Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity

Abstract

Importance: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases.

Objective: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD.

Design, setting, and participants: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D.

Exposures: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively.

Main outcomes and measures: Islet autoimmunity and CD autoimmunity were defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity.

Results: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02).

Conclusions and relevance: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

Figure 1. Overview of Antibiotic Use in The Environmental Determinants of Diabetes in the Young (TEDDY) Study

A, Count of the 20 most often used antibiotics in the first 48 months of life in the TEDDY study. B, Procedure for forming antibiotic groups. Medications listed under the headings were extracted from the TEDDY medication database. These medications were grouped into major antibiotic categories (cephalosporins, amoxicillins, penicillin, macrolides, and carbapenems). These categories were further collapsed into any antibiotic, β-lactam antibiotics, and all penicillins, as indicated by the flowchart. All antibiotic categories except carbapenems were considered for analysis. C, Percentage of any antibiotic use in the first 48 months of life for the chosen antibiotic groups. D, Table of the percentage of antibiotic use attributed to otitis media and the second most common reasons for use. USP indicates United States Pharmacopeia.

Figure 2. Example of Sampling and Lag Periods in Relation to Islet Autoimmunity or Celiac Disease Autoimmunity Seroconversion

In this example, the 27-month and 30-month serum samples are confirmed positive for islet or tissue transglutaminase autoantibodies. Therefore, the date of seroconversion is set at 27 months. The seroconversion period is the 3-month interval between the last negative (24-month sample) and the first positive (27-month sample) autoantibody sample.

Figure 3. Frequency of Use by Antibiotic Type

Frequency of use (in doses) is shown categorically for each specific antibiotic up to age 1 year (A) and up to age 4 years (B).