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Lack of Association between Antibiotic Use in the First Year of Life and Asthma, Allergic Rhinitis, or Eczema at Age 5 Years

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital; Division of Pulmonary and Critical Care Medicine, Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard School of Public Health; and Dana-Farber Cancer Institute, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Juan C. Celedón, M.D., Dr.P.H., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: juan.celedon{at}channing.harvard.edu

ABSTRACT

Five retrospective studies have reported an association between antibiotic use in early life and asthma in childhood. We studied the relationship between the use of oral antibiotics in the first year of life and asthma, allergic rhinitis, and eczema at age 5 years among 448 children with a parental history of atopy monitored from birth. After adjustment for potential confounders, we found no significant association between antibiotic use in the first year of life and asthma (odds ratio [OR] for one versus no courses of antibiotics, 0.5; 95% confidence interval [CI] for OR, 0.2 to 1.5; OR for two or more versus no courses of antibiotics, 1.0; 95% CI for OR, 0.5 to 2.2), recurrent wheezing, allergic rhinitis, or eczema at age 5 years. There was no significant association between antibiotic use in the first year of life and having at least one of three atopic diseases (asthma, allergic rhinitis, or eczema) at age 5 years (OR for one versus no courses of antibiotics, 0.7; 95% CI, 0.4 to 1.4; OR for two or more versus no courses of antibiotics, 0.9; 95% CI, 0.5 to 1.4). Our findings do not support the hypothesis that antibiotic use in early life is associated with the subsequent development of asthma and atopy in childhood.

Key Words: antibiotic use • asthma • early life

Asthma, a major public health problem, affects more than 17 million people in the United States (1). Over the last 30 years, the prevalence of asthma has increased significantly in the United States and other countries with a Western life style (2–4). Reduced exposure to infections (5) and the use of oral antibiotics in early childhood (6) have been proposed as factors that may explain the asthma epidemic in industrialized countries.

Five retrospective studies (6–10) have found an association between antibiotic use in early life and asthma in childhood. Because oral antibiotics are frequently prescribed for children with infections of the upper and lower respiratory tract (11), understanding the relationship between antibiotic use in early life and the development of asthma and other allergic diseases in childhood has significant implications for public health practitioners and clinicians worldwide.

The Home Allergens and Asthma Study is a prospective birth cohort study of children with a parental history of asthma or allergies in the Boston metropolitan area. In this report, we examine the association between frequency of use of oral antibiotics in the first year of life and asthma, recurrent wheezing, allergic rhinitis, and eczema at age 5 years among study participants.

METHODS

The 505 infants with a history of allergy or asthma in at least one parent were recruited between September 1994 and August 1996 (12). Every 2 months, beginning when the child was 2 months old, a telephone questionnaire was administered to the child's primary caregiver until the child's second birthday. Afterwards, interviews were conducted every 6 months. Of the 505 children, 7 were excluded from analysis because they were monitored for 4 months or less during their first year of life. The study was approved by the Institutional Review Board of the Brigham and Women's Hospital (Boston, MA).

Every 2 months during the child's first year of life, the primary caregiver was asked about the child's use of antibiotics. If the child was prescribed one or more courses of antibiotics by a physician, the interviewer recorded the route of administration and the indication for each course of antibiotics.

Variables considered for inclusion in the multivariate analysis were sociodemographic factors such as the child's race (12), annual household income, and day care attendance in the first year of life (13). Perinatal and familial factors included in utero exposure to smoking; number of months of breast-feeding (0–2, 3–8, or 9–12); paternal history of asthma (ever, and ever with current symptoms [active]), paternal history of hay fever (ever), and paternal history of eczema (ever); maternal history of asthma (ever, and ever with current symptoms [active]), maternal history of hay fever (ever), and maternal history of eczema (ever); number of older siblings (14 years of age or less) in the household; and average number of cigarettes per day smoked by all adults in the household.

At age 5 years, asthma was defined as physician-diagnosed asthma and one or more episodes of wheezing in the previous 12 months; allergic rhinitis as physician-diagnosed allergic rhinitis and a history of nasal discharge or sneezing apart from colds in the previous 12 months; and eczema as physician-diagnosed eczema and a history of a pruritic rash lasting at least 6 months in the previous year.

Every year—starting at the age of 2 years—the primary caregiver was asked the following: "How many attacks or episodes of wheezing has your child had in the past 12 months?" (zero; one; two, but < one per month; one per month; one every week; daily or nearly every day). Transient wheezing was defined as 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 was defined as no episodes of wheezing before the age of 3 years and one or more episodes of wheezing between 4 and 5 years of age. Persistent wheezing was defined as one or more episodes of wheezing before the age of 3 years and one or more episodes of wheezing between 4 and 5 years of age. Recurrent wheezing at age 5 years was defined as two or more episodes of wheezing in the previous 12 months.

Bivariate relationships between predictor and outcome variables were analyzed by ² tests in the case of pairs of categorical variables, or two-tailed t tests in the case of a categorical and a continuous variable. Logistic regression was used to study the relationship between antibiotic use in the first year of life and the outcomes of interest. Stepwise logistic regression was used to develop the multivariate models. In the final models, we included those variables that satisfied a change-in-estimate criterion (10% or more in the odds ratio [OR] estimate), or that were significant at the p < 0.05 level.

RESULTS

Table 1 shows the characteristics of the study subjects. Three hundred and fifty-two (70.7%) of the 498 study participants received 752 courses of oral antibiotics in their first year of life (Table 1). As reported by the primary caregivers of participating children, the indications for use of doctor-prescribed oral antibiotics in the first year of life were ear infections (62.1%), wheezing (21.4%), cough (10.9%), nasal congestion and nasal discharge (3.9%), difficulty in breathing (1%), and difficulty in eating (0.7%). Of the 498 study participants, 448 (90%) were monitored up to the age of 5 years. Subjects who dropped out of the study before the age of 5 years were significantly more likely to come from low-income families and to not be breast-fed in the first year of life than subjects who were monitored up to the age of 5 years. There was no significant difference in frequency of use of oral antibiotics in the first year of life between those who were monitored up to the age of 5 years and those who dropped out of the study before the age of 5 years (p > 0.2).

The estimates of the association between the use of oral antibiotics in the first year of life and the outcomes of interest were similar whether the child received antibiotics in the first or second 6 months of life. Thus, the use of oral antibiotics in the first and second 6 months of life was combined. Because the estimate of the association between using oral antibiotics in the first year of life and the outcomes of interest were similar whether the child received two or three courses of antibiotics, the frequency of use of oral antibiotics in the first year of life was categorized as zero, one, and two courses. Table 2 shows the results of the bivariate and multivariate analyses of the relationship between frequency of antibiotic use in the first year of life (number of courses of oral antibiotics) and asthma, allergic rhinitis, and eczema at age 5 years. Among participating children, there was no significant association between use of oral antibiotics in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. In the multivariate analysis, active maternal history of asthma (OR, 4.5; 95% confidence interval [CI], 1.8 to 11.0) and male sex (OR, 3.3; 95% CI, 1.5 to 7.7) were strongly associated with asthma in the child. There was no significant association between use of oral antibiotics in the first year of life and recurrent wheezing at age 5 years (unadjusted OR for one versus no courses of antibiotics, 0.9; 95% CI, 0.4 to 2.3; unadjusted OR for two or more versus no courses of antibiotics, 0.9; 95% CI, 0.4 to 2.0).

Table 3 shows the analysis of the association between the use of oral antibiotics in the first year of life and transient and persistent wheezing. Although antibiotic use in the first year of life was significantly associated with transient wheezing in the bivariate analysis, this association became weaker and not statistically significant after adjustment for other variables (Model 1). In the multivariate analysis, a low household income (less than $30,000/yr) was significantly associated with transient wheezing (OR, 3.0; 95% CI, 1.1 to 8.2), and there was a nonstatistically significant trend for an association between day care in the first year of life and transient wheezing (OR, 1.4; 95% CI, 0.9 to 2.2). We found no significant association between antibiotic use in the first year of life and persistent wheezing. In the multivariate analysis (Model 3), active maternal history of asthma and male sex (OR, 2.2; 95% CI, 1.1 to 4.4) were significantly associated with persistent wheezing.

We found no significant association between antibiotic use in the first year of life and late-onset wheezing (n = 20) on bivariate analysis (OR for one versus no courses of antibiotics, 0.8; 95% CI, 0.2 to 3.1; OR for two or more versus no courses of antibiotics, 1.4; 95% CI, 0.5 to 4.0). There was no significant difference in geometric mean total serum IgE level at age 2 years between children who received oral antibiotics in the first year and those who did not (16.1 [± 1 SD = 4.2, 61.2] IU/ml versus 13.8 [± 1 SD = 3.7, 51.2] IU/ml, p > 0.2).

DISCUSSION

Among children with a familial history of atopy, the use of oral antibiotics in the first year of life was not associated with recurrent wheezing, asthma, allergic rhinitis, or eczema at age 5 years. In addition, there was no association between antibiotic use in the first year of life and total serum IgE level at age 2 years. To our knowledge, this is the first prospective birth cohort study to examine the association between antibiotic use in the first year of life and asthma, allergic rhinitis, and eczema later in childhood.

In a retrospective study conducted in England, treatment with oral antibiotics in the first 2 years of life was strongly associated with having asthma (OR for one or more versus no courses of antibiotics, 3.2; 95% CI, 2.4 to 4.2) and at least one atopic disorder (OR for two versus no courses of antibiotics, 3.1; 95% CI, 2.1 to 4.3; OR for three versus no courses of antibiotics, 8.4; 95% CI, 3.3 to 21.4) later in childhood (6). A cross-sectional study of children ages 5–10 years attending Rudolf Steiner schools in New Zealand showed a strong association between use of oral antibiotics in the first year of life and a history of asthma (OR, 4.0; 95% CI, 1.5 to 10.6), but no significant association between antibiotic use in early life and current wheezing, hay fever, or eczema (8). In a retrospective study of 7- and 8-year-old Belgian children, the use of oral antibiotics in the first year of life was associated with asthma, allergic rhinitis, and eczema only among children with a familial history of hay fever (OR for asthma, 2.3; 95% CI, 1.1 to 5.1; OR for hay fever, 2.8; 95% CI, 1.5 to 5.1) (9). In a cross-sectional study of 5- to 14-year-old German children, antibiotic use in the first year of life was strongly associated with childhood asthma (OR for one or more versus no courses of antibiotics in the first 6 months of life, 9.9; 95% CI, 3.1 to 31.4) and wheezing (OR for one or more versus no courses of antibiotics in the first 6 months of life, 7.9; 95% CI, 4.8 to 12.8), but not with sensitization to allergens or an elevated total serum IgE level (10). More recently, a prospective birth cohort study of German children showed no association between the use of antibiotics in the first 3 years of life for reasons other than lower respiratory illnesses and physician-diagnosed asthma, current wheeze, or bronchial hyperreactivity at age 7 years (14). In that study, there was no description of the association between antibiotic use in the first year of life and the outcomes of interest.

In humans, the immune response of newborns is associated predominantly with the helper T cell type 2 (Th2) cytokine phenotype (15). Whereas rapid suppression of Th2 immune responses during the first year of life occurs in nonatopic children, atopic individuals exhibit a continuation of fetal allergen-specific Th2 responses during infancy (15). Because antibiotic use in infant mice leads to alterations of the intestinal flora and impaired Th1 immune responses (16), it has been hypothesized that the previously observed association between antibiotic use in early life and asthma in humans is due to antibiotic-induced changes in intestinal flora leading to a Th2-polarized immune deviation (6, 10). Our longitudinal findings and the lack of association between antibiotic use in early life and either sensitization to allergens or an elevated total serum IgE level in a retrospective study (10) do not support this hypothesis.

In our study, antibiotic use in the first year of life was associated with transient wheezing on bivariate analysis. This association was no longer present after the analysis was restricted to antibiotic use for reasons other than wheezing-associated respiratory illnesses, suggesting that children who wheezed in the first year of life received more antibiotics than nonwheezers. In fact, there was a strong cross-sectional association between antibiotic use and two or more episodes of wheezing in the first year of life (OR for one versus no courses of antibiotics, 2.5; 95% CI, 1.1 to 5.6; OR for two versus no courses of antibiotics, 3.8; 95% CI, 1.9 to 7.8). It is thus likely that the finding of an association between antibiotic use in early life and asthma in retrospective studies was due to recall bias and/or "reverse causation" (children with asthma receiving more antibiotics in early life).

We recognize limitations to our findings. First, our study was not designed to be a random sample of the population in the greater Boston area, because we selected a stable population with a parental history of allergy or asthma. Our findings, however, are relevant to a group at high risk for the development of asthma (children with a parental history of asthma or atopy). Second, the diagnosis of asthma in early childhood is fraught with difficulties (17). Our results were not different, however, when we examined outcomes that are independent of a physician's diagnosis of asthma (total serum IgE level at age 2 years, recurrent wheezing at age 5 years, and persistent wheezing) and that may correlate with a higher likelihood of asthma later in childhood. Third, our estimated 80% statistical power to find a significant association (p < 0.05) between antibiotic use in the first year of life and eczema was limited (we could detect only an OR > 3.3). However, we did have adequate statistical power to detect associations between antibiotic use in the first year of life and having asthma and at least one atopic disorder at age 5 years of similar or greater magnitude to those reported in previous retrospective studies (6–10). In particular, we had 80% power to detect an OR > 2.3 for the association between the use of two or more courses of oral antibiotics in the first year of life and either asthma or allergic rhinitis at age 5 years. For the association between the use of two courses of antibiotics in the first year of life and having one atopic disorder at age 5 years, we had 80% power to detect an OR > 1.9. Fourth, our definition of eczema was not based on direct examination of the skin of participating children, likely resulting in an underestimation of the prevalence of eczema in our study population.

In summary, the use of oral antibiotics in the first year of life was not associated with an increased risk of recurrent wheezing, asthma, allergic rhinitis, or eczema at age 5 years among children with a parental history of atopy. Our results do not support the hypothesis that antibiotic use in early life is associated with the subsequent development of atopic diseases.

Acknowledgments

The authors thank the study participants, Ms. Diane Sredl for assistance with computer programming, and Ms. Jaylyn Olivo for editorial assistance.

Supported by grant AIEHS35786 from the National Institutes of Health. Dr. Celedón is supported by a Charles A. King Trust Fellowship Award.

Received in original form September 21, 2001; accepted in final form January 31, 2002

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