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Proton pump inhibitors (PPIs) were strongly linked with serious infection risk among infants and young children in a large national study, suggesting caution in prescribing.

In more than one million children followed for approximately 4 years, use of PPIs was associated with a 34% increase in risk for infections requiring hospitalization (HR 1.34, 95% CI 1.32-1.36), said researchers led by Marion Lassalle, PharmD, PhD, of the French National Agency for the Safety of Medicines and Health Products in Saint-Denis.

Excess risk extended to infections in the digestive tract; ear, nose, and throat sphere; lower respiratory tract; kidneys or urinary tract; and nervous system, the group reported in .

Risk for bacterial infections was 56% higher (HR 1.56, 95% CI 1.50-1.63) and risk for viral infections was 30% higher (HR 1.30, 95% CI 1.28-1.33) in children who received PPIs compared with those who did not.

"To our knowledge, this is the first study investigating the risk of serious infections associated with PPI use in young children for various sites and pathogens," the researchers said. "Proton pump inhibitors should not be used without a clear indication in this population."

Use of PPIs in young children has been increasing, Lassalle and colleagues noted. In France, 6.1% of children younger than 2 years of age were given PPIs in 2019, up from 3.6% in 2010. In other countries such as Sweden, Norway, and Denmark, use of PPIs in children has increased three- to five-fold since 2000, they said.

Lassalle's group discussed some potential mechanisms for the link between PPIs and infections in children. By altering gastric pH, PPIs may change gastric microbiota in a way that promotes enteric infections. In infancy, the gut microbiota undergoes major changes, and PPI exposure could have a significant impact, they said.

In addition, PPIs could lead to respiratory infections via micro-aspiration of gastric fluid enriched in bacteria or, alternatively, via the gut-lung axis. And PPIs might also interfere with functions of the immune system, including various neutrophil functions, the researchers suggested.

In an accompanying , Jay Berry, MD, MPH, and Jonathan Mansbach, MD, MPH, both of Boston Children's Hospital, said that physicians are increasingly using PPIs to manage healthy infants with gastroesophageal reflux (GER, or "spitting up"), who present with excessive crying and regurgitation.

"Physicians are also using PPIs in children with complex, chronic health conditions to manage suspected GERD," which is GER with complications, they wrote. "While the subset of these children with impaired oromotor function are more likely to have GERD than healthy children, there is no strong evidence to support the use of PPIs in either population. Worse: there may be harm."

Given these "compelling" results as well as the plausible mechanisms, "it is time to limit PPI use in infants and children, especially when they are otherwise healthy and until further investigation distinguishes who has the most favorable risk-benefit ratio," Berry and Mansbach advised.

The nationwide cohort study included all 1.26 million children born in France from 2010 to 2018 who got a first-time treatment prescription for medications that would treat gastric acid-related disorders. About half got PPIs, while the rest got histamine 2 receptor antagonists (H2RAs), or antacids/ alginate between birth and Dec. 31, 2019.

"These drugs share the same indications, so restricting the study population to children receiving these treatments at baseline would mitigate residual confounding," the researchers noted. "Only PPIs dramatically reduce gastric acid secretion and are therefore most likely to lead to infections."

The median age at which a child received PPIs was 88 days (interquartile range 44-282 days). The data came from the Mother-Child EPI-MERES Register, developed from the French National Health Data System, which includes all pregnancies in France since 2010.

The cohort was followed through December 2019. During that time, 152,055 children were newly diagnosed with a serious infection requiring hospitalization. The researchers used Cox models to estimate associations between PPI use and infections, applying a 30-day lag to minimize reverse causality. The researchers also adjusted for sociodemographic factors, pregnancy characteristics, child comorbidities, and healthcare utilization.

They study found increased risk for the following types of infections:

• Digestive tract (HR 1.52, 95% CI 1.48-1.55)
• Ear, nose, and throat (HR 1.47, 95% CI 1.41-1.52)
• Lower respiratory tract (HR 1.22, 95% CI 1.19-1.25)
• Kidneys or urinary tract (HR 1.20, 95% CI 1.15-1.25)
• Nervous system (HR 1.31, 95% CI 1.11-1.54)

The study did not include information on breast feeding or social interaction, which are notable risk factors for infection, Lassalle and colleagues noted. In addition, the study did not distinguish between children experiencing GERD from those inappropriately treated for uncomplicated GER, they said.

"PPIs are often prescribed off-label for this indication," they said. "However, their efficacy on crying and irritability, vomiting and regurgitation, or even signs and symptoms of GERD (feeding refusal, chronic cough, or arching) is not demonstrated."

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