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Acid-suppressor, antibiotic use in infancy tied to later allergic disease
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Infants who are prescribed acid suppressors, such as a histamine-2 receptor antagonist or a proton pump inhibitor, or antibiotics within their first 6 months of life may be more likely to develop allergic disease in early childhood, according to findings published in JAMA Pediatrics. However, significant concerns have been raised about the study’s methodology and conclusions (see Perspective, below).
“Both gastric acid-suppressive medications and antibiotics have been implicated as factors that may enhance the development of allergic diseases,” Edward Mitre, MD, from the department of microbiology and immunology at the F. Edward Hébert School of Medicine in the Uniformed Services University of the Health Sciences, and colleagues wrote. “Use of these medications, which can directly cause intestinal dysbiosis, is of concern in light of increasing evidence that alterations in the human microbiome can increase the risk for allergy development.”
“Furthermore, acid-suppressive medications, which reduce protein digestion, can affect how ingested antigens are processed in the intestinal tract,” the researchers continued.
To examine whether treating infants 6 months of age or younger with antibiotics or acid-suppressive medications is associated with allergic disease in early childhood, Mitre and colleagues conducted a retrospective cohort study that included infants who were labeled as beneficiaries through the Department of Defense TRICARE. All infants included had a birth medical record stored within the Military Healy System and were born between Oct. 1, 2001, and Sept. 30, 2013.
Additionally, the infants included in this study must have been enrolled in the program within 35 days of birth until at least 1 year of age. Children were excluded from the study if they stayed in the hospital for more than 7 days following birth or received a diagnosis of food allergy, anaphylaxis, asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, contact dermatitis, medication allergy or other allergy within the first 6 months of life.
Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years.
When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.
Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.
Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.
“While there has been increasing recognition of the potential risks of antibiotic use during infancy, H2RAs and PPIs are considered to be generally safe and are commonly prescribed for children younger than 1 year,” Mitre and colleagues wrote. “… These medications are frequently given to infants who regurgitate food and appear to be fussy. For most infants, however, regurgitation of gastric contents is not a disease but rather is a developmentally normal process.”
“A systematic review found little evidence to support the efficacy of H2RAs in infants, and trials have not found clinical benefit of PPI therapy in infants with symptoms attributed to gastroesophageal reflux,” the researchers added. – by Katherine Bortz
Disclosures: The authors report no relevant financial disclosures.
Editor’s note: This article has been revised to reflect concerns over the study’s findings.
Perspective
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David R. Stukus, MD
The recent study by Mitre E, et al in JAMA Pediatrics looked at the association of exposure to antacids and antibiotics prior to 6 months of age with later development of allergic conditions. This publication has received significant media attention and the authors should be commended for their efforts to use a large database to investigate this association. Unfortunately, their findings are subject to misinterpretation without understanding of study design and limitations.
The authors used a large electronic database for military personnel to retrospectively investigate almost 800,000 infants born into their medical system between 2001 and 2013. Their objective was to identify if there was an association between early life exposure to H2 receptor antagonists (H2RAs), proton pump inhibitors (PPIs), or antibiotics with various allergic diagnoses later in childhood, including food allergy, asthma, allergic rhinitis and atopic dermatitis. Data analysis included use of adjusted HRs (aHRs) to compare differences in allergic conditions based upon prescription history. The authors report a significantly increased association of all allergic conditions included in their study with prescriptions for antacids and antibiotics. The association was much higher for H2RAs and PPIs compared with antibiotics. Among the allergic conditions included, the association was highest for any food allergy with an aHR of 2.18 for H2RAs (95% CI, 2.04-2.33) and an aHR of 2.59 (95% CI, 2.25-3.00) for PPIs.
The authors conclude that a strong association exists between early life exposure to antacids and the development of allergic conditions. They speculate that the pathophysiology causing this association may be due to alterations in the microbiome, which has also been suggested by other research and potential biological mechanisms. As allergic conditions, particularly food allergies, have increased in prevalence over the past 2 decades, parents, researchers and physicians are understandably looking for any possible way to halt this trend and prevent children from developing allergies. As such, many may now be reluctant to give antacids or antibiotics to infants.
However, several significant limitations of this study need to be addressed in order to fully understand how this data can be interpreted and applied to treatment decisions. First and foremost, this was a retrospective study that used prerecorded information within a database to look at an association of two events. This study was not designed, and cannot be interpreted, as demonstrating any cause and effect relationship. There are many confounding factors that were not controlled or evaluated for, including family history, timing of introduction of foods, environmental exposures, or other factors known to influence the development of allergies. In addition, as the authors state, reverse causality may have occurred for some of these infants who had predisposition to developing allergies, or early manifestation of disease, that then led to increased use of antacids or antibiotics.
The authors used ICD-9 codes within the medical record to identify allergic conditions. This is problematic and does not accurately reflect which of these children truly had food allergies, asthma, allergic rhinitis, etc. Without understanding the clinical history, diagnostic test results, or method of diagnosis, it should be assumed that many of these children were likely misdiagnosed and mischaracterized for purposes of this study, which is very common in clinical practice. For example, many children are mistakenly diagnosed with food allergy by testing alone, or without confirmatory testing. In addition, allergic rhinitis is often mistakenly diagnosed in young children whose symptoms are due to recurrent viral infections or other causes.
No one should argue that prescribing medications, especially for infants, should occur without thoughtfulness and consideration of risks, benefits and adverse effects. Interestingly, actual exposure to antacids or antibiotics was also not determined through this study design. The authors used prescription dispensing as their proxy for exposure. However, it is widely known that nonadherence to medications is common and that many of these infants likely never received the medication as it was prescribed.
Lastly, commentary regarding the role of the microbiome should be seen only as speculative. This study was not designed to measure, identify changes, or include any data that correlates with the microbiome. While the microbiome is a hot topic, there are no clinical data that show manipulation of the microbiome directly alters allergic diseases.
This study should be interpreted properly with a full understanding of the methodology used and inherent limitations. Findings should be used to help drive future randomized controlled interventional trials, but are not strong enough to make any conclusions or impact treatment decisions at this time. Many previous signals of associations between two occurrences obtained through large population studies have not withstood the rigors of prospective interventional trials. In the future, we may find causal evidence that early life exposures to antacids and antibiotics are part of the complicated heterogeneous milieu that determines which child develops allergies and which one does not. Unfortunately, at this time, these answers remain elusive.
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