Abstract
Several epidemiological studies reported an association between antibiotic consumption in the first year of life and later asthma, but results are conflicting and affected by potential biases. We examined this controversial issue in a population-based birth cohort. Using administrative data, we identified 143,163 children born in 1995–2011 in Friuli-Venezia Giulia (Italy) (median follow-up 5.25 years, 927,350 person-years). Antibiotic prescriptions in the first year of life and subsequent treated asthma (defined as ≥2 anti-asthmatic drug prescriptions within a 12-month period) were retrieved from drug prescription records. We estimated incidence rate ratios (IRR) using Poisson regression models, adjusted for perinatal variables and for hospitalizations for infections in the first year of life. We identified 34,957 new-onset asthma cases. Antibiotic consumption in the first year of life increased the risk of new-onset asthma [IRR 1.51, 95 % confidence interval (CI) 1.48–1.54] with a dose–response relationship (p-trend <0.001). The risk was highest for asthma identified at 13–35 months of life (IRR 2.07, 95 % CI 2.00–2.14), but remained statistically significant for asthma identified at 36–71 months (IRR 1.17, 95 % CI 1.14–1.21) and at ≥72 months (IRR 1.15, 95 % CI 1.08–1.22). Antibiotics increased the risk of current asthma at ≥6 years (IRR 1.35, 95 % CI 1.30–1.41) and at ≥13 years of age (IRR 1.19, 95 % CI 1.08–1.33). Antibiotic exposure in infancy is associated with an increased risk of asthma up to adolescence. The association detected at older ages is not explained by reverse causation; however, confounding by respiratory infections not leading to hospital admission cannot be excluded.
This is a preview of subscription content,
to check access.References
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. Revised 2014. www.ginasthma.org/local/uploads/files/GINA_Report_2014_Aug12.pdf.
Lai CK, Beasley R, Crane J, Foliaki S, Shah J, Weiland S, et al. Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2009;64:476–83.
Anandan C, Nurmatov U, van Schayck OC, Sheikh A. Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy. 2010;65:152–67.
Strachan DP. Hay fever, hygiene, and household size. BMJ. 1989;299:1259–60.
Sommer F, Backhed F. The gut microbiota–masters of host development and physiology. Nature Reviews Microbiology. 2013;11:227–38.
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nature Reviews Immunology. 2009;9:313–23.
Murk W, Risnes KR, Bracken MB. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics. 2011;127:1125–38.
Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis. European Respiratory Journal. 2011;38:295–302.
Kozyrskyj AL, Ernst P, Becker AB. Increased risk of childhood asthma from antibiotic use in early life. Chest. 2007;131:1753–9.
Harris JM, Mills P, White C, Moffat S, Newman Taylor AJ, Cullinan P. Recorded infections and antibiotics in early life: associations with allergy in UK children and their parents. Thorax. 2007;62:631–7.
Mai XM, Kull I, Wickman M, Bergstrom A. Antibiotic use in early life and development of allergic diseases: respiratory infection as the explanation. Clinical and Experimental Allergy. 2010;40:1230–7.
Canova C, Zabeo V, Pitter G, Romor P, Baldovin T, Zanotti R, et al. Association of maternal education, early infections, and antibiotic use with celiac disease: a population-based Birth Cohort Study in Northeastern Italy. American Journal of Epidemiology. 2014;180:76–85.
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. New England Journal of Medicine. 1995;332:133–8.
Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, Frischer T, Gotz M, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63:5–34.
Almqvist C, Wettermark B, Hedlin G, Ye W, Lundholm C. Antibiotics and asthma medication in a large register-based cohort study—confounding, cause and effect. Clinical and Experimental Allergy. 2012;42:104–11.
Risnes KR, Belanger K, Murk W, Bracken MB. Antibiotic exposure by 6 months and asthma and allergy at 6 years: findings in a cohort of 1,401 US children. American Journal of Epidemiology. 2011;173:310–8.
Rusconi F, Gagliardi L, Galassi C, Forastiere F, Brunetti L, La Grutta S, et al. Paracetamol and antibiotics in childhood and subsequent development of wheezing/asthma: association or causation? International Journal of Epidemiology. 2011;40:662–7.
Wang JY, Liu LF, Chen CY, Huang YW, Hsiung CA, Tsai HJ. Acetaminophen and/or antibiotic use in early life and the development of childhood allergic diseases. International Journal of Epidemiology. 2013;42:1087–99.
Hoskin-Parr L, Teyhan A, Blocker A, Henderson AJ. Antibiotic exposure in the first two years of life and development of asthma and other allergic diseases by 7.5 yr: a dose-dependent relationship. Pediatric Allergy and Immunology. 2013;24:762–71.
Semic-Jusufagic A, Belgrave D, Pickles A, Telcian AG, Bakhsoliani E, Sykes A, et al. Assessing the association of early life antibiotic prescription with asthma exacerbations, impaired antiviral immunity, and genetic variants in 17q21: a population-based birth cohort study. The Lancet Respiratory Medicine. 2014;2:621–30.
Ortqvist AK, Lundholm C, Kieler H, Ludvigsson JF, Fall T, Ye W, et al. Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis. BMJ. 2014;349:g6979.
Metsala J, Lundqvist A, Virta LJ, Kaila M, Gissler M, Virtanen SM. Prenatal and post-natal exposure to antibiotics and risk of asthma in childhood. Clinical and Experimental Allergy. 2015;45:137–45.
Celedon JC, Fuhlbrigge A, Rifas-Shiman S, Weiss ST, Finkelstein JA. Antibiotic use in the first year of life and asthma in early childhood. Clinical and Experimental Allergy. 2004;34:1011–6.
Marra F, Marra CA, Richardson K, Lynd LD, Kozyrskyj A, Patrick DM, et al. Antibiotic use in children is associated with increased risk of asthma. Pediatrics. 2009;123:1003–10.
Foliaki S, Pearce N, Bjorksten B, Mallol J, Montefort S, von Mutius E, et al. Antibiotic use in infancy and symptoms of asthma, rhinoconjunctivitis, and eczema in children 6 and 7 years old: International Study of Asthma and Allergies in Childhood Phase III. Journal of Allergy and Clinical Immunology. 2009;124:982–9.
Fuchs O, von Mutius E. Prenatal and childhood infections: implications for the development and treatment of childhood asthma. The Lancet Respiratory Medicine. 2013;1:743–54.
McKeever TM, Lewis SA, Smith C, Collins J, Heatlie H, Frischer M, et al. Early exposure to infections and antibiotics and the incidence of allergic disease: a birth cohort study with the West Midlands General Practice Research Database. Journal of Allergy and Clinical Immunology. 2002;109:43–50.
Willing BP, Russell SL, Finlay BB. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nature Reviews Microbiology. 2011;9:233–43.
Gagliotti C, Morsillo F, Resi D, Milandri M, Moro ML. Antibiotic treatments for children ages 0–23 months in a northern Italy region: a cohort study. Infection. 2006;34:155–7.
Holstiege J, Garbe E. Systemic antibiotic use among children and adolescents in Germany: a population-based study. European Journal of Pediatrics. 2013;172:787–95.
Mangrio E, Wremp A, Moghaddassi M, Merlo J, Bramhagen AC, Rosvall M. Antibiotic use among 8-month-old children in Malmo, Sweden–in relation to child characteristics and parental sociodemographic, psychosocial and lifestyle factors. BMC Pediatrics. 2009;9:31.
Thacher JD, Gruzieva O, Pershagen G, Neuman A, Wickman M, Kull I, et al. Pre- and postnatal exposure to parental smoking and allergic disease through adolescence. Pediatrics. 2014;134:428–34.
Martel MJ, Rey E, Malo JL, Perreault S, Beauchesne MF, Forget A, et al. Determinants of the incidence of childhood asthma: a two-stage case-control study. American Journal of Epidemiology. 2009;169:195–205.
Acknowledgments
All phases of this study were supported by a grant from the University of Padua to Dr. Cristina Canova (Senior Grant Holder, year 2013, F.S. 4.18.01.05).
Ethical standards
The manuscript does not contain clinical studies or identifiable patient data.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Pitter, G., Ludvigsson, J.F., Romor, P. et al. Antibiotic exposure in the first year of life and later treated asthma, a population based birth cohort study of 143,000 children. Eur J Epidemiol 31, 85–94 (2016). https://doi.org/10.1007/s10654-015-0038-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10654-015-0038-1