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: In a large population-based study, antibiotic use during the first six months of life was associated with a two-fold increase in asthma and a 1.5-fold increase in allergic disease during early childhood.

SOURCE: Mitre E, Susi A, Kropp LE, et al. Association between use of acid-suppressive medications and antibiotics during infancy and allergic diseases in early childhood. JAMA Pediatrics 2018;172:e180315.

Aware that allergic diseases are prevalent in pediatric patients and concerned that alterations in the microbiome might predispose patients to develop allergies, a group of U.S. military researchers retrospectively reviewed charts of 792,130 children who were covered by Department of Defense insurance. Subjects of the study had to enter the insurance-supported system by 35 days of age and continue through at least the first year of life. Those who spent more than a week in the hospital right after delivery and those who were diagnosed with allergy during the first six months of life were excluded from the study. The study subjects were born from 2001 to 2013.

Researchers noted whether the participants had received an antibiotic during the first six months of life. A positive “outcome” included children who, after the first six months of life, developed any allergy, including anaphylaxis, urticaria, asthma, food or medication allergy, allergic rhinitis or conjunctivitis, or atopic or contact dermatitis. Follow-up data were available on included children for a median of 4.6 years.

Overall, 17% of children were prescribed an antibiotic during the first six months of life. The risk of being diagnosed with an allergy increased with antibiotic exposure. Based on adjusted hazard ratios, the risk of developing asthma increased 2.09-fold with antibiotic exposure. Similarly, the risk increased 1.75-fold for allergic rhinitis, 1.51-fold for anaphylaxis, and 1.42-fold for allergic conjunctivitis. The risk of developing food allergy was 1.14-fold higher with antibiotic exposure; this included increased risks of milk and egg allergy but no increased risk of peanut and seafood allergy. The risk did not differ based on whether the children received a full 10-day course of antibiotics or a prescription for a shorter duration.

The authors pointed out that their findings were consistent with a 2011 systematic review linking infant antibiotic use to a 1.52-fold higher risk of developing allergies as well as a 2017 paper demonstrating that antibiotic use in the first three months of life was associated with increased risk of both food and non-food allergies.

Mitre and colleagues advanced the notion of altered microbiomes due to antibiotic use as a plausible explanation for the link between early antibiotic use and the subsequent development of allergic disorder, presumably because of the gut flora’s influence on T cell regulation. This is not merely a human phenomenon. These investigators cited mouse studies showing that early life antibiotic exposure in those rodents also increased the risk of developing allergies later.

Incidentally, this study included a concurrent evaluation of the risk of antacid use during infancy on the subsequent development of allergic disease. As with antibiotic use, the use of antacids during the first six months of life was associated with an increased risk of developing allergic disease later — 1.25-2.59-fold risk for developing various allergies following the early life use of either an H2 blocker or a proton pump inhibitor.

COMMENTARY

The new availability of antibiotic therapy during the last century was credited with saving the life of pneumonia-stricken Winston Churchill. Of course, millions of people since then also have been affected, often favorably, by antibiotic use. Antibiotics can be powerful medications, but they also carry significant risk.

Antibiotic use is common, even during the first six months of life. In the population of U.S. military dependents studied by Mitre and colleagues, 17% of children received at least one course of antibiotics. Antibiotic use also is common in other parts of the world. In several cities in Asia, Africa, and South America, the majority of children receive antibiotics during the first six months of life.1 In Europe, antibiotics are used less, and use varies in different countries; upper respiratory tract infections are treated with antibiotics 19% of the time in Italy but only 1% of the time in Switzerland, and otitis media prompts antibiotic use 82% of the time in Italy but just 55% of the time in the Netherlands.2 Overall, antibiotics are given 0.2 to 1.3 times per child during the first year of life in various European countries.2

Despite the proven effectiveness of antibiotics in treating infections, there are widespread risks to antimicrobial therapy. Childhood obesity is more common in children who received antibiotics during infancy, and using antibiotics during the first six months of life increases the risk of overweight and obesity 1.2-fold.3,4 Now, we have further evidence linking early antibiotic use and the subsequent development of asthma and allergies. In fact, early antibiotic use might be blamed for doubling the incidence of asthma and increasing obesity by 20%; these risks seem subtle, as they are dispersed through the population, but they could have mushroom cloud-type devastating consequences on the current generation of growing children. However, these new data should be considered carefully before blaming antibiotics for too many of our problems.

The obvious conclusion is that antibiotics alter the pediatric patient in ways that make future development of allergies more likely. Mitre and colleagues postulated that the mechanism of the association might be through alterations in the microbiome. Clearly, antibiotic use alters intestinal flora, and allergic disease has been associated with alterations in the microbiome. The authors further speculated that antacids increase the risk of allergic disease through intestinal fluid pH changes that also alter intestinal flora.

Is the obvious conclusion correct? The authors wisely noted that some of the antibiotics might have been given to children whose symptoms actually were from allergies even though the allergic disease had not yet been diagnosed. However, there could be other explanations. Even if allergic disease varies with changes in the microbiome, it could be that there were other reasons for alterations in intestinal flora. The study was conducted in a military population, and military children potentially are subject to frequent geographical displacement. International travel exposes children to varied germs and changes their microbiomes. Perhaps it was travel that prompted altered microbiota (and subsequent allergies) rather than the antibiotic. And, perhaps it was the travel that provoked fussiness that was interpreted as a need for antibiotic or antacid treatment. Of course, this is speculative, but further studies will be needed to determine if the association of antibiotic use with subsequent allergic disease holds true when other factors also are studied.

Furthermore, there is a “chicken-and-egg” question. Even if antibiotic use is causally linked to future allergic disease, it is not clear which is the cause and which is the effect. It is conceivable that children who are destined to develop allergies in the second and subsequent years of life already have pre-clinical changes in inflammatory responses and mucosal anatomy that make them more likely to develop respiratory infections (and, thus, to receive antibiotic treatment) early in life.

So, these new data are intriguing. It is possible that the link between antibiotic use and allergies is causal; but, further studies will be needed to prove that. In the meantime, the authors of this study wisely advised that antibiotics only be used in infants when there is clear clinical benefit. Antimicrobial stewardship is important, whether antibiotics cause future allergies or not.

REFERENCES

  1. Rogawski ET, Platts-Mills JA, Seidman JC, et al. Use of antibiotics in children younger than two years in eight countries: A prospective cohort study. Bull World Health Organ 2017;95:49-61.
  2. Stam J, van Stuijvenberg M, Gruber C, et al. Antibiotic use in infants in the first year of life in five European countries. Acta Paediatr 2012;101:929-934.
  3. Bailey LC, Forrest CB, Zhang P, et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014;168:1063-1069.
  4. Rasmussen SH, Shrestha S, Bjerregaard LG, et al. Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta-analysis. Diabetes Obes Metab 2018;20:1508-1514.