 to 28, after adjustment for confounders. The increase in ICS use with decreasing gestational age at delivery was similar in boys and girls, and declined with older age., Conclusion: Preterm birth increased the risk of ICS use in these 6- to 19-year-olds by degree of immaturity, from extremely preterm to early term birth.

The aim of this review was to assess the evidence from recent prospective studies that long-term traffic pollution could contribute to the development of asthma-like symptoms and allergic sensitization in children. We have reviewed cohort studies published since 2002 and found in PubMed in Oct 2008. In all, 13 papers based on data from 9 cohorts have evaluated the relationship between traffic exposure and respiratory health. All surveys reported associations with at least some of the studied respiratory symptoms. The outcome varied, however, according to the age of the child. Nevertheless, the consistency in the results indicates that traffic exhaust contributes to the development of respiratory symptoms in healthy children. Potential effects of traffic exhaust on the development of allergic sensitization were only assessed in the four European birth cohorts. Long-term exposure to outdoor air pollutants had no association with sensitization in ten-year-old schoolchildren in Norway. In contrast, German, Dutch and Swedish preschool children had an increased risk of sensitization related to traffic exhaust despite fairly similar levels of outdoor air pollution as in Norway. Traffic-related effects on sensitization could be restricted to individuals with a specific genetic polymorphism. Assessment of gene-environment interactions on sensitization has so far only been carried out in a subgroup of the Swedish birth cohort. Further genetic association studies are required and may identify individuals vulnerable to adverse effects from traffic-related pollutants. Future studies should also evaluate effects of traffic exhaust on the development and long term outcome of different phenotypes of asthma and wheezing symptoms.

Aim: To assess the temporal trend for asthma and asthma-like symptoms over a period of 20 years., Method: Repeated cross-sectional surveys with identical study design were carried out among all school children (7-16 years) in a well-defined area in Sweden in 1985, 1995 and 2005., Results: In 2005, the parents of 1110 out of 7825 children (14.2%) answered yes to a screening question on asthmatic symptoms. Of these, 783 out of 1110 (70.5%) replied to a postal questionnaire with detailed questions concerning symptoms and asthma management. The rate of affirmative response to the screening question was unchanged between 1995 and 2005. However, the percentage of children with wheezing or three or more asthma-like symptoms decreased, whereas the percentage of children with physician-diagnosed asthma increased steadily since 1985. The number of reported symptoms was closely associated with the number of days with physical restriction. The annual sale of inhaled steroids from local pharmacies was stable between 1995 and 2005., Conclusion: The increase in asthmatic symptoms in school children has peaked. Reduced severity of symptoms and divergent trends for wheezing and physician-diagnosed asthma suggest an increased awareness of asthma with improved management of the symptoms. However, differences in trends between allergic and nonallergic asthma could not be excluded.

The role of pet keeping during infancy for the development of allergy and asthma is still controversial. The objective of this population-based birth cohort study was to assess the development of atopy and different wheezing phenotypes during the first 4 yr of life in relation to heredity and early pet keeping. The cohort comprised all 1228 infants living in a Swedish county who were born over a 1-yr period. The parents replied to repeated questionnaires and 817 of the children were skin prick tested both at 1 and 4 yr. Cat keeping during the first year of life was associated with an increased risk of a positive skin prick test to cat at 1 yr of age [odds ratio (OR) 2.2, 95% confidence interval (CI) 0.9-5.6], but neither with sensitivity nor clinical symptoms of allergy at 4 yr. Dog keeping during the first year of life was associated with an increased risk of early-onset transient wheezing, but only in children with parental asthma (adjusted OR 4.3, 95% CI 1.5-12.1). In contrast, early dog keeping had an inverse association with sensitivity to pollen allergen at 4 yr (adjusted OR 0.3, 95% CI 0.1-0.9) and late-onset wheezing (adjusted OR 0.4, 95% CI 0.2-1.0). Thus, pet keeping during the first year of life was not associated with an increased risk of atopy at 4 yr, although a positive SPT to cat was more common at 1 yr. Our findings may even suggest that dog keeping during the first year of life might provide some protection from pollen allergy and late-onset wheezing and increase the risk of early-onset transient wheezing in children with heredity for asthma.

Background: Data relating to hospital admissions of very young children for wheezing illness have been conflicting. Our primary aim was to assess whether a previous increase in hospital admissions for lower respiratory illness had continued in young Swedish children. We have included re-admissions in our analyses in order to evaluate the burden of lower respiratory illness in very young children. We have also assessed whether changes in the labelling of symptoms have affected the time trend., Methods: A retrospective, population based study was conducted to assess the time trend in admissions and re-admissions for lower respiratory illness. Data were obtained from the Swedish Hospital Discharge Register for all children with a first hospital admission before nine years of age, a total of 109,176 children. The register covers more than 98% of all hospital admissions in Sweden. The coding of diagnoses was based on ICD-9 from 1987 to 1996 and ICD-10 from 1997., Results: The first admission rates declined significantly in children with a first admission after two years of age. However, an increasing admission trend was observed in children aged less than one year and 35% of first admissions occurred in this age group. The annual increase was 3.8% (95% CI 1.3-6.3) in boys and 5.0% (95% CI 2.4-7.6) in girls. A diagnostic shift appeared to occur when ICD-10 was introduced in 1997. The asthma and pneumonia admission rate in children aged less than one year levelled off, whereas the increase in admissions for bronchitis continued. The re-admission rates for asthma decreased and the probability of re-admission was higher in boys. National drug statistics demonstrated a substantial increase in the delivery of inhaled steroids to all age groups but most prescriptions occurred to children aged one year or more., Conclusion: Hospital admissions for lower respiratory illness are still increasing in children aged <1 year. Our findings are in line with other recent studies suggesting a change in the responsiveness to viral infections in very young children, but changes in admission criteria cannot be excluded. An increased use of inhaled steroids may have contributed to decreasing re-admission rates.

Abstract Background Avoidance of pets as a strategy for preventing atopic diseases has been questioned. This study aimed to identify the risk of sensitization and allergic symptoms at age 13 in relation to dog‐ and cat‐keeping during and after the first year of life. Methods The study included all children born at Östersund Hospital in Northern Sweden between February 1996 and January 1997 (n = 1231). At inclusion, parents were asked to answer questionnaires about lifestyle, including cat‐ and dog‐keeping. Dog allergy, cat allergy, hay fever, and asthma were diagnosed based on parental reported allergic symptoms at 13 years of age (n = 834). The risks of sensitization or allergy in relation to dog‐ and cat‐keeping during and after the first year of life were analyzed with logistic regression. To adjust for reverse causation, all subjects that had reported avoidance of pets due to allergic symptoms of the child or allergy in the family (n = 177) were excluded. Results Dog‐ or cat‐keeping during the first year of life reduced the risk of sensitization to dog or cat allergens, respectively, and to birch and to at least one of the 10 allergens tested. Cat‐keeping, both during and after the first year of life, reduced the risk of cat allergy and hay fever. Having a dog at home during the first year of life reduced the risk of dog and cat allergy, whereas dog‐keeping after the first year of life did not affect allergic symptoms. Conclusions Cat ownership, either during or after the first year of life, may be a strategy for preventing the development of cat allergy and hay fever later in life. Dog ownership reduced the risk of sensitization to dog and birch allergen, and also the risk of cat and dog allergy, but had no effect on hay fever.

Abstract Background A seasonal effect of month of birth and risk of allergic disease has been suggested by numerous studies. Few studies have directly measured pollen exposures at different points during pregnancy and in early life, and assessed their effects on risk of respiratory disease outcomes. Methods Pollen exposure was calculated for the first and last 12 weeks of pregnancy and the first 12 weeks of infancy for all children conceived by women residing in Stockholm, Sweden, between 1988 and 1995. Hospital admission data for respiratory conditions in the first year of life was also collected. Results Out of 110,381 children, 940 had been hospitalised for asthma by 12-months of age. Pollen levels showed both marked seasonal variations and between year differences. Exposure to high levels of pollen in the last 12 weeks of pregnancy was associated with an increased risk of asthma hospitalisation (aOR = 1.35, 95% CI = 1.07-1.71 for highest quartile versus remaining infants). Exposure to high levels of pollen in the first three months of life was associated with a reduced risk (aOR = 0.76, 95% CI = 0.59-0.98) but only in children of heavy smoking mothers. Conclusions High levels of pollen exposure during late pregnancy were somewhat unexpectedly associated with an elevated risk of hospitalisation for asthma within the first year of life.

Background: A farm upbringing has been associated with lower risk of asthma and methylation of asthma-related genes. As such, a farm upbringing has the potential to transfer asthma risk across generations, but this has never been investigated. We aimed to study the generational effects from a parental farm upbringing on offspring asthma.Methods: Our study involved three generations: 5759 participants from the European Community Respiratory Health Survey (ECRHS) study (born 1945-1971, denoted G1), their 9991 parents (G0) and their 8260 offspring (G2) participating in RHINESSA (Respiratory Health In Northern Europe, Spain and Australia). Questionnaire data were collected on G0 and G1 from G1 in 2010 and on G2 from themselves in 2013. The parental/grandparental place of upbringing was categorized: (i) both parents from farm; (ii) mother from farm, father from village/city; (iii) father from farm, mother from village/city; (iv) both parents from village or one parent from village and one from city; (v) both parents from city (reference group). Grandparental upbringing was equivalently categorized. Offspring asthma was self-reported and data were analysed using Cox-regression models with G2 age as the time scale.Results: A parental farm upbringing was not associated with offspring asthma when compared with city upbringing [hazard ratio (HR) 1.12, 95% confidence interval (CI) 0.74-1.69]. Findings remained similar when stratified by offspring upbringing and asthma phenotypes. Quantitative bias analyses showed similar estimates for alternative data sources. A grandparental farm upbringing was not associated with offspring asthma in either the maternal (HR 1.05, 95% CI 0.67-1.65) or paternal line (HR 1.02, 95% CI 0.62-1.68).Conclusions: This multigenerational analysis suggests no evidence of an association between parental/grandparental farm upbringing and offspring asthma. [ABSTRACT FROM AUTHOR]

Background: While direct effects of occupational exposures on an individual's respiratory health are evident, a new paradigm is emerging on the possible effects of pre-conception occupational exposure on respiratory health in offspring. We aimed to study the association between parental occupational exposure starting before conception and asthma in their offspring (at 0-15 years of age).Methods: We studied 3985 offspring participating in the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) generation study. Their mothers or fathers (n = 2931) previously participated in the European Community Respiratory Health Survey (ECRHS). Information was obtained from questionnaires on parental job history pre- and post-conception which was linked to an asthma-specific job-exposure matrix (JEM). We assessed the association between parental occupational exposure and offspring asthma, applying logistic regression models, clustered by family and adjusted for study centre, offspring sex, parental characteristics (age, asthma onset, place of upbringing, smoking) and grandparents' level of education.Results: Parental occupational exposure to microorganisms, pesticides, allergens or reactive chemicals pre-conception or both pre- and post-conception was not related to offspring asthma; in general, subgroup analyses confirmed this result. However, maternal exposure both pre- and post-conception to allergens and reactive chemicals was associated with increased odds for early-onset asthma in offspring (0-3 years of age); odds ratio 1.70 (95% CI: 1.02-2.84) and 1.65 (95% CI: 0.98-2.77), respectively.Conclusions: This study did not find evidence that parental occupational exposure, defined by an asthma JEM before conception only or during pre- and post-conception vs non-exposed, was associated with offspring asthma. [ABSTRACT FROM AUTHOR]

Background: Mode of delivery may affect the risk of asthma but the findings have not been consistent and factors shared by siblings may confound the associations in previous studies. Methods: The association between mode of delivery and dispensed inhaled corticosteroid (ICS) (a marker of asthma) was examined in a register based national cohort (n=199 837). A cohort analysis of all first born children aged 2-5 and 6-9 years was performed. An age-matched sibling-pair analysis was also performed to account for shared genetic and environmental risk factors. Results: Analyses of first-borns demonstrated that elective caesarean section was associated with an increased risk of dispensed ICS in both 2-5 (adjusted odds ratio (aOR)=1.19, 95% confidence interval (CI) 1.09-1.29) and 6-9 (aOR=1.21, 1.09-1.34) age groups. In the sibling-pair analysis, the increased risk associated with elective caesarean section was confirmed in 2-5 year olds (aOR=1.22, 1.05-1.43) but not in 6-9 year olds (aOR=1.06, 0.78-1.44). Emergency caesarean section and vacuum extraction had some association with dispensed ICS in the analyses of first-borns but these associations were not confirmed in the sibling-pair analyses. Conclusions: Confounding by familial factors affects the association between mode of delivery and dispensed ICS. Despite this confounding, there was some evidence that elective caesarean section contributed to a modestly increased risk of dispensed ICS but only up to five years of age. [ABSTRACT FROM AUTHOR]

Summary: Obesity and overweight have been associated with an increased risk of asthma in children as well as adults. The association between atopy and body mass index (BMI) is less clear. It has also been suggested that the link between a high BMI and asthma could be a recent phenomenon. The objective of this study was to assess whether the association with BMI differed between allergic rhinoconjunctivitis and asthma and if these associations have changed over time. The Swedish Military Service Conscription Register was linked to the Register of the Total Population and the Population and Housing Censuses. Asthma (with and without allergic rhinoconjunctivitis) and allergic rhinoconjunctivitis at conscription were analysed in relation to BMI for 1,247,038 male conscripts in successive cohorts born between 1952 and 1977. Obesity was associated with asthma without allergic rhinoconjunctivitis, adjusted OR 1.53 (95% CI 1.43–1.63), and with asthma with allergic rhinoconjunctivitis, adjusted OR 1.34 (95% CI 1.20–1.50), but not with allergic rhinoconjunctivitis, OR 1.00 (95% CI 0.97–1.03) after multivariate analyses with adjustments for confounders. The odds ratios were similar in three successive cohorts (conscripts born in 1952–1961, 1962–1971 and 1972–1977). Underweight was associated with a slightly increased risk for all three conditions. The increased risk of asthma in young Swedish men with obesity has remained unchanged over a period of three decades. [Copyright &y& Elsevier]