Our study is the first to investigate the association between number and types of antibiotic exposures in different stages of childhood and the onset of four common pediatric ADs (DM, AIT, JIA, or IBD) in a mutual setting. We showed that the relationship between the number of antibiotic exposures and the onset of ADs seems to be non-linear. In addition, the likelihood of developing ADs after antibiotic exposures in infancy remained low, especially regarding DM, AIT, and IBD. Despite of being the most common antibiotic used in childhood, penicillins (predominantly amoxicillin) would be relatively safe to use at any age in relation with the development of ADs, while exposures to macrolides within the two years prior to diagnosis may present minor association. Regarding specific diagnosis, the number of antibiotic exposures throughout childhood was mainly associated with JIA. Even then, exposures to penicillin group antibiotics did not increase the likelihood of JIA, while exposures to cephalosporin, macrolide, and amoxicillin-clavulanic (especially before the age of three) might moderately do so.
In our study, antibiotic exposures in infancy did not increase the likelihood of developing any ADs. Furthermore, we showed that frequent antibiotic exposures after first year of life may be related with ADs when compared with occasional exposures, but not when compared with those having no records of antibiotic purchases in each observation period. However, this finding seems to be predominantly related to JIA and DM, but not with AIT and IBD. How do these findings align with previous studies? A Swedish register-based study presented a connection between prescribed antibiotics during infancy and the onset of DM , while studies from which countries have not reported significant association between early childhood antibiotic exposures and DM [19, 24]. Studies from United Kingdom and Finland have associated both lifetime and early life antibiotic exposures and the onset of JIA [14, 15]. As for IBD, early antibiotic exposures have been related with Crohn’s disease but not with ulcerative colitis [17, 25]. Most of these studies assumed a linear association between antibiotic exposures and the onset of a particular AD, thus assuming that the lowest risk for ADs is retained by those without previous antibiotic exposures. Our study challenges this presumption. Since infancy is the most susceptible period for common infectious diseases and is the period of most frequent antibiotic use , it is reassuring that antibiotics used in early childhood hardly increased the likelihood of developing pediatric ADs. Beyond first year of life, occasional antibiotic courses (approximately 1-2 courses per year) can generally be seen as a low-risk approach in relation to the development of ADs.
We showed that exposures to macrolides within the two years before obtaining diagnosis may be related with the overall development of ADs. In addition, exposures to antibiotics with broader spectrum (cephalosporine, macrolide, and amoxicillin-clavulanic acid), particularly before the age of three years, were moderately associated with JIA. On the contrary, penicillins (as the most common antibiotic type used to treat infections throughout childhood) were not related to the development of any ADs at any age. Hence, the relationship between antibiotics and ADs could not solely be explained by number of infections, as often speculated.
Several studies have reported an association between gut dysbiosis and autoimmune diseases [27–30]. Since antibiotics have been shown to have an influence on gut microbial homeostasis , antibiotic exposures could as well be related to ADs through facilitating gut dysbiosis. Variations in magnitude and specificity of gut microbiota modification by different antibiotics have been reported, hence requiring variable recovery time after exposures [32–34]. For example, macrolides have both a broad spectrum and long-term influence on gut microbiota that may persist even for several years [35, 36]. In our study, azithromycin was the most often used antibiotic among macrolides. Azithromycin has a broad bacteriostatic spectrum, a marked tissue penetration, a high stability and a low clearance rate due to its long half-life, which enable it to reach a higher cellular concentration compared to penicillin . These characteristics may explain the long-term influences of azithromycin (as a macrolide) on gut microbiota compared with penicillin. Furthermore, previous Fin-HIT study showed that azithromycin presented the strongest inverse association with salivary microbiota diversity . Since dysbiosis of gut and salivary microbiota have also been associated with ADs , we suggest that macrolides might catalyze longer-term dysbiosis, explaining their association with the development of ADs, particularly up to two years prior to diagnosis, while penicillin was not associated with any type of ADs at any ages. Further studies to examine the potential link between the use of broad-spectrum antibiotics, the time of their influence on gut microbiota, gut dysbiosis, and the onset of ADs is warranted.
The strength of our study lies in the comprehensive longitudinal data from national registers. For example, we were able to trace purchased antibiotics as outpatients rather than just prescribed. In addition, we studied several ADs in a mutual setting, using rather homogenous Fin-HIT cohort with small variations in socioeconomic status as the source of study population. The control population was matched with details based on age (with only up to 4 days of age difference), sex, residential area, gestational age, and delivery method to limit the number of potential confounding factors. Therefore, our study setting made it possible to examine the association between childhood antibiotic exposures and onsets of the four pediatric ADs together, and to reliably compare one disease to another in this subject.
As for limitations, we lack the information on the children’s genetic susceptibility to infections or to ADs. We also did not know why the antibiotics were purchased – for treating infections (and if so, for what kind of infection) or for prophylactic purposes – and on whether secondary antibiotic courses for the same infection were needed. In addition, we had no access on the length of purchased antibiotic courses nor on the antibiotics given during inpatient care. Yet, antibiotic treatments during hospitalization are often continued orally after discharge, and our data cover these post-discharge antibiotic purchases.