Pharmacoepidemiological studies of proton pump inhibitor use in the pediatric population

Proton pump inhibitors (PPIs) are widely effective in the treatment of gastric acid-related disorders. Although use of PPIs has increased markedly among children and these drugs are frequently prescribed off-label in the recent decade, the evidence regarding the pediatric safety profile of PPI use is limited. The studies in this thesis aimed to advance the knowledge about the safety of PPI use in children. The specific aims of study I to IV were to evaluate the association between PPI use and risk of fracture, asthma, depression and anxiety as well as pneumonia, respectively.

In study I to III, we conducted nationwide register-based cohort-studies in Sweden, during the period 2006-2016. Children younger than 18 years who initiated PPI use were matched on propensity score and age with those who did not initiate PPI use. Comparing PPI initiators to their propensity score-matched non-initiators, the primary analyses of study I to III estimated hazard ratios (HRs) for risk of fracture and five fracture subtypes, asthma, as well as depression and anxiety.

In study I, we primarily observed that PPI use was significantly associated with an 11% increased risk of fracture among 115,933 pairs of PPI initiators and non-initiators in children. PPI was associated with increased risk of upper limb fracture (HR, 1.08; 95%CI, 1.03-1.13), lower limb fracture (HR, 1.19; 95%CI, 1.10-1.29), other fracture (HR, 1.51; 95%CI, 1.16-1.97) but not head fracture (HR, 0.93; 95%CI, 0.76-1.13) and spine fracture (HR, 1.31; 95%CI, 0.95-1.81). The HRs for fracture according to cumulative duration of PPI use were 1.08 (95%CI, 1.03-1.13) for ≤30 days, 1.14 (95%CI, 1.09-1.20) for 31-364 days and 1.34 (95%CI, 1.13-1.58) ≥365 days. The association was consistent in most sensitivity analyses, although a null association was observed in the analysis of PPI vs histamine-2 receptor antagonist. Overall, study I suggested that PPI use was associated with a small but statistically significant increased risk of any fracture.

In study II, we found an overall 57% increased risk of asthma among 80,870 children who initiated PPIs and 80,870 propensity score-matched non-initiators. The risk of asthma was significantly increased across all age groups, with infants (<6 months) and toddlers (6 months - <2 years) having the highest HRs (P for interaction <0.001). In analyses of the timing of asthma onset following PPI initiation, the HRs were 1.75 (95%CI, 1.53-2.00) for 0-90 days, 1.72 (95%CI, 1.51-1.97) for 91-180 days, and 1.54 (95%CI, 1.46-1.63) for 181 days to end of follow-up. Both short-term use and longer use of PPI were associated with an increased risk of asthma. The association was consistent through analysis of individual drugs and all sensitivity analyses. Collectively, study II indicated that PPI initiation was associated with 1.57-fold increased risk of asthma in children compared with non-initiation.

In study III, our results showed a 2.61-fold increased risk of depression and anxiety in 29,320 PPI initiators compared with 29,320 propensity score-matched non-initiators among children aged 7-17 years old. In analyses of the timing of depression and anxiety onset after PPI initiation, the HRs were 3.71 (95%CI, 2.17-6.34) for 1-30 days, 3.47 (95%CI, 2.33-5.18) for 31-90 days, 2.71 (2.04-3.60) for 91-180 days, 2.52 (2.00-3.16) for 181-365 days, and 2.34 (1.94-2.82) for 366-730 days. Significant associations were observed across all age groups but with a heterogeneity. A gradient increase in the risk of depression and anxiety was found with cumulative duration of PPI use (p for trend <0.0001). To conclude, study III suggested that PPI use was associated with increased risk of depression and anxiety in children while further research is warranted to confirm or refute this potential association.

In study IV, a self-controlled case series study was used to examine incidence rate ratios for risk of pneumonia in children during ongoing PPI treatment versus unexposed periods without any PPI use. A total 2,356 cases of pneumonia were included. We observed a 40% elevated risk of pneumonia during ongoing PPI use compared to the unexposed period. The increased risk was only observed within the first 90 days since start of PPI treatment, but not later. Further, we observed an 80% increased risk in a 30-day period immediately before PPI initiation. In study IV, our data did not suggest a causal relationship between PPI use and risk of pneumonia because the observed increased risk was present both immediately before and immediately after PPI initiation, which can likely be explained by an underlying risk of pneumonia due to factors transiently present at the time around PPI initiation.

Conclusions: Taken together, the findings in this thesis provide new understanding regarding the safety of PPI use in children and assist in clinical decision making when these drugs are considered to be prescribed to children.

List of scientific papers

I. Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association between proton pump inhibitor use and risk of fracture in children. JAMA pediatrics. 2020;174(6):543-551.
https://doi.org/10.1001/jamapediatrics.2020.0007

II. Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association between proton pump inhibitor use and risk of asthma in children. JAMA pediatrics. 2021;175(4):394-403.
https://doi.org/10.1001/jamapediatrics.2020.5710

III. Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association between proton pump inhibitor use and risk of depression and anxiety in children: nationwide cohort study. Clin Transl Sci. 2022 May;15(5):1112-1122.
https://doi.org/10.1111/cts.13225

IV. Wang YH, Svanström H, Wintzell V, Ludvigsson JF, Pasternak B. Association between proton pump inhibitor use and risk of pneumonia in children: nationwide self-controlled case series study in Sweden. [Accepted]
https://doi.org/10.1136/bmjopen-2022-060771