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Figure 3. Forest plot of the association between PPI use and CDI. Vertical line corresponds to no difference point between the 2 groups. Squares correspond to risk ratios. Horizontal lines represent the 95% confidence intervals. The diamond indicates the pooled relative risk ratios. Note. df, degrees of freedom; M-H, Mantel-Haenszel.
Figure 4. Forest plot of the association between H2RA use and CDI. Vertical line corresponds to no difference point between the 2 groups. Squares correspond to risk ratios. Horizontal lines represent the 95% confidence intervals. The diamond indicates the pooled relative risk ratios. Note. df, degrees of freedom; M-H, Mantel-Haenszel.
significant (OR, 1.36; 95% CI, 0.31–5.98; P = .68) (Fig. 4). There was significant heterogeneity among these studies (I2 = 68%).
Gender We identified 4 studies that reported adjusted data on gender as a risk factor for CDI. Meta-analysis of the 4 adjusted studies did not show a significantly increased risk of CDI associated with female gender (OR, 0.87; 95% CI, 0.74–1.03; P = .10) (Fig. 5). There was significant heterogeneity among these studies (I2 = 76%).
Other risk factors Several additional risk factors associated with pediatric CDI were not included in the meta-analysis because they were reported in<3 studies. These risk factors and their corresponding estimated effect sizes have been listed in Supplemental Table 2 (online). Notably, underlying comorbidities that have been previously reported such as inflammatory bowel disease (IBD), solid organ transplant, and malignancies10,19,20 were also reported by multiple studies included in this review (Supplemental Table 2 online).
Publication bias
We did not assess publication bias because there were <10 included studies (for each risk factor that was meta-analyzed). A minimum number of 10 studies is suggested when assessing publication bias using a funnel plot or other more advanced regression-based methods. However, we constructed a funnel plot for 2 of the variables, antibiotic exposure and PPI use, because these risk factors had a large number of patients included from 7 and 4 studies, respectively (Supplemental Fig. 1 online).
Discussion
In this meta-analysis of 14 studies, prior antibiotic exposure and PPI use were significantly associated with increased risk of devel- oping CDI. Children with prior antibiotic exposure have approx- imately twice the risk of developing CDI compared to patients without a recent history of antibiotic exposure. However, the asso- ciation was not statistically significant after pooling studies provid- ing adjusted data.
Antibiotic exposure was a significant risk factor in the pediatric
inpatient population in our meta-analysis. This finding is consis- tent with results from the adult population, where antibiotic expo- sure has been observed to be the most important modifiable risk factor for the development of CDI.9 These findings are consistent with the observation that usage of antibiotics can eliminate the natural gut microbiota and establish a favorable environment for C. difficile.21 Multiple classes of antibiotics have been independ- ently associated with CDI in the adult population.22 In hospitalized pediatric patients, several antibiotic classes were independently associated with CDI. Specifically, carbapenems were identified as a significant risk factor by 2 studies,23,24 while aminoglycosides and cephalosporins were identified by only 1 study.24 Individual studies included in this systematic review demonstrated significant risks with use of carbapenems, aminoglycosides, and thrd- or fourth-generation cephalosporins (Supplemental Table 2 online). However, none of the individual antibiotic classes were evaluated by at least 3 different studies and were therefore deemed ineligible for the meta-analysis. Although certain antibiotic classes may in fact be independently associated with increased risk for CDI, more studies performed in the pediatric population are needed to further evaluate these associations. Specifically, design of future studies should clarify on the duration of antibiotic or gastric acid suppres- sion treatment and identify specific antibiotic classes used. Although our findings are consistent with current acceptance of
antibiotic exposure as a risk factor for pediatric CDI, the signifi- cance of our results should be considered with caution. Due to the limited availability of studies on the risk factors of CDI in pedi- atric inpatients, our meta-analysis of antibiotic exposure included <10 studies for antibiotic exposure. Additionally, our analysis of antibiotic exposure is subject to confounding due to the inclusion of unadjusted studies because few studies provided adjusted data. Furthermore, the 2 studies that provided adjusted data for antibi- otic exposure did not demonstrate a significant association. The loss of significance may be attributed to adjustments for age, sex, chemotherapy, and use of PPIs, H2Ras, and steroids. Previous investigations of gastric acid suppression as a risk fac-
tor for pediatric CDI have been conflicting. Biologically, there is strong plausibility for gastric acid suppression as a risk factor for CDI because the loss of acidity may disrupt the normal
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