There were several strengths to our study. We recruited pregnant women from many different clinics and pregnancy care providers. The original cohort was enriched so that 40% of mothers had asthma, providing increased power and enabling us to study the effects related to family history of asthma. In other respects, the study cohort is broadly representative of the southern New England population. The study was designed to determine pre- and perinatal risk factors for childhood asthma, and the detailed, prospectively collected measures of potential pre- and perinatal confounders are strengths of these analyses.
Asthma is a complex clinical manifestation that is difficult to diagnose reliably before the age of 6 years (1
). Our analyses included as cases children with a physician-verified diagnosis of asthma and current symptoms during the sixth year of life.
Many studies that have attempted to assess the association between antibiotic use and the development of asthma have been confounded by possible protopathic bias that applies if early asthma symptoms are the reason for antibiotic treatment (20
). Protopathic bias may be minimized by considering only antibiotic exposure that occurs several years before the onset of asthma symptoms (21
). Protopathic bias may also be avoided by studying the associations when antibiotics are used for indications that do not include symptoms similar to asthma, typically lower respiratory tract infections. The present study developed several strategies to reduce the influence of protopathic bias: We excluded from all analyses cases of asthma diagnosed within the first 6 months of age, we conducted separate analyses for asthma first diagnosed after 3 years of age, and we assessed the association in children who had not reported a LRTI in the first year of life. The association between antibiotic exposure before 6 months age and asthma diagnosed after 3 years of age was quite strong. The strong association in children who did not report any diagnosis of lower respiratory infections during the first year of life further supports the interpretation that protopathic bias was limited. Other studies have found weaker results in asthma diagnosed after 3 years age compared with an earlier diagnosis (11
). In a large Canadian database study, however, age at diagnosis did not affect the estimated associations (12
Ascertainment of antibiotic use in this study is dependent upon maternal recall after 5.5 years, warranting cautious interpretation of results. Inaccuracy in these retrospectively collected exposure data could bias estimated associations if mothers of asthmatic children overreported—or if mothers of nonasthmatic children underreported—antibiotic use. Inaccurate maternal recall that is unrelated to the child's asthma status will usually bias estimates toward the null. We did not have access to medical records to evaluate information on antibiotic exposure. The number of factors that could be validated for accuracy was limited, but the high level of observed agreement between interview data and hospital data and the agreement between cases and controls are reassuring regarding the quality of the data in the 6-year questionnaire. Several studies evaluating patient recall (23
) report that agreement with medical records varies by medical condition. In one study, parental reports of asthma and bronchitis reached agreement with medical records by 85%–90% (24
), while another study found that one third of parents had forgotten about first-year-of-life wheezing by the time the child was 11 years of age (26
). Another report specifically validated parental antibiotic recall in a study about childhood atopic diseases and found agreement between questionnaire and medical records of 91% for antibiotic use (27
). In the present study, it is reassuring that the level of exposure, about 30% of children receiving antibiotics by 6 months of age, corresponds well with findings from the largest and most recent database study (11
) that also assessed antibiotic exposure before 6 months in their analyses. We conclude that the likelihood that associations are overestimated because of recall bias is limited.
The association of antibiotics and asthma in the present study was particularly strong in children with no family history of asthma. A similar finding was reported in a Canadian cohort (10
) and corresponds to negative findings in cohorts that included only children with a family history of asthma (15
). One study reported a strong association in children of asthmatic parents (28
), but no test for interaction was performed, and the study included only 53 cases of asthma.
The hygiene hypothesis, although controversial (29
), suggests that microbial exposure in early life enhances postnatal maturation of the immune system that may protect against development of allergic diseases (2
). Normal postnatal development incurs a change from fetal predominantly T helper 2 (known as “TH
2”) to more mature T helper 1 (known as “TH
1”) immunity (4
). Overexpression of TH
2 responses to allergens is the hallmark of allergic diseases (33
). One important mechanism to support the hygiene hypothesis is that microbial exposure, particularly in the intestinal tract, is necessary for postnatal transition to a balanced immune response in healthy children (3
). It has been suggested that the early postnatal period is particularly vulnerable to imbalances in immune response, and that delayed postnatal maturation of TH
1 cell function is a key component of genetic risk for atopy (35
). The present findings are compatible with an interpretation that children with no family history of asthma are more susceptible to the proatopic effects of antibiotics than children with a genetic predisposition to asthma.
Information on antibiotic use did not include details about the type of antibiotics, and this may be a limitation for the biologic interpretation of our findings. Broad-spectrum antibiotics potentially alter microflora more than narrow-spectrum antibiotics. Some studies that could separately assess the effects of broad-spectrum antibiotics found stronger associations with atopic disease than did those with narrow spectrum (9
), possibly supporting the interpretation that early antibiotic exposure alters atopic disease risk through alterations in microflora. In contrast, a large database study (12
) reported that penicillin exposure was associated with a particularly high risk of asthma. It may be of relevance to the strong association found in the present study that US outpatient data from the period of our study show increased use of broad-spectrum antibiotics in small children (37
In our data, we found a strong association between early antibiotic exposure with reported positive immunoglobulin E blood or skin test reactivity. Studies that have assessed the association of antibiotic exposure with immunoglobulin E levels in children (13
) did not report evidence of an association. Two studies assessed a possible association with a positive skin prick test (28
) and found none. Two studies included only high-risk children with a family history of asthma (15
). If antibiotics do not affect the immune response in children with a genetic predisposition to asthma, this could explain the negative findings in these studies. However, the same explanation cannot apply to the negative findings of studies in children more representative of the general population (28
). These studies allergy tested all participants at 7–8 years of age, and the study outcomes were positive allergy tests, regardless of allergy symptoms. The validity of blood or skin prick tests to diagnose allergy in a general population is limited. The positive predictive value for allergic reactions can be as low as 50% (41
). The diagnosis of allergy, therefore, has to be based on clinical history, with supplementary testing (42
). Our study was observational, and tests were performed in children who reported an allergic reaction, suggesting that a positive test result was a reasonably valid indicator of allergy in this cohort. Further studies are warranted to establish whether early antibiotic exposure is associated with childhood allergy.
We conclude that antibiotic exposure before 6 months of age is associated with asthma and allergy at 6 years of age and that protopathic bias is unlikely to account for the main findings. The adverse effect of antibiotics on asthma risk was particularly strong in children with no parental history of asthma, which should encourage physicians to avoid unnecessary antibiotic use in low-risk children with no genetic predisposition to asthma.