By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: A population-based cohort study showed that exposure to antibiotics during the first two years of life is associated with increased rates of subsequently developing asthma, allergic rhinitis, atopic dermatitis, attention deficit hyperactivity disorder, celiac disease, and obesity.

SOURCE: Aversa Z, Atkinson EJ, Schafer MJ, et al. Association of infant antibiotic exposure with childhood health outcomes. Mayo Clin Proc 2020; Nov 6. doi 10.1016/j.mayocp.2020,07.019. [Online ahead of print].

The efficacy and seeming safety of antibiotics to reduce morbidity and mortality caused by infections have led to widespread antibiotic use. There have been reports of antibiotics possibly prompting the subsequent development of some specific diseases, perhaps related to alterations in the microbiome. Aversa and colleagues used a county population’s epidemiologic database to determine associations between the frequency, type, and timing of infant antibiotic use and the subsequent risk of developing immunological, metabolic, and neurobehavioral diseases during childhood.

A total of 14,572 children born between January 2003 and December 2011 were included in the study. Medical record review and antibiotic prescription data were determined using the Rochester Epidemiology Project infrastructure. Post-birth follow-up was for a median of 8.8 years.

Overall, 70% of the children received an antibiotic at least once during the first two years of life. Of those receiving an antibiotic, 32% received five or more courses of treatment. Penicillins were used most commonly (in 64% of infants receiving some antibiotic), with macrolides (26%) and cephalosporins (23%) also commonly used. (Since some children received multiple different antibiotics, these percentages add up to more than 100%.) Sulfonamides were used less commonly (5%). Almost all (99%) antibiotics were given orally.

Antibiotic use was not associated with the subsequent development of food allergy, autism, or learning disability.

Antibiotic use was associated with the subsequent development of asthma in both boys and girls, with increased risk associated with increased numbers of antibiotic prescriptions. Among girls, for instance, the risk of developing childhood asthma was 1.57-fold greater with one to two antibiotic prescriptions (vs. no antibiotic use), 1.85-fold higher with three to four prescriptions, and 3.0-fold higher with five or more prescriptions.

Using five or more courses of antibiotics was associated with a doubled risk of allergic rhinitis (as compared to no antibiotic use). Celiac disease was about 10 times as likely in girls, but not boys, who received antibiotics during infancy. Overweight and obesity were more common in children who received at least three courses of antibiotics. Similarly, attention deficit hyperactivity disorder was only more common in those who received three or more courses of antibiotics during infancy.

The risk of developing these childhood conditions was greater in those receiving penicillins and cephalosporins than in those receiving macrolides. The risk of developing atopic dermatitis was most related to the use of antibiotics during the first six months of life.

The authors speculated that antibiotic-induced alterations in the microbiome were most likely responsible for the subsequent development of these disease conditions.

COMMENTARY

It is striking how many infants receive antibiotics; in this population-based study, 70% of infants received at least one antibiotic prescription during the first two years of life. It is possible that the prevalence of antibiotic use has dropped some since the children in this study were born because of the 2004 American Academy of Pediatrics otitis media management guidelines that included the option of “watchful waiting” (without antibiotic treatment), but there are still many infants being treated with antibiotics.1

It also is striking how strong the relationship was between antibiotic use and the risk of developing asthma, celiac disease, overweight, obesity, and attention deficit hyperactivity disorder. Although the causal mechanisms of the association are unknown, it certainly is plausible that alterations in the microbiome could alter immunological responses related to at least allergic and atopic conditions.

Of course, it should be emphasized that this was a study of associations, not causality. It is possible that children who subsequently would manifest asthma, for example, might have been at increased risk of developing infections (and receiving antibiotics) prior to the asthma declaring itself. It could be that pre-morbid asthma is linked to a risk of infection and a need for antibiotics — rather than the antibiotics causing the asthma de novo. Or, it could be that the earlier infection (and not the antibiotics given for the infection) caused the child to develop asthma subsequently.

Recognizing the uncertainty of the cause-and-effect relationships between antibiotics during infancy and subsequent childhood medical conditions, it still is wise to use antibiotics only when truly needed. If antibiotics are causally related to asthma, overweight, obesity, attention deficit hyperactivity disorder, and celiac disease, then there could be huge reductions in subsequent medical costs, morbidity, and mortality if we would use antibiotics more judiciously during infancy.

REFERENCE

  1. Sun D, McCarthy TJ, Liberman DB. Cost-effectiveness of watchful waiting in acute otitis media. Pediatrics 2017;139: e20163086.