When poorly conducted systematic reviews and meta-analyses can mislead: a critical appraisal and update of systematic reviews and meta-analyses examining the effects of probiotics in the treatment of functional constipation in children

Background: Recent systematic reviews and meta-analyses on the efficacy of probiotics in the treatment of functional constipation in children have yielded conflicting results. Objectives: The aim of this study was to critically review and update the evidence in this field by mapping all the steps involved against those reported in previous reviews, in an attempt to understand the nature of their conflicting results. Methods: Four literature databases, trial registries, and citations were searched through December 1, 2018. We included randomized controlled trials (RCTs) that assessed the effects of probiotics compared with placebo or treatment as usual on defecation frequency [bowel movements (BMs)/wk] or treatment success rates in children with functional constipation. Independent reviewers extracted the data and assessed risk of bias in each RCT. Data were pooled with (inverse variance) random-effects models. Results: We identified 17 RCTs, of which 14 and 11 provided sufficient data to enable meta-analysis of the effects of probiotics compared with control on defecation frequency (n = 965) or treatment success (n = 835), respectively. When compared to (any) control intervention, probiotics did not significantly increase defecation frequency [weighted mean difference (WMD): 0.28 BMs/wk; 95% CI:-0.12, 0.69; P = 0.165] but were more efficacious in achieving treatment success (RR: 1.24; 95% CI: 1.03, 1.50; P = 0.024). These effects did not differ by type of control (i.e., active or inactive) intervention. However, in analyses confined to the RCTs that were free of high risk of bias (only 5), probiotics did not confer any beneficial effects on defecation frequency (WMD: -0.55 BMs/wk; 95% CI: -1.37, 0.26; P = 0.185) and achievement of treatment success (RR: 1.01; 95% CI: 0.90, 1.13; P = 0.873), compared with control interventions. Conclusions: The current evidence thus does not support the use of probiotics as a single or coadjuvant therapy for treatment of functional constipation in children and refutes recently published reviews reporting favorable effects of probiotics. Conflicting findings of previous reviews resulted from methodologic errors, highlighting the susceptibility of evidence synthesis to oversights in study selection, quality assessments, and data extraction and collation. This review was registered at PROSPERO as CRD42019119109.