Anne K. Örtqvist

Familial Factors Do not Confound the Association Between Birth Weight and Childhood Asthma

OBJECTIVE: Studies have found associations between low birth weight and asthma. However, this association could be due to familial confounding. Our objective was to investigate whether fetal growth and birth weight affect the risk of asthma in childhood, controlling for gestational age (GA), and shared (familial) environment and genetic factors. PATIENT AND METHODS: Information on asthma, zygosity, birth characteristics, and potential confounders was collected for all 9- and 12-year-old twins through the Swedish Twin Register and Medical Birth Register. To obtain an overall effect of birth weight on risk of asthma, we performed cohort analyses on all twins (N = 10918). To address genetic and shared environmental confounding, we performed a co-twin control analysis by using the 157 monozygotic and 289 dizygotic same-sex twin pairs who were discordant for asthma. RESULTS: The overall rate of asthma ever was 13.7%. In the cohort analysis, the adjusted odds ratio (OR) for asthma in relation to a 1000-g decrease in birth weight was 1.57 (95% confidence interval [CI]: 1.38–1.79), and for each reduced gestational week the OR was 1.10 (95% CI: 1.07–1.13). In the co-twin control analyses, a 1000-g decrease in birth weight corresponded to an OR of 1.25 (95% CI: 0.74–2.10) for dizygotic same-sex twins and 2.42 (95% CI: 1.00–5.88) for monozygotic twins. CONCLUSIONS: There is an association between fetal growth and childhood asthma that is independent of GA and shared (familial) environment and genetic factors, which indicates that fetal growth restriction affects lung development, supporting additional studies on the early metabolic and physiologic mechanisms of childhood asthma.

Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis

Objective To investigate the association between exposure to antibiotics in fetal and early life and asthma in childhood, with adjustment for confounding factors. Design Nationwide prospective population based cohort study, including sibling control design. Setting Swedish population identified from national demographic and health registers. Participants 493 785 children born 2006-10; 180 894 of these were eligible for sibling analyses. Main outcome measure Asthma defined as having both an asthma diagnosis and dispensed asthma drugs. The association between antibiotic exposure and asthma was investigated in the whole cohort with Cox proportional hazard regression. A stratified proportional hazards model conditional on sibling group was used to adjust for shared factors within families. Confounding by respiratory infections was assessed by investigating whether specific groups of antibiotics were associated with asthma. Results Antibiotic exposure in fetal life was associated with an increased risk of asthma in cohort analyses (hazard ratio 1.28, 95% confidence interval 1.25 to 1.32), but not in sibling analyses (0.99, 0.92 to 1.07). In cohort analyses, antibiotics used to treat respiratory infections in childhood were associated with a more pronounced increased risk of asthma (4.12, 3.78 to 4.50) than antibiotics used for urinary tract and skin infections (1.54, 1.24 to 1.92). In sibling analyses, the excess risks after exposure to antibiotics for respiratory infections decreased (2.36, 1.78 to 3.13) and disappeared for antibiotics for urinary tract and skin (0.85, 0.47 to 1.55). Conclusions Previous positive associations between exposure to antibiotics in fetal and early life and subsequent childhood asthma could have been caused by confounding by shared familial factors, in addition to confounding by respiratory infections.

Validation of asthma and eczema in population-based Swedish drug and patient registers

Validated measures of asthma and eczema at the population level remain a challenge. Our aim was to ascertain if register‐based information on asthma/eczema medication can function as a proxy for an asthma/eczema diagnosis and to validate register‐based asthma diagnoses.

Fetal growth and risk of childhood asthma and allergic disease.

Early genetic and environmental factors have been discussed as potential causes for the high prevalence of asthma and allergic disease in the western world, and knowledge on fetal growth and its consequence on future health and disease development is emerging.

Early Exposure to Dogs and Farm Animals and the Risk of Childhood Asthma

IMPORTANCE The association between early exposure to animals and childhood asthma is not clear, and previous studies have yielded contradictory results. OBJECTIVE To determine whether exposure to dogs and farm animals confers a risk of asthma. DESIGN, SETTING AND PARTICIPANTS In a nationwide cohort study, the association between early exposure to dogs and farm animals and the risk of asthma was evaluated and included all children born in Sweden from January 1, 2001, to December 31, 2010 (N = 1,011,051), using registry data on dog and farm registration, asthma medication, diagnosis, and confounders for parents and their children. The association was assessed as the odds ratio (OR) for a current diagnosis of asthma at age 6 years for school-aged children and as the hazard ratio (HR) for incident asthma at ages 1 to 5 years for preschool-aged children. Data were analyzed from January 1, 2007, to September 30, 2012. EXPOSURES Living with a dog or farm animal. MAIN OUTCOMES AND MEASURES Childhood asthma diagnosis and medication used. RESULTS Of the 1,011,051 children born during the study period, 376,638 preschool-aged (53,460 [14.2%] exposed to dogs and 1729 [0.5%] exposed to farm animals) and 276,298 school-aged children (22,629 [8.2%] exposed to dogs and 958 [0.3%] exposed to farm animals) were included in the analyses. Of these, 18,799 children (5.0%) in the preschool-aged childrens cohort experienced an asthmatic event before baseline, and 28,511 cases of asthma and 906,071 years at risk were recorded during follow-up (incidence rate, 3.1 cases per 1000 years at risk). In the school-aged childrens cohort, 11,585 children (4.2%) experienced an asthmatic event during the seventh year of life. Dog exposure during the first year of life was associated with a decreased risk of asthma in school-aged children (OR, 0.87; 95% CI, 0.81-0.93) and in preschool-aged children 3 years or older (HR, 0.90; 95% CI, 0.83-0.99) but not in children younger than 3 years (HR, 1.03; 95% CI, 1.00-1.07). Results were comparable when analyzing only first-born children. Farm animal exposure was associated with a reduced risk of asthma in both school-aged children and preschool-aged children (OR, 0.48; 95% CI, 0.31-0.76, and HR, 0.69; 95% CI, 0.56-0.84), respectively. CONCLUSIONS AND RELEVANCE In this study, the data support the hypothesis that exposure to dogs and farm animals during the first year of life reduces the risk of asthma in children at age 6 years. This information might be helpful in decision making for families and physicians on the appropriateness and timing of early animal exposure.

Impaired fetal growth decreases the risk of childhood atopic eczema: a Swedish twin study.

Background Studies have found associations between birth weight and risk of atopic eczema or allergic rhinitis (AR), although this could be due to confounding.

Individual maternal and child exposure to antibiotics in hospital : a national population-based validation study

Exposure to antibiotics in early life may affect future health. Most antibiotics are prescribed in outpatient care, but inpatient exposure is also important. We estimated how specific diagnoses in hospitals corresponded to individual antibiotic exposure.

No association between macrolide treatment in infancy and later pyloric stenosis in Sweden

In a recent paper in the BMJ, Lund et al. [1] reported an increased risk of infantile hypertrophic pyloric stenosis (IHPS) in infants exposed to macrolides, especially during days 0–13 (adjusted rate ratio (ARR) 29.8, 95 % CI 16.4–54.1) . The excess risk decreased rapidly with exposure later in life (days 14–120: ARR 3.24; 95 % CI 1.20–8.74). Also a retrospective cohort study of children to US uniformed personnel recorded in the TRICARE database found a positive association between macrolides and IHPS [2]. In Sweden, one of the most common uses of erythromycin in newborns is to stimulate the gastrointestinal motility and we believe that the positive association between macrolides and IHPS is due to reverse causation [3]. Lund et al. also mention that some macrolides are used for dysmotility in smaller children. In a nationwide cohort of 582,494 children born between July 2005 and December 2010 in Sweden we examined the use of macrolides and the risk of IHPS. Data on pregnancy and birth factors were obtained from the Swedish Medical Birth Registry [4], while we used the Swedish Patient Registry [5] (contains data on hospitalbased outpatient and inpatient care since 2001) to identify cases of IHPS (international classification of disease (ICD) codes; Q40.0, K31.1). We defined exposure as macrolide use (ATC code: J01FA) according to the Swedish Prescribed Drug Registry [6]. In Sweden, the Prescribed Drug Registry contains dispensed drug data but not data on over the counter drugs or drugs administered at hospital. A priori we had planned to use Cox regression to examine the risk of IHPS in children exposed to macrolides. Four hundred and fifty (450) children had a diagnosis of IHPS (equivalent to 0.8 per 1000 births). The median age at diagnosis was 35 days, ranging from birth to 1038 days (four children had their first recorded diagnosis of IHPS beyond the age of 500 days). Some 17,659 children had a record of macrolides, but only 32 had been prescribed macrolides (all had received erythromycin) during days 0–13 (the youngest was 5 days old) and 1275 children during days 14–120. In total 240 children had a record of macrolides by day 35 (238 (99 %) with erythromycin). No infant in our study had a record of macrolides prior to IHPS, but 18 children had received macrolides after the IHPS diagnosis. No case among 240 exposed corresponds to a proportion of 0 % with a 95 % confidence interval of 0–1.5 % based on the binomial distribution. Assuming a risk ratio of 30 for the association between macrolides during day 0–13 and IHPS, there would be a probability of 47 % to find no cases among 32 exposed, based on the IHPS incidence in Sweden. Thus our data do not contradict the findings of Lund et al. and we cannot rule out that early macrolide exposure contributes to IHPS, especially when administered in high doses. Besides, a major weakness of our study is that we did not have access to antibiotics administered in hospital. For newborns, hospital-administered antibiotics are an important exposure. Still, we were able to identify 240 children with & Jonas F. Ludvigsson jonasludvigsson@yahoo.com

Cohort Profile: Swedish Twin Study on Prediction and Prevention of Asthma (STOPPA).

Asthma is a common childhood disease and several risk factors have been identified; however, the impact of genes and environment is not fully understood. The aim of the Swedish Twin study On Prediction and Prevention of Asthma (STOPPA) is to identify environmental (birth characteristics and early life) and genetic (including epigenetic) factors as determinants for asthmatic disease. Based on the Child and Adolescent Twin Study in Sweden (CATSS) (parental interview at 9 or 12 years, N ~23,900) and an asthma and/or wheezing algorithm, we identified a sample of monozygotic (MZ) and dizygotic (DZ) same-sexed twin pairs. The twin pairs were classified as asthma concordant (ACC), asthma discordant (ADC) and healthy concordant (HCC). A sample of 9- to 14-year-old twins and their parents were invited to participate in a clinical examination. Background characteristics were collected in questionnaires and obtained from the National Health Registers. A clinical examination was performed to test lung function and capacity (spirometry with reversibility test and exhaled nitric oxide) and collect blood (serology and DNA), urine (metabolites), feces (microbiota), and saliva (cortisol). In total, 376 twin pairs (752 individual twins) completed the study, response rate 52%. All participating twins answered the questionnaire and >90% participated in lung function testing, blood-, and saliva sampling. This article describes the design, recruitment, data collection, measures, and background characteristics, as well as ongoing and planned analyses in STOPPA. Potential gains of the study include the identification of biomarkers, the emergence of candidates for drug development, and new leads for prevention of asthma and allergic disease.

Parental antibiotics and childhood asthma—a population-based study

In this population-based study on antibiotic treatment before, during, and after pregnancy, using paternal exposure as negative control, we confirm that associations between maternal antibiotic exp ...