The sample sizes of the trials varied from 45 to 159 children with functional constipation. Of the trials, 2 were conducted in Poland,[30–33] 1 in the Netherlands and Poland, and the remaining one in China. The mean age of the included children ranged from 34.6 to 81.0 months, and the duration of constipation ranged from 14.3 to 40.8 months. Two of the included trials defined constipation as <3 sBMs per week for at least 2 months or 12 weeks,[30,31] whereas the remaining 2 trials defined it according to the Rome III criteria.[32,33] All included trials were of high study quality, as assessed using the Jadad scale. Overall, 3 trials had a score of 5,[30,32,33] whereas the remaining one trial had a score of 4.
After pooling all included trials, we noted that probiotics have no significant effect on treatment success rate compared with placebo (RR 1.05, 95% CI 0.81–1.38, P = .697; Fig. 2), but potential evidence of significant heterogeneity was observed. A sensitivity analysis for treatment success was consequently performed, and after each study was sequentially excluded from the pooled analysis, the conclusion was not affected by the exclusion of any specific study (Table 2). Finally, we examined the funnel plots, which indicated no significant publication bias for treatment success (Fig. 3).
The summary results for other outcomes are presented in Table 3. The pooled analysis showed that children who received probiotics had lower frequency of glycerin enema use (WMD −2.40, 95% CI −4.03 to −0.77, P = .004) and abdominal pain (WMD −4.80, 95% CI −7.08 to −2.52, P < .001). However, probiotics had no significant effect on sBMs per week (WMD 0.89, 95% CI −2.18 to 3.95, P = .571), fecal soiling episodes per week (WMD 0.15, 95% CI −0.48 to 0.79, P = .642), straining during defecation (WMD −0.30, 95% CI −1.01 to 0.41, P = .408), use of lactulose (WMD −1.80, 95% CI −4.79 to 1.19, P = .238), use of laxatives (RR 0.72, 95% CI 0.44–1.18, P = .190), fecal incontinence (RR 0.75, 95% CI 0.51–1.10, P = .139), pain during defecation (RR 1.16, 95% CI 0.81–1.66, P = .410), flatulence (RR 0.65, 95% CI 0.39–1.10, P = .109), and adverse events (RR 1.01, 95% CI 0.62–1.63, P = .979).
The present meta-analysis aimed to evaluate the efficacy of probiotics in children with functional constipation. Four trials that included 382 patients were identified. The results showed that probiotic supplementation resulted in lower frequency of glycerin enema use and abdominal pain but had no significant effect on other outcomes. These results may help better clarify the efficacy of probiotics in children with functional constipation and can aid physicians in selecting appropriate treatment strategies.
A previous meta-analysis suggested that the use of probiotics was associated with increased treatment success rate but had no significant effect on the frequency of abdominal pain. Further, the summary results did not indicate a significant improvement in stool patterns. The inherent limitation of the previous meta-analysis is that the effect of probiotics on functional constipation was not evaluated. Moreover, many other outcomes were not reported. Dimidi et al conducted a meta-analysis of RCTs on the effect of probiotics on functional constipation in adults and found that probiotics could improve whole gut transit time, stool frequency, and stool consistency. However, the treatment effect of probiotics in children remains unclear. Therefore, we conducted a comprehensive systematic review and meta-analysis to evaluate the efficacy and safety of probiotics in children with functional constipation.
There was no significant difference in treatment success rate between probiotics and placebo. Majority of the included studies reported the nonsignificant effect of probiotics on treatment success, except for the trial performed by Bu et al. They reported that Lactobacillus casei rhamnosus was associated with a reduced treatment success rate compared with placebo, with no significant difference between Lactobacillus casei rhamnosus and magnesium oxide. Further, they suggested that Lactobacillus casei rhamnosus was associated with a reduced frequency of abdominal pain. Banaszkiewicz and Szajewska reported that the treatment success rate was 68% and 65% in the Lactobacillus GG group and 72% and 64% in the placebo group at 12 and 24 weeks, respectively, and that there were no significant differences in sBMs per week, fecal soiling episodes per week, adverse events, and overall tolerance between both groups at 4, 8, and 12 weeks. Tabbers et al indicated that both fermented dairy product containing Bifidobacterium lactis DN-173010 and control product could improve stool frequency from baseline to after 3 weeks, with no significant difference between both, and that no serious adverse events were observed in constipated children. Finally, Wojtyniak et al suggested that Lactobacillus casei rhamnosus was not associated with significant improvement in symptoms in children with functional constipation aged less than 5 years and did not recommend the use of probiotics in children with functional constipation.
The findings of this study suggested that probiotic supplementation led to significant persistent improvement in glycerin enema use and abdominal pain. However, probiotics were not associated with several important indices. This could be because most trials were designed with other outcomes as the primary endpoint and because their sample sizes were too small to detect potentially clinically relevant differences. Further, the few trials that reported these outcomes showed no statistically significant differences. Therefore, we simply reported a relative result and provided a synthetic and comprehensive review.
The strengths of our study should be highlighted. First, the large sample size allowed us to quantitatively assess the efficacy of probiotics in children with functional constipation; thus, our findings are potentially more robust than those of any individual study. Second, the study reported children with functional constipation, and no such meta-analysis has been previously performed. Third, the summary results for sBMs per week, fecal soiling episodes per week, straining and pain during defecation, use of lactulose, glycerin enema, and laxatives, abdominal pain, fecal incontinence, flatulence, and adverse events were presented.
The limitations of our study are as follows: Publication bias was inevitable because this meta-analysis was based on published studies, which might overestimate the treatment effects of probiotics. Subgroup analysis was not performed as a small number of trials were included. The meta-analysis used pooled data (individual data were not available), which prevented a detailed analysis to obtain more comprehensive results.
The results of this study suggested that probiotic supplementation might result in reduced frequency of glycerin enema use and abdominal pain but has no significant effect on treatment success, sBMs per week, fecal soiling episodes per week, straining and pain during defecation, use of lactulose and laxatives, fecal incontinence, flatulence, and adverse events. Future studies should focus on specific types of probiotics and children with specific characteristics.
Conceptualization: Lei Jin.
Formal analysis: Lei Jin.
Investigation: Lin Deng, Wei Wu, Jianhua Liu.
Project administration: Lei Jin.
Resources: Wanjin Shao, Jianhua Liu.
Software: Zhenyi Wang.
Supervision: Wei Wu.
Validation: Lin Deng, Zhenyi Wang.
Visualization: Wanjin Shao.
Writing – original draft: Lei Jin.
Writing – review & editing: Lei Jin.
. van den Berg MM, Benninga MA, Di Lorenzo C. Epidemiology of childhood
constipation: a systematic review
. Am J Gastroenterol 2006;101:2401–9.
. Benninga MA, Voskuijl WP, Taminiau JA. Childhood
constipation: is there new light in the tunnel? J Pediatr Gastroenterol Nutr 2004;39:448–64.
. Chitkara DK, Rawat DJ, Talley NJ. The epidemiology of childhood
recurrent abdominal pain in Western countries: a systematic review
. Am J Gastroenterol 2005;100:1868–75.
. American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain; North American Society for Pediatric Gastroenterology Hepatology, and Nutrition.. Chronic abdominal pain in children. Pediatrics 2005;115:e370–81.
. Di Lorenzo C, Colletti RB, Lehmann HP, et al. Chronic abdominal pain in children: a technical report of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005;40:249–61.
. Baker SS, Liptak GS, Colletti RB, et al. Constipation in infants and children: evaluation and treatment. A medical position statement of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 1999;29:612–26.
. Brown AC, Valiere A. Probiotics
and medical nutrition therapy. Nutr Clin Care 2004;7:56–68.
. Lemberg DA, Ooi CY, Day AS. Probiotics
in paediatric gastrointestinal diseases. J Paediatr Child Health 2007;43:331–6.
. Silva M, Jacobus NV, Deneke C, et al. Antimicrobial substance from a human Lactobacillus strain. Antimicrob Agents Chemother 1987;31:1231–3.
. O’Mahony L, Mccarthy J, Kelly P, et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005;128:541–51.
. Weizman Z, Abu-Abed J, Binsztok M. Lactobacillus reuteri DSM 17938 for the management of functional abdominal pain in childhood
: a randomized, double-Blind, placebo-controlled trial. J Pediatr 2016;174:160.e1–4.e1.
. Jadresin O, Hojsak I, Misak Z, et al. Lactobacillus reuteri DSM 17938 in the treatment of functional abdominal pain in children: RCT study. J Pediatr Gastroenterol Nutr 2017;64:925–9.
. Begtrup LM, de Muckadell OB, Kjeldsen J, et al. Long-term treatment with probiotics
in primary care patients with irritable bowel syndrome—a randomised, double-blind, placebo controlled trial. Scand J Gastroenterol 2013;48:1127–35.
. Eftekhari K, Vahedi Z, Kamali Aghdam M, et al. A randomized double-blind placebo-controlled trial of Lactobacillus reuteri for chronic functional abdominal pain in children. Iran J Pediatr 2015;25:e2616.
. Maragkoudaki M, Chouliaras G, Orel R, et al. Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain. Acta Paediatr 2017;106:1857–62.
. Bauserman M, Michail S. The use of Lactobacillus GG in irritable bowel syndrome in children: a double-blind randomized control trial. J Pediatr 2005;147:197–201.
. Francavilla R, Miniello V, Magista AM, et al. A randomized controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics 2010;126:e1445–52.
. Guandalini S, Magazzu G, Chiaro A, et al. VSL#3 improves symptoms in children with irritable bowel syndrome: a multicenter, randomized, placebo-controlled, double-blind, crossover study. J Pediatr Gastroenterol Nutr 2010;51:24–30.
. Gawrońska A, Dziechciarz P, Horvath A, et al. A randomized double-blind placebo-controlled trial of Lactobacillus GG for abdominal pain disorders in children. Aliment Pharmacol Ther 2007;25:177–84.
. Romano C, Ferrau V, Cavataio F, et al. Lactobacillus reuteri in children with functional abdominal pain (FAP). J Paediatr Child Health 2014;50:E68–71.
. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–2.
. DerSimonian R, Laird N. Meta-analysis
in clinical trials. Control Clin Trials 1986;7:177–88.
. Ades AE, Lu G, Higgins JP. The interpretation of random-effects meta-analysis
in decision models. Med Decis Making 2005;25:646–54.
. Tobias A. Assessing the influence of a single study in the meta-analysis
estimate. Stata Tech Bull 1999;8:7526–9.
. Deeks JJ, Higgins JPT. DG. A. Analyzing data and undertaking meta-analyses. In: Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 5.0.1
. Oxford, UK: The Cochrane Collaboration; 2008:chap 9.
. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.
. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997;315:629–34.
. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–101.
. Banaszkiewicz A, Szajewska H. Ineffectiveness of Lactobacillus GG as an adjunct to lactulose for the treatment of constipation in children: a double-blind, placebo-controlled randomized trial. J Pediatr 2005;146:364–9.
. Bu LN, Chang MH, Ni YH, et al. Lactobacillus casei rhamnosus Lcr35 in children with chronic constipation. Pediatr Int 2007;49:485–90.
. Tabbers MM, Chmielewska A, Roseboom MG, et al. Fermented milk containing Bifidobacterium lactis DN-173 010 in childhood
constipation: a randomized, double-blind, controlled trial. Pediatrics 2011;127:e1392–9.
. Wojtyniak K, Horvath A, Dziechciarz P, et al. Lactobacillus casei rhamnosus Lcr35 in the management of functional constipation
in children: a randomized trial. J Pediatr 2017;184:101–5.
. Korterink JJ, Ockeloen L, Benninga MA, et al. Probiotics
functional gastrointestinal disorders: a systematic review
. Acta Paediatr 2014;103:365–72.
. Dimidi E, Christodoulides S, Fragkos KC, et al. The effect of probiotics
on functional constipation
in adults: a systematic review
of randomized controlled trials. Am J Clin Nutr 2014;100:1075–84.
childhood; functional constipation; meta-analysis; probiotics; systematic review
Supplemental Digital Content
Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.