Antibiotics Before Age 1 Tied to Celiac Disease Risk

Exposure to systemic antibiotics in the first year of life was modestly associated with later diagnosis of celiac disease, a national study of Danish and Norwegian children found.

In the observational study of two independent cohorts numbering more than 1.7 million children, a dispensed systemic antibiotic in the first year of life consistently correlated with diagnosed celiac disease, with a pooled odds ratio (OR) of 1.26 (95% CI 1.16-1.36), according to Stine Dydensborg Sander, MD, PhD, of Hans Christian Andersen Children’s Hospital in Odense, Denmark, and colleagues.

And a dose-dependent relationship emerged as the number of antibiotic prescriptions increased (OR 1.08, 95% CI 1.05-1.11), they reported in Gastroenterology.

“These findings indicate that childhood exposure to systemic antibiotics may be a risk factor for celiac disease,” the authors stated.

Other studies have found no such association, including the 2017 TEDDY study, a multinational cohort of children at high genetic risk of type 1 diabetes and celiac disease. TEDDY “found no association between parentally reported antibiotic exposure and persistently positive celiac disease,” at age 4 years, Sander and colleagues noted.

“In contrast to population-based cohort studies that do not include cases of undiagnosed children, screening for celiac disease autoimmunity as the outcome captured all the children with celiac disease and some who never will develop celiac disease. Our findings may be affected if factors related to being diagnosed as opposed to remaining undiagnosed are related to the use of antibiotic,” they stated.

Neither a specific type of antibiotic nor age at exposure were prominent factors in celiac disease, suggesting there is no particularly vulnerable age and no differing effect among antibiotic classes. The association was at least as strong for exposure from 0 to 24 months as for 0 to 12 months, Sander’s group reported.

The study cohorts consisted of children born in Denmark from 1995 to 2012 (the Danish National Birth Cohort) and followed until May 2015, and children born in Norway from 2004 to 2012 (the Norwegian Mother and Child Cohort Study) and followed until December 2013. The mothers answered questionnaires, sometimes aided by computer-assisted telephone interviews, on infectious diseases and feeding.

The final analysis in the Danish cohort included 1,168,656 children with a median age at end of follow-up of 11.6 years. A diagnosis of celiac disease was registered for 1,427 of these children (0.12%). Systemic antibiotics in the first year of life were dispensed to 451,196 participants without celiac disease (38.7%) and to 622 with celiac disease (43.6%).

The final Norwegian cohort consisted of 537,457 children, with a median age at end of follow-up of 5.4 years. Celiac disease was diagnosed in 1,919 (0.36%) of participants. Systemic antibiotics in the first year of life were dispensed to 98,538 without celiac disease (18.4%) and to 390 with celiac disease (20.3%).

Data from two large subgroups within the final cohort looked at the potentially confounding impact of adjustment for the number of children’s maternally reported infections as well as the duration of breastfeeding, examined 6 and 18 months postpartum for 55,082 Danish children (100 with celiac disease) and 53,257 Norwegian children (464 with celiac disease). Neither variable had a measurable impact, nor did prescriptions for topical antifungal drugs, although these were more common in those registered for systemic antibiotics.

The authors pointed out that the intestinal microbiota is considered a player in pathogenesis of celiac disease and one strongly influenced by systemic antibiotics, especially in early life. Early-life infections have been proposed as promoters of celiac disease development and important potential confounders. Some studies have reported associations with types of infection, as well as the number of hospital admissions for infectious diseases, medically attended infectious diseases, and parentally reported infectious diseases.

Jocelyn A. Silvester, MD, of Boston Children’s Hospital and Harvard Medical School, commented that understanding the potential ties between antibiotics and celiac disease poses a challenge.

“This is a very difficult question to answer, even though this is one of the largest datasets we have to look at,” said Silvester, who was not involved in the study.

She added that it is difficult to tease out the true relationship because of potential confounding factors, noting that not all antibiotic types have the same effect on the microbiota, and not all the infections treated with antibiotics were bacterial but may have included viral and fungal.

Underlying infection rather than antibiotics may have been driving the celiac risk. “But having large well-done studies that try to answer difficult questions is always a step in the right direction,” Silvester said.

Study limitations included the difficulty of disentangling the effect of infections and antibiotics in an observational study lacking details of the infections and indications for antibiotic use.

The authors concluded that the findings could have resulted from reverse causality, in which the symptoms of celiac disease can mimic infection, exaggerate infectious symptoms, or raise the risk of infectious diseases, thereby increasing the propensity for prescriptions for antibiotics.