Table E1: Antibiotic use in infancy and wheeze and asthma: longitudinal studies until January 2010
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1 Table E1: Antibiotic use in infancy and wheeze and asthma: longitudinal studies until January 2010 Mai 2010, Sweden [32] Dom 2010, Belgium [33] Su 2010, USA [34] Sobko 2010, Sweden [49] Schmitt 2009, Germany [35] Marra 2009, Canada [36] 1. Prosespective birth cohort 1. AB use in 1 st year of life 0 AB use associated with wheeze and asthma at age years (n=3306) 2. Wheeze, asthma (> 3 episodes of wheeze OR wheeze+inhalation corticosteroids OR asthma symptoms) in first 8 years of life. 4 and 8 years, but not after adjustment of respiratory infections and exlusion of children with early respiratory symptoms. 3. Questionnaires 3. URTI s, LRTI s and other 1. Prospective birth cohort 1. AB use in 1 st year of life (also AB in 2 nd year of life) 0 No statistically significant association between AB years (n=773) 2. Recurrent wheeze (> 2 episodes in 6-month use in 1 st year and subsequent recurrent wheeze. periods) 3. Questionnaires, interviews, serology 3. LRTI s and other 1. Prospective birth cohort 1. AB use in first 9 months of life 0 Statistically significant association between AB use years (n=424) 2. Parentally reported physicians-diagnosed active asthma in first 5 years of life in first 9 months of life and ever asthma (in first 5 years of life) disappeared after adjusting for 3. Questionnaires, interviews, serology 3. illness visits to a physician, others number of illness visits. 1. Historical Cohort 1. Neonatal intravenous AB without infection 0 No statistically significant association with asthma 2. 0 to 7-23 years (n = 834) 2. Asthma (ISAAC-questions) 3. Medical records 3. other 1. Historical cohort 1. AB use in 1 st year of life 0 No statistically significant association with allergic years (n = 370) 2. Allergic asthma (ICD-10 code j45, coded at least twice in first 2 years of life) asthma. 3. Administrative health-care and prescription database 3. other 1. Historical cohort 1. AB use in the 1 st year of life + Use of AB was associated with a small risk of years (n= ) 2. Asthma after the first two years of life (1 hospital discharge for asthma (ICD-9 code 493); or 2 developing asthma, and this risk increased with the number of courses of AB prescribed. medical fee-for-service claims (coded ICD-9 493) within a moving 12-month period; or 2 prescriptions for a known asthma medication within a moving 12-month period). 3. Administrative (health) data 3. Otitis media, acute or chronic bronchitis, upper and lower respiratory tract infections, other
2 Martel 2009, 1. Case-control study nested in a birth cohort Canada [37] Kusel 2008, Australia [38] 1. At least 1 prescription of AB prior to index date or within the first 6 months of age years (n=1578) 2. Childhood asthma (at least 1 diagnosis for asthma (ICD-9 code 493) and at least 1 prescription for asthma medication filled within a 2-year period) 3. Health-care and prescription databases, questionnaires 3. Respiratory tract infections prior to index date, other 1. Birth Cohort years (n =198); high risk children 1. AB in 1 st year of life 2. History of doctor-diagnosed asthma, current 0 wheeze (between 4-5 years of age), current 0 asthma (doctor-diagnosis and current wheeze), current atopic asthma (current asthma AND SPT positivity or elevated total IgE) 3. Questionnaire interviews, skin prick test, serology 3. Acute respiratory tract infections/lower respiratory tract infections, other (propensity score) + At least 1 prescription of AB prior to index date (date at which a subject fulfilled the criteria to become a case) or within the first 6 months of age associated with increased childhood asthma risk. AB associated with increased asthma risk, but not after adjustment for propensity score. AB not associated with current wheeze, atopic asthma Wickens 2008, New-Zealand [3] Simon 2008, USA [39] 1. Birth Cohort 1. AB use before 3 months of age and before 15 months of age years (n ~1000) 2. Current asthma at 15 months (History of doctordiagnosed asthma AND wheeze or inhaler use in past 12 months), Current asthma at 4 years (History of doctor-diagnosed asthma AND wheeze or inhaler use in past 12 months) 3. Questionnaires, skin prick test 3. Ear infection, parity, subsequent AB use, chest infections, other 0 AB associated with increased asthma and wheeze risk, but not after adjustment for chest infections. Effect may be explained by confounding by chest infection in early life. 1. Birth Cohort 1. AB in first 6 months of life + AB in first 6 months associated with increased risk years (n=372) 2. Transient wheeze (wheezing in the last 12 months that occurred at the ages of 1, 2, and/or 4 years but not 6 years) of transient wheeze. 3. Interviews, telephone questionnaires, home visits, skin prick testing 3. Fever in 1 st year, other
3 Alm 2008, Sweden [40] 1. Birth Cohort 1. Neonatal AB + Neonatal AB increased risk of wheeze ever in first months (n=4987) 2. Wheeze ever in 1 st year (1 or more episodes of wheezing); wheezing disorder treated with inhaled corticosteroid year and wheezing disorder treated with inhaled corticosteroid. 3. Questionnaires 3. Rhino conjunctivitis, admission to ward; other Verhulst 2008, Belgium [41] Kummeling 2007, Netherlands [42] Kozyrskyj 2007, Canada [43] 1. Birth Cohort 1. AB use in week 0-3, 3 wk-6 months, 6-12 months 0 AB in first year associated with wheeze in first year, but AB use in first 3 weeks not associated months (n=154) 2. Wheeze ever in 1 st t year (standard ISAAC with wheeze in first year. indicate possible question: ever had wheezing or whistling in the reverse causation. chest at any time) 3. Questionnaires, stool 3. Several measures of bacteria as determined from stool samples; other 1. Birth Cohort 1. AB during months 0-6 (direct and via breast milk) + AB in first half year of life increased risk of wheeze years (n = 2764) 2. Recurrent wheeze (ever symptoms of wheeze in first two years of life (also after exclusion of (standard ISAAC question: ever had wheezing or children with wheeze during months 0-6). whistling in the chest at any time) with at least 4 attacks ever) 3. Questionnaires, serology 3. Fever, other 1. Historical cohort 1. AB use in first year and number of prescriptions + AB in first year associated with asthma 2. 7 years (n=13.116) 2. Current asthma at age 7 years (at least two physician visits for asthma, one asthma hospitalisation, or two prescriptions for any asthma drug in the year following the 7 th birthday) 3. Health-care and prescription databases 3. Lower respiratory tract infections and nonrespiratory tract infections, other development by age 7 (but only for BS antibiotics and not NS antibiotics). Strong evidence against reverse causation is the finding of an association between asthma and AB use for the treatment of non-respiratory tract infections.
![Rhino conjunctivitis, admission to ward; other Verhulst 2008, Belgium [41] Kummeling 2007, Netherlands [42] Kozyrskyj 2007, Canada [43] 1. Birth Cohort 1.](/docs-images/46/21266373/images/page_3.jpg "AB use in week 0-3, 3 wk-6 months, 6-12 months 0 AB in first year associated with wheeze in first year, but AB use in first 3 weeks not associated 2. 0-12 months (n=154) 2.")
4 Harris 2007, UK [44] Thomas 2006, UK [50] Celedon 2004, USA [45] 1. Birth Cohort 1. AB prescription by age 5, years (n=642) 2. Current wheeze at age 8 years (standard ISAAC question: ever had wheezing or whistling in the chest in past 12 months) 3. Questionnaires, skin prick test, general practice 3. Other medical records (infections, AB use) 0 0 Associations found between AB use and current wheeze, but: 1. After excluding children with wheeze at age 1 or 2 years from the analyses (n=257), none of the associations between AB use and current wheeze were statistically significant; 2. After stratification for respiratory vs. nonrespiratory infections the associations were not present in case of non-respiratory infection; similar for seasonal rhinitis. 1. Case control nested in a birth cohort study 1. AB use in first 3 years +/0 In the first year of life, significantly more cases than years (n=74) 2. Atopic wheeze (sensitised to at least one allergen as measure by skin prick test and at least three parentally-reported wheezy epidsodes) controls received one or more AB courses; by age 3 a similar association was found but not statistically significant 3. Primary care medical records, parental diaries 3. No available 1. Historical cohort 1. AB in first year of life 0 AB use in first year associated with diagnosis of 2. 5 years (n=4408) 2. Asthma aged 1-2 years (1 st diagnosis > age 1 year) Asthma aged 2-5 years (1 st diagnosis > age 2 years) (at least 2 ambulatory visits; or at least one emergency department visit; or at least one hospitalization for asthma (ICD-9 codes 349.*); or at least 2 dispensings of any asthma medication in the previous 12 months) asthma at age 1-2 years, but not with asthma diagnosed after 2 years that persisted to 5 years. These results do not support a causal effect but rather suggest that AB use in first year associated with diagnosis of asthma at age 1-2 years is explained by confounding-by-indication. 3. Medical record data 3. Lower respiratory tract illnesses in the first year of life, other
5 Celedon 2002, USA [46] McKeever 2002, UK [47] 1. Birth Cohort 1. AB use during 1 st year of life 0 No association between antibiotic use in first year years (n=448); high risk children only 2. Asthma at age 5 (physician-diagnosed asthma and one or more episodes of wheezing in the previous 12 months), transient wheezing (one or more episodes of wheezing before the age of 3 years, but no episodes of wheezing between 4 and 5 years of age), Late-onset wheezing ( no episodes of wheezing before the age of 3 years and one or more episodes of wheezing between 4 and 5 years), persistent wheezing (one or more episodes of wheezing before the age of 3 years and one or more episodes of wheezing between 4 and 5 years), recurrent wheezing at age 5 (2 or more episodes of wheezing in the previous 12 months) and outcome variables at age 5 in high risk children. 3. Interviews with primary care giver, serology 3. Other 1. Historical cohort 1. AB use during 1 st year of life + Antibiotic use was statistically significant years (n=29.238) 2. Asthma, diagnosed after age of 1 year (Oxford associated with asthma after adjustment of Medical Information System and Read Codes) consulting behaviour. 3. Primary care data set 3. Other
6 Illi 2002, Germany [31] Ponsonby 1999, USA [48] 1. Birth Cohort 1. AB treatment in first 3 years of life; excluding AB given for lower respiratory tract infections years (n=1314) 2. Doctor s diagnosis of ever asthma or having current wheeze at age 7 years (a wheezy or whistling noise while breathing) 3. Questionnaires, bronchial histamine challenge, serology 3. Other 0 No associations between AB and respiratory outcomes 1. Historical cohort 1. AB use in first 35 days of life 0 Antibiotic use by home interview was not years (n=863) 2. Asthma (standard ISAAC question: has your child associated with subsequent asthma ever had asthma?), 3. Home interviews, telephone interviews, questionnaires * Of the studies included in the meta-analyses the selected outcome is presented in bold 3. Chest infection (only after exposure period), cold (URTI), other
Subject ID: Subject Initials Date completed Interviewer. Person answering questions. 1 yes 2 no
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