Acid Suppressors in Early Infancy Linked to Allergies Later

Troy Brown

April 02, 2018

Infants who received acid suppressive medications or antibiotics during the first 6 months of life were significantly more likely to develop allergic disease later in childhood, a large study found.

"In this retrospective cohort study of 792 130 children, we found significant associations between the use of acid-suppressive medications or antibiotics in infancy and the development of allergic diseases in childhood. Use of acid-suppressive medications was positively associated with increased risks for all major categories of allergic disease and most strongly associated with food allergy," the researchers explain.

Edward Mitre, MD, from the Department of Microbiology and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and colleagues report their findings in an article published online April 2 in JAMA Pediatrics.

"It's possible that medications that affect the microbiome might affect whether or not we have allergies. Acid-suppressing medications and antibiotics are two classes of drugs that could conceivably affect the microbes that live in our gut in unpredictable ways," Aaron Carroll, digital media editor, JAMA Pediatrics, said in a podcast. "It's also possible that acid-suppression drugs might change the ways in which we respond to orally ingested antigens. At least that's what's been seen in some animal studies."

Mitre and colleagues used the US Department of Defense TRICARE Management Activity Military Health System database to identify children who received prescriptions for an outpatient histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotic at any time during the first 6 months of life. They excluded children diagnosed with an allergy during the first 6 months of life and children who were hospitalized for longer than 1 week at birth. The researchers adjusted their analyses for prematurity, whether a child was born by Cesarean delivery, sex, the other drug classes, and any significant first-order interaction terms.

With a median age at follow-up of 4.6 years, infants who received H2RAs or PPIs during the first 6 months of infancy were more than twice as likely to develop food allergies and had slightly less than twofold the risk for medication allergies as those who did not. They were also more likely to experience anaphylaxis, allergic rhinitis, and asthma.


  H2RA aHR (95% Confidence Interval) PPI aHR (95% Confidence Interval)
Food allergy 2.18 (2.04 - 2.33) 2.59 (2.25 - 3.00)
Medication allergy 1.70 (1.60 - 1.80) 1.84 (1.56 - 2.17)
Anaphylaxis 1.51 (1.38 - 1.66) 1.45 (1.22 - 1.73)
Allergic rhinitis 1.50 (1.46 - 1.54) 1.44 (1.36 - 1.52)
Asthma 1.25 (1.21 - 1.29) 1.41 (1.31 - 1.52)

Antibiotic exposure during the first 6 months of life was significantly associated with the major categories of allergic diseases as well. Infants who received antibiotics during the first 6 months of life had adjusted hazard ratios (aHRs) of 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.

"This study adds to the mounting evidence that agents that disrupt the normal intestinal microbiome during infancy may increase the development of allergic diseases," the researchers write.

A possible study limitation is potential bias from reverse causality, as it is possible that acid-suppressive drugs or antibiotics were administered for allergic disorders that were mistakenly diagnosed as gastroesophageal reflux disease (GERD) or infections.

However, this potential limitation is unlikely to explain the totality of the study findings, according to the authors. "With regard to food allergy, which can be confused with GERD in infants, the rates of this disease in children younger than 6 months may be too low to have been the main driver of acid-suppressive medication prescriptions in this study," the authors write.

Moreover, the increased rates of anaphylaxis, urticaria, and medication allergy seen in the study are probably not the result of reverse causality, as their clinical manifestations do not overlap significantly with GERD or infectious diseases.

"To our knowledge, this is the largest study demonstrating an association between H2RAs, PPIs, and antibiotics given during infancy and the subsequent development of allergic diseases. The results are consistent with those of prior studies and have biological plausibility," the researchers conclude. "Thus, this study provides further impetus that antibiotics and acid-suppressive medications should be used during infancy only in situations of clear clinical benefit. Additional studies will be required to confirm causality and determine the mechanism of action."

The authors have disclosed no relevant financial relationships.

JAMA Pediatrics. Published online April 2, 2018. Full text

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