Prenatal or Early-Life Exposure to Antibiotics and Risk of Childhood Asthma: A Systematic Review

To the Editors:

In the article describing their systematic review, Murk et al. (1) suggest that a weak association between antibiotic exposure early in life and childhood asthma exists, but methodological and protopathic bias seem to make this relationship difficult to determine. Three different study designs were considered and, as in the systematic review by Marra et al. from 2006 (2), the authors found that retrospective studies had higher pooled risk estimate for asthma than database and prospective studies. As in the recent systematic review by Penders et al. (3), the authors took into account studies from a few countries in which the prevalence of antibiotic prescriptions to children, especially broad-spectrum antibiotics, is wide (4). We compared these data with our analysis of a large Italian population. In a cohort of 48,020 Italian children born in 2000-2001 in the Lombardy Region (the most important and populated Italian region) and followed up to 7 years of age, 2,518 potential asthmatic patients at 6 years of age were identified through a validated strategy (5) using anti-asthmatic drug prescriptions as a reliable proxy of disease (sensitivity 90%, specificity 98%). A total of 5,036 non-asthmatic controls were randomly selected from the same cohort and matched for gender, year of birth, and local health unit of residence. A case-control ratio of 1:2 was chosen to detect an OR >=1.2, with a power of more than 0.90, based on the following assumptions: an alpha error level of 0.05 and an expected incidence of antibiotic use among controls during the first 6 months of life of 25%, calculated on the basis of a previous study (6). In all, 29% of cases and 27% of controls received at least one antibiotic drug prescription during the first 6 months (OR 1.13, 95% CI 1.01-1.26, p=0.02). A slight trend in the association was therefore found also in our database study, comparable to database designed studies that took into account later asthma onset, commented in Murk et al's article. Some considerations should be made: first of all, in some studies children were selected based on the physician's diagnosis of asthma, while in others (as with our methodology based on anti-asthmatic prescriptions, and with other methodologies based on anti-asthmatic prescriptions or hospitalizations for asthma, or medical claims for asthma) patients with actual symptoms requiring drug treatment or hospitalization were retrieved. In other words, asthmatic children whose disease was under control and who were therefore not under therapy, or who did not undergo a doctor's visit or hospitalization, were not considered as asthma cases. Another consideration, as made by Penders et al (3), is the time of asthma onset. The age of asthma diagnosis seems to be a very important point, as demonstrated in the Celedon et al., Marra et al. and Martel et al. studies (7-9), which observed the greatest OR in preschoolers. Diagnosis of asthma in children younger than 6 is difficult to make because they may wheeze without ever developing asthma (transient wheezers). It is very possible that prolonging the time of the follow up, even though this would not exclude a reverse causation in persistent wheezers, would help to exclude transient wheezers, since many of them, at 6-7 years of age are no longer wheezing. The third point is the following: if antibiotic use alters intestinal flora in infants and leads to atopy, the fact that only an association with asthma is found and not an association with hay fever or eczema (10) also raises the doubt of a reverse causation. In conclusion, we found that in the Italian setting exposure to antibiotics in the first 6 months of age slightly increases the risk of asthma at 6 years, but we are not able to exclude confounding biases which, when taken into account, weaken the association "early antibiotic treatment-later onset of asthma". After three very well performed systematic reviews (1-3) and many studies, we now believe that only a large, prospective, multi centered, international study would solve the question. In such an ideal study, only children with asthma diagnosis made at >5 years, as in a recent article (11) or, in the case of database prescription studies, only children who never received anti- asthmatic prescriptions for wheezing before their 6th birthday, should be enrolled. Furthermore, a group of children in whom there may be an association between antibiotics and atopic diseases other than asthma should be included.

REFERENCES 1. Murk W, Risnes KR, Bracken MB. Prenatal or Early-Life Exposure to Antibiotics and Risk of Childhood Asthma: A Systematic Review. Pediatrics 2011 May 23. [Epub ahead of print] 2. Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, Marra CA. Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest. 2006; 129:610-8. 3. Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk - A systematic review and meta-analysis. Eur Respir J. 2011 Jan 13 [Epub ahead of print] 4. Rossignoli A, Clavenna A, Bonati M. Antibiotic prescription and prevalence rate in the outpatient paediatric population: analysis of surveys published during 2000-2005. Eur J Clin Pharmacol. 2007;63:1099- 106. 5. Bianchi M, Clavenna A, Sequi M, Bonati M. Asthma diagnosis vs. analysis of anti-asthmatic prescriptions to identify asthma in children. Eur J Clin Pharmacol. 2011 Mar 25. [Epub ahead of print] 6. Clavenna A, Berti A, Gualandi L, Rossi E, De Rosa M, Bonati M. Drug utilisation profile in the Italian paediatric population. Eur J Pediatr 2009;168:173-180 7. Marra F, Marra CA, Richardson K, Lynd LD, Kozyrskyj A, Patrick DM, Bowie WR, Fitzgerald JM. Antibiotic use in children is associated with increased risk of asthma. Pediatrics. 2009;123:1003-10. 8. Martel MJ, Rey E, Malo JL, Perreault S, Beauchesne MF, Forget A, Blais L. Determinants of the incidence of childhood asthma: a two-stage case- control study. Am J Epidemiol. 2009;169:195-205. 9. Celedon JC, Fuhlbrigge A, Rifas-Shiman S, Weiss ST, Finkelstein JA. Antibiotic use in the first year of life and asthma in early childhood. Clin Exp Allergy. 2004;34:1011-6. 10. Sobko T, Schiott J, Ehlin A, Lundberg J, Montgomery S, Norman M. Neonatal sepsis, antibiotic therapy and later risk of asthma and allergy. Paediatr Perinat Epidemiol. 2010;24:88-92. 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. Am J Epidemiol. 2011;173(3):310-8.

Conflict of Interest:

None declared