September 24, 2012 — Children who received antianaerobic antibiotics in the first year of life had a 5.5-fold increased risk of developing inflammatory bowel disease (IBD) compared with those who were never exposed, according to a retrospective cohort study of more than 1 million children.
Matthew P. Kronman, MD, MSCE, an assistant professor of pediatric infectious diseases in the Division of Infectious Diseases at Seattle Children's Hospital and the University of Washington in Seattle, and colleagues presented their findings in an article published online September 24 in Pediatrics.
"We sought to examine the association between childhood antianaerobic antibiotic exposure and subsequent IBD development using a large population-based cohort, hypothesizing that exposure to antibiotics with anaerobic activity would be associated with the development of IBD," the authors write.
They analyzed data from 464 ambulatory practices in the United Kingdom that were participants in the Health Improvement Network. All children with at least 2 years of data from 1994 to 2009 were followed up between practice enrollment and IBD development, practice deregistration, 19 years of age, or death. The investigators excluded children with previous IBD.
A total of 1,072,426 patients provided 6.6 million person-years of follow-up. Of those patients, 748 (0.07%) developed IBD, for an overall incidence rate of 1.2/10,000 person-years. Of the 225,100 patients followed from birth, only 30 developed IBD, so meaningful analyses were not possible in this subgroup.
Among the 748 children who developed IBD, the median latency period between the first healthcare visit with a gastrointestinal diagnosis suspicious for IBD and the first IBD diagnosis was 3.9 months (interquartile range [IQR], 0.5 - 17.9 months), and 68.2% had latencies of 1 year or less. Fewer than 25% of the other children had diagnoses consistent with possible IBD within 5 years before censorship.
Exposure to Antibiotics
More than half (57.7%) of the patients received at least 1 antianaerobic antibiotic, defined as penicillin, amoxicillin, ampicillin, penicillin/b-lactamase inhibitor combinations, tetracyclines, clindamycin, metronidazole, cefoxitin, carbapenems, and oral vancomycin.
The patients took antianaerobic antibiotics for a median of 1 week (IQR, 0 - 2 weeks), with 42.3% receiving none, 31.9% receiving them for 1 to 2 weeks, and 25.8% receiving them for more than 2 weeks.
In both the unexposed and exposed groups, 0.07% of children developed IBD; however, the IBD incidence rates were 0.83/10,000 person-years in the unexposed group and 1.52/10,000 person-years in the exposed group, for an absolute risk increase of 0.69 cases/10,000 person-years and an 84% relative risk increase.
In univariate analysis, any antianaerobic antibiotic exposure was associated with developing IBD (P < .001, log-rank test), there was a dose-response effect (P < .001, log-rank test), and this association remained significant throughout childhood.
In their multivariate analysis, the investigators adjusted for family history of IBD, gender, chronic granulomatous disease, primary sclerosing cholangitis, and socioeconomic deprivation. They found that exposure by 1 year of age was associated with a 5.5-fold increased IBD risk (adjusted hazard ratio [aHR], 5.51; 95% confidence interval [CI], 1.66 - 18.28) compared with those never exposed, with IBD risks decreasing every 5 (aHR, 2.62; 95% CI, 1.61 - 4.25) and 15 (aHR, 1.57; 95% CI, 1.35 - 1.84) years.
Each course of antianaerobic antibiotics was associated with a 6% increased IBD hazard (aHR, 1.06; 95% CI, 1.04 - 1.08), and each week of exposure was associated with a 1% increase in hazard (aHR, 1.01; 95% CI, 1.00 - 1.02).
Exposure to more than 2 courses of antianaerobic antibiotics in the first year of life had a higher association with IBD development than exposure to 1 to 2 courses, with an aHR of 4.77 (95% CI, 2.13 - 10.68) vs 3.33 (95% CI, 1.69 - 6.58).
Exposure to any antibiotic, penicillins, broad-spectrum penicillins, and cephalosporins was associated with development of IBD, but exposure to macrolide, sulfonamide, and tetracycline were not.
Exposure to metronidazole or fluoroquinolones (2 potential IBD treatments) was associated with IBD development.
"[T]hese class-specific findings remained significant after re-setting the IBD outcome at the first metronidazole or fluoroquinolone prescription in the year before IBD diagnosis, suggesting that outcome misclassification was not significantly present," the authors write. Exposure to any fluoroquinolone (aHR, 2.09; 95% CI, 1.10 - 3.98]) and any metronidazole (aHR, 186.25; 95% CI, 10.86 - 3193.65) by 1 year of age.
Results were similar for the 2 IBD subgroups, Crohn's disease, and ulcerative colitis, but they did not vary with age. The primary outcome was not changed when sensitivity analysis was conducted by assigning all missing Townsend scores first in the highest and then in the lower deprivation category.
When sensitivity analysis was conducted using a 1-year latency period, the primary outcome's precision and magnitude were altered, but not its direction: any antianaerobic antibiotic exposure in the first year of life (aHR, 3.73; 95% CI, 1.17 - 11.84), each course of antibiotics (aHR, 1.03; 95% CI, 0.99 - 1.06), exposure to 1 to 2 courses of antibiotics (aHR, 2.18; 95% CI, 1.07 - 4.50), and exposure to more than 2 courses of antibiotics (aHR, 4.14; 95% CI, 1.74 - 9.87).
"Our study suggests that reduction in childhood antianaerobic antibiotic use may have the potential to help curb the rising incidence of childhood IBD. Many unanswered questions remain, however, such as whether specific difficult-to-culture organisms could play roles in either IBD pathogenesis or protection against IBD, and whether alteration of flora through antibiotic exposure alters the immune system directly," the authors write.
Sonia Michail, MD, an investigator at the Saban Research Institute of Children's Hospital Los Angeles, California, and an associate professor of clinical pediatrics at the Keck School of Medicine of the University of Southern California, commented on the study in an email interview with Medscape Medical News.
Dr. Michail was not surprised by the association between antibiotics and the development of IBD, but she was surprised by the strength of the association.
"This work further confirms the strong contribution of the gut microbiome towards the development of disease and suggests that perturbations of the gut microbiome at an early stage in life when the immune system is still developing may have an impact on disease incidence several years later. These findings fit well with what we now know about the effect of antimicrobial therapy on the gut microbiome," Dr. Michail said.
"This study highlights the importance of judicial use of antibiotics, especially in young infants and children at higher risk for developing [IBD] such as those with a strong family history of IBD. It adds yet another depth to the potential risk of using antimicrobial therapy in infants and children," Dr. Michail said.
Dr. Kronman received support for this study from a National Research Service Award Institutional Research Training grant at the Children's Hospital of Philadelphia in Pennsylvania, as well as a University of Pennsylvania Center for Education and Research on Therapeutics grant from the Agency for Healthcare Research and Quality. This work was also supported by a National Institutes of Health Clinical and Translational Science Award and was funded by the National Institutes of Health. One author has received research support from Merck and Company Inc for other projects and has served as a consultant for Pfizer Inc, HemoCue Inc, Merck and Company Inc, Cubist Pharmaceuticals, and Astellas Pharma US Inc. He has also received a lecture honorarium from Merck and Company Inc. Another author previously received research support from Sage Pharmaceuticals Inc for other projects. The remaining authors and Dr. Michail have disclosed no relevant financial relationships.
Pediatrics. Published online September 24, 2012. Abstract