Are PPI Unsafe for Pediatric Use?

To

The Editor

We read with interest the recent systematic review published on safety of use of proton pump inhibitors (PPI) in pediatric population. ¹ The review presents a comprehensive search of the available evidence regarding the side effect profile till date. We would like to highlight additional information on PPI use and side effects that may add merit to the understanding. Informed consent and ethical approval was not required for this submission.

The risk of acute and long term side-effects with PPI use is reported in adults. This risk becomes higher when PPI use is continued for unjustified duration in GERD or for non-specific indications. ² The time of recording the side effects of PPI was variable in all these studies except 1 study by Lassalle et al, ³ that mentioned a lag period after the start of PPI to record the potential side effects. Similar information if available from the pediatric studies can improve the time-to-event analysis of the side effects.

The variable definitions used to define clinical indication of PPI use and its recorded side effect could be a potential source of bias. Studies that used diagnostic and pharmaceutical codes eliminated potential confounders and limited bias. Similar information was not available for all these studies that could have introduced bias. ¹

PPI have been associated with small intestinal bacterial overgrowth with disruption of acidic milieu thereby causing non-specific abdominal complaints like pain and diarrhea. PPI use is associated with gut dysbiosis that can result in nutritional deficiencies and extraintestinal manifestations. The underlying molecular pathways revealed upregulation of various genes related to carbohydrate, nucleotide sugar, and sphingolipid metabolism pathways in PPI users that may be causal in the long-term side effects with PPI. ⁴ These findings may suggest the need to closely monitor children on PPI for side-effects in the future.

A recent Cochrane review on pharmacological treatment of GER in children with extracted data from 14 randomized controlled trials concluded very low-certainty evidence for efficacy of PPI due to heterogeneity of the enrolled studies. The safety profile of these agents was not discussed. ⁵

The risk of long-term side-effects like renal, neurological, cardiovascular, and osteoporosis also need to be ascertained in the pediatric population in the future. Therefore, the use of PPI in children should be judicious with correct prescribing information on dosing and timing in relation to meals to ensure its effect and minimize risk profile. ² Like antimicrobial stewardship, there is a need for PPI stewardship to ensure 4Ds are followed- correct drug, dose, duration, and de-escalation plan.