What are Normal Defecation Patterns in Healthy Children up to Four Years of Age? A Systematic Review and Meta-Analysis.

OBJECTIVE: To summarize available data on defecation frequency and stool consistency of healthy children up to age 4 in order to estimate normal references values. STUDY DESIGN: Systematic review including cross-sectional, observational, and interventional studies published in English, that reported on defecation frequency and/or stool consistency in healthy children 0-4 years old. RESULTS: Seventy-five studies were included with 16 393 children and 40 033 measurements of defecation frequency and/or stool consistency. Based on visual inspection of defecation frequency data, a differentiation was made between two age categories: young infants (0-14 weeks old) and young children (15 weeks-4 years old). Young infants had a mean defecation frequency of 21.8 per week (95 % CI, 3.9-35.2) compared with 10.9 (CI, 5.7-16.7) in young children (P < .001). Among young infants, human milk-fed (HMF) infants had the highest mean defecation frequency per week (23.2 [CI, 8.8-38.1]), followed by formula-fed (FF) infants (13.7 [CI 5.4-23.9]), and mixed-fed (MF) infants (20.7 [CI, 7.0-30.2]). Hard stools were infrequently reported in young infants (1.5%) compared with young children (10.5%), and a reduction in the frequency of soft/watery stools was observed with higher age (27.0% in young infants compared with 6.2% in young children). HMF young infants had softer stools compared with FF young infants. CONCLUSIONS: Young infants (0-14 weeks old) have softer and more frequent stools compared with young children (15 weeks-4 years old).

Development of a Core Outcome Set for Children Aged 1-18 Years with Gastroesophageal Reflux Disease.

OBJECTIVE: To develop a core outcome set for clinical studies assessing gastroesophageal reflux disease (GERD) in children. STUDY DESIGN: This core outcome set was developed using a 2-round Delphi technique and adhering to the Outcome Measures in Rheumatology Initiative (OMERACT 2.0) recommendations. Healthcare professionals (HCPs) and (parents of) children (age 1-18 years) with a GERD diagnosis (ie, the presence of bothersome symptoms), listed up to 5 harmful and/or beneficial outcomes that they considered important in the treatment of GERD. Outcomes mentioned by more than 10% of participants were put forward and rated and prioritized by HCPs, parents, and children in a second round. Outcomes with the highest rank formed the draft core outcome set. The final core outcome set was created during an online consensus meeting between an expert panel. RESULTS: The first round was completed by 118 of 125 HCPs (94%), 146 of 146 parents (100%), and 69 of 70 children (99%). A total of 80 of 118 HCPs (68%), 130 of 140 parents (93%), and 77 children (100%) completed round 2. "Adequate relief," "evidence of esophagitis," "feeding difficulties," "heartburn (≥4 years)," "hematemesis," "regurgitation," "sleeping difficulties," "vomiting," and "adverse events" were included in the final core outcome set for GERD in children aged 1-18 years. CONCLUSIONS: We identified a total set of 9 core outcomes and suggest these outcomes to be minimally measured in clinical studies assessing GERD in children. Implementation of this core outcome set is likely to increase comparison between studies and may thus provide future recommendations to improve treatment of GERD in children.

Nonpharmacologic Treatment for Children with Functional Constipation: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of nonpharmacologic interventions for the treatment of childhood functional constipation. STUDY DESIGN: Randomized controlled trials (RCTs) evaluating nonpharmacologic treatments in children with functional constipation which reported at least 1 outcome of the core outcome set for children with functional constipation. RESULTS: We included 52 RCTs with 4668 children, aged between 2 weeks and 18 years, of whom 47% were females. Studied interventions included gut microbiome-directed interventions, other dietary interventions, oral supplements, pelvic floor-directed interventions, electrical stimulation, dry cupping, and massage therapy. An overall high risk of bias was found across the majority of studies. Meta-analyses for treatment success and/or defecation frequency, including 20 RCTs, showed abdominal electrical stimulation (n = 3), Cassia Fistula emulsion (n = 2), and a cow's milk exclusion diet (n = 2 in a subpopulation with constipation as a possible manifestation of cow's milk allergy) may be effective. Evidence from RCTs not included in the meta-analyses, indicated that some prebiotic and fiber mixtures, Chinese herbal medicine (Xiao'er Biantong granules), and abdominal massage are promising therapies. In contrast, studies showed no benefit for the use of probiotics, synbiotics, an increase in water intake, dry cupping, or additional biofeedback or behavioral therapy. We found no RCTs on physical movement or acupuncture. CONCLUSIONS: More well-designed high quality RCTs concerning nonpharmacologic treatments for children with functional constipation are needed before changes in current guidelines are indicated.

Prevalence of Functional Gastrointestinal Disorders in European Infants and Toddlers.

OBJECTIVE: To assess the prevalence of functional gastrointestinal disorders (FGIDs) in young children in a cross-sectional, multicenter study in Belgium, Italy, and The Netherlands. STUDY DESIGN: Children were enrolled if they were age 0-48 months, attending a general pediatrician (Belgium, Italy) or a well-baby clinic (The Netherlands) for routine follow-up. Separate questionnaires were developed for infants age 0-12 months and for toddlers age 13-48 months. Questionnaires evaluated the clinical history, symptoms, sociodemographic information on the family, and exposure to stressful life events. FGIDs were defined according to Rome IV criteria. RESULTS: In total 2751 children were included: 1698 infants age 0-12 months and 1053 children age 13-48 months. The prevalence of any FGID in infants age 0-12 months and 13-48 months was 24.7% and 11.3%, respectively. The most common disorders were infant regurgitation (13.8%) in infants and functional constipation (9.6%) in toddlers. Multivariable regression analyses demonstrated that younger age (P = .030) and formula feeding (P = .045) were associated with the prevalence of any FGID among infants. Country (Italy) (P = .033) and parents subjected to domestic violence (P = .035) were associated with the prevalence of any FGID in toddlers age 13-48 months. CONCLUSIONS: FGIDs are common in a community sample of Western European infants and toddlers. Regurgitation is most prevalent in infants and functional constipation is most common in toddlers. Younger age, formula feeding, and domestic violence to parents are associated with the prevalence of FGIDs.

A Core Outcome Set for Clinical Trials in Pediatric Functional Abdominal Pain Disorders.

OBJECTIVE: To ensure consistency and reduce outcome measure reporting heterogeneity in clinical trials on pediatric functional abdominal pain disorders (FAPDs), a core outcome set (COS) was developed for pediatric FAPD trials. STUDY DESIGN: A mixed-method 2-round Delphi technique was used and key stakeholders, including healthcare professionals (HCPs), patients with FAPD, and their parents were invited to participate. In the first round, key stakeholders identified outcomes of importance through an open-ended questionnaire. Outcomes mentioned by ≥10% of the participants were included in a shortlist. In the second round, this shortlist was rated and prioritized. During a consensus meeting with an expert panel, the final COS was defined. RESULTS: The first round was completed by 152 of 210 (72%) HCPs, 103 (100%) parents, and 50 of 54 (93%) patients. A total of 104 from 167 (62%) HCPs, 102 (100%) parents, and 53 (100%) patients completed round 2. Pain intensity, pain frequency, quality of life, school attendance, anxiety/depression, adequate relief, defecation pattern (disease specific, irritable bowel syndrome), and adverse events were included in the final COS for FAPDs. CONCLUSION: A set of 8 core outcomes has been identified that should minimally be measured in pediatric FAPD trials. Implementation of the use of this COS will increase comparison between studies and, therefore, improve management of children with FAPDs.

Physiotherapy for Children with Functional Constipation: A Pragmatic Randomized Controlled Trial in Primary Care.

OBJECTIVE: To determine the effectiveness of physiotherapy plus conventional treatment compared with conventional treatment alone for the treatment of functional constipation in children age 4-17 years in primary care. STUDY DESIGN: Pragmatic randomized controlled trial with 8 months follow-up. Primary care physicians recruited children diagnosed with functional constipation (n = 234), and pediatricians recruited newly referred children with a diagnosis of functional constipation (n = 11). Conventional treatment comprised toilet training, nutritional advice, and laxative prescribing, whereas physiotherapy focused on resolving dyssynergic defecation. The primary outcome was treatment success over 8 months, defined as the absence of functional constipation (Rome III criteria) without laxative use. Secondary outcomes included the absence of functional constipation irrespective of continuation of laxative use and global perceived treatment effect. RESULTS: Children were allocated to conventional treatment plus physiotherapy or conventional treatment alone (67 per group), mean (SD) age was 7.6 (3.5) years. Results of longitudinal analyses in the intention-to-treat population showed that the treatment success percentage was not statistically improved by adding physiotherapy to conventional treatment (adjusted relative risk [aRR] 0.80, 95% CI 0.44-1.30). At 4 months, fewer children receiving physiotherapy had treatment success (17%) than children receiving conventional treatment alone (28%), but this had equalized by 8 months (42% and 41%, respectively). The percentage of children without functional constipation, irrespective of continuation of laxative use, was not statistically different between groups over 8 months (aRR 1.12, 95% CI 0.82-1.34). Notably, parents reported significantly more global symptom improvement after physiotherapy than after conventional treatment (aRR 1.40; 95% CI 1.00-1.73). CONCLUSIONS: We find no evidence to recommend physiotherapy for all children with functional constipation in primary care. TRIAL REGISTRATION: Netherlands Trial Registry: NTR4797.

Quality of Life in Children with Functional Constipation: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review the literature on health-related quality of life (HRQoL) in children with functional constipation and to identify disease-related factors associated with HRQoL. STUDY DESIGN: The Pubmed, Embase, and PsycINFO database were searched. Studies were included if they prospectively assessed HRQoL in children with functional constipation according to the Rome criteria. Articles were excluded if patients had organic causes of constipation and if HRQoL was only assessed after successful therapeutic interventions. A meta-analysis was performed calculating sample size-weighted pooled mean and SD of HRQoL scores. The quality of the studies was also assessed. RESULTS: A total of 20 of 2658 studies were included, providing HRQoL data for 2344 children. Quality of evidence was considered to be poor in 9 of the 20 studies (45%); 13 of the 20 studies reported sufficient data to be included in the meta-analysis. Pooled total HRQoL scores of children with functional constipation were found to be lower compared with healthy reference samples (65.6 vs 86.1; P < .01). Similar HRQoL scores were found according to self-report and parent proxy report. Hospital-based studies reported lower HRQoL scores as compared with community-based studies. Two studies reported on HRQoL scores of children with and without fecal incontinence, but no significant difference was found. CONCLUSIONS: HRQoL is compromised in children with functional constipation.

Definitions of Pediatric Functional Abdominal Pain Disorders and Outcome Measures: A Systematic Review.

OBJECTIVE: To systematically review definitions of functional abdominal pain orders (FAPDs) and outcome measures used in therapeutic randomized controlled trials in pediatric FAPDs adhering to the Outcome Measures in Rheumatology recommendations. STUDY DESIGN: Cochrane, MEDLINE, Embase, and Cinahl databases were systematically searched from inception to April 2018. English-written therapeutic randomized controlled trials concerning FAPDs in children aged 4-18 years were included. Definitions of FAPDs, interventions, outcome measures, measurement instruments, and outcome assessors of each study were tabulated descriptively. Quality was assessed using the Delphi List. RESULTS: A total of 4771 articles were found, of which 64 articles were included (n = 25, 39% of high methodologic quality). The Rome III (50%), Rome II (17%), Apley (16%), and author-defined (17%) criteria were used to define FAPDs. Fourteen studies (22%) assessed a pharmacologic, 25 (39%) a dietary, and 25 (39%) a psychosocial intervention. Forty-four studies (69%) predefined their primary outcomes. In total, 211 reported predefined outcome measures were grouped into 23 different outcome domains; the majority being patient-reported (n = 27, 61%). Of the 14 studies that evaluated a pharmacologic intervention, 12 (86%) reported on adverse events. CONCLUSIONS: Studies on pediatric FAPDs are of limited methodologic quality and show large heterogeneity and inconsistency in defining FAPDs and outcome measures used. Development of a core outcome set is needed to make comparison between intervention studies possible.

Prevalence of Functional Defecation Disorders in Children: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review the literature regarding the epidemiology of functional constipation and functional nonretentive fecal incontinence (FNRFI) in children. Secondary objectives were to assess the geographical, age, and sex distribution of functional constipation and FNRFI and to evaluate associated factors. STUDY DESIGN: The Cochrane Library, PubMed, and Embase databases were searched from 2006 until September 2017. The following inclusion criteria were applied: (1) prospective studies of population-based samples; (2) reporting on the prevalence of functional constipation or FNRFI according to the Rome III/IV criteria; (3) in children aged 0-18 years; and (4) published in full manuscript form. A quality assessment of included studies was conducted. Random effect meta-analyses with meta-regression analyses of study characteristics were performed. RESULTS: Thirty-seven studies were included, of which 35 reported on the prevalence of functional constipation and 15 of FNRFI. The reported prevalence of functional constipation ranged from 0.5% to 32.2%, with a pooled prevalence of 9.5% (95% CI 7.5-12.1). The prevalence of FRNFI ranged from 0.0% to 1.8%, with a pooled prevalence of 0.4% (95% CI 0.2-0.7). The prevalence of functional constipation was 8.6% in boys compared with 8.9% in girls (OR 0.99, 95% CI 0.9-1.4). Geographical location, dietary habits, and exposure to stressful life events were reported to be associated with the prevalence of functional constipation. Data on FNRFI were scarce and no associated factors were identified. CONCLUSION: Functional constipation is common in childhood and is associated with geographical location, lifestyle factors, and stressful life events. FNRFI is rare, and no associated factors were identified.

E-Healthcare for Celiac Disease-A Multicenter Randomized Controlled Trial.

OBJECTIVE: To evaluate the (cost-)effectiveness of online consultations in follow-up of patients with celiac disease (CD). STUDY DESIGN: Multicenter randomized, controlled trial involving 304 patients aged ≤25 years with CD for ≥1 year, randomized to an online (n = 156) or outpatient consultation (n = 148). An online consultation included questionnaires for symptom and growth measurement. Antitransglutaminase-type-2 antibodies were determined using a point-of-care (POC) test. Controls had a traditional consultation with antitransglutaminase-type-2 antibodies testing in laboratories. Both groups completed questionnaires concerning CD-specific health-related quality of life (HRQOL), gluten-free diet adherence, and patient satisfaction. Six months later, participants repeated HRQOL and patient satisfaction questionnaires and the POC test. The primary outcome was anti-transglutaminase-type-2 antibodies after 6 months, and the secondary outcomes were health problems, dietary adherence, HRQOL, patient satisfaction, and costs. RESULTS: The performance of the POC test was inferior to laboratory testing (2/156 positive POC tests vs 13/148 positive laboratory tests; P = .003). Health problems were detected significantly more frequently using online consultation. The detection of growth problems and dietary transgressions was similar. HRQOL (from 1 [good] to 5 [poor]) improved after online consultation (from 3.25 to 3.16 [P = .013] vs controls from 3.10 to 3.23; P = .810). Patient satisfaction (from 1 [low] to 10 [high]) was 7.6 (online) vs 8.0 (controls; P = .001); 58% wished to continue online consultations. Mean costs per participant during the studied period were €202 less for the online group (P < .001). CONCLUSIONS: The primary outcome could not be tested because the POC test was unreliable. Nevertheless, our results indicate that online consultations for children and young adults with CD are cost saving, increase CD-specific HRQOL, and are satisfactory for the majority. TRIAL REGISTRATION: Trialregister.nl: NTR3688.

The Placebo Response in Pediatric Abdominal Pain-Related Functional Gastrointestinal Disorders: A Systematic Review and Meta-Analysis.

OBJECTIVE: To investigate the magnitude and determinants of the placebo response in studies with pediatric abdominal pain-related functional gastrointestinal disorders. STUDY DESIGN: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL were searched for systematic reviews and randomized placebo-controlled trials concerning children 4-18 years of age with an abdominal pain-related functional gastrointestinal disorder. The primary outcome was the pooled proportion of subjects assigned to placebo with improvement as defined by the authors. The effect of trial characteristics on the magnitude of the placebo response was investigated using univariate meta-regression analysis. RESULTS: Twenty-one trials were identified. The pooled proportion of subjects with improvement was 41% (95% CI, 34%-49%; 17 studies) and with no pain was 17% (95% CI, 8%-32%; 7 studies). The pooled standardized mean difference on the Faces Pain Scales compared with baseline was -0.73 (95% CI, -1.04 to -0.42; 8 studies). There was significant heterogeneity across studies with respect to both outcomes. Lower dosing frequency (P = .04), positive study (P = .03), longer duration of treatment (P < .001), and higher placebo dropout (P < .001) were associated with higher report of no pain. Response on Faces Pain Scales was greater in studies conducted in the Middle East (P = .002), in studies that did not report the randomization schedule (P = .02), and in studies with a higher percentage of females (P = .04). CONCLUSIONS: Approximately 41% of children with abdominal pain-related functional gastrointestinal disorders improve on placebo. Several trial characteristics are correlated significantly with the proportion of patients with no pain on placebo and with the magnitude of the placebo response on Faces Pain Scales. These data could be valuable for the design of future studies.

Pharmacologic treatment in pediatric functional abdominal pain disorders: a systematic review.

OBJECTIVE: To systematically review literature assessing efficacy and safety of pharmacologic treatments in children with abdominal pain-related functional gastrointestinal disorders (AP-FGIDs). STUDY DESIGN: MEDLINE and Cochrane Database were searched for systematic reviews and randomized controlled trials investigating efficacy and safety of pharmacologic agents in children aged 4-18 years with AP-FGIDs. Quality of evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation approach. RESULTS: We included 6 studies with 275 children (aged 4.5-18 years) evaluating antispasmodic, antidepressant, antireflux, antihistaminic, and laxative agents. Overall quality of evidence was very low. Compared with placebo, some evidence was found for peppermint oil in improving symptoms (OR 3.3 (95% CI 0.9-12.0) and for cyproheptadine in reducing pain frequency (relative risk [RR] 2.43, 95% CI 1.17-5.04) and pain intensity (RR 3.03, 95% CI 1.29-7.11). Compared with placebo, amitriptyline showed 15% improvement in overall quality of life score (P = .007) and famotidine only provides benefit in global symptom improvement (OR 11.0; 95% CI 1.6-75.5; P = .02). Polyethylene glycol with tegaserod significantly decreased pain intensity compared with polyethylene glycol only (RR 3.60, 95% CI 1.54-8.40). No serious adverse effects were reported. No studies were found concerning antidiarrheal agents, antibiotics, pain medication, anti-emetics, or antimigraine agents. CONCLUSIONS: Because of the lack of high-quality, placebo-controlled trials of pharmacologic treatment for pediatric AP-FGIDs, there is no evidence to support routine use of any pharmacologic therapy. Peppermint oil, cyproheptadine, and famotidine might be potential interventions, but well-designed randomized controlled trials are needed.

Diagnostic accuracy of tests in pediatric gastroesophageal reflux disease.

OBJECTIVE: To systematically review the literature evaluating the diagnostic accuracy of commonly used diagnostic tests over conventional history taking and physical examination in children ≤ 18 months and >18 months suspected of gastroesophageal reflux disease (GERD). STUDY DESIGN: We searched Medline, Embase, and the Cochrane database for studies assessing the diagnostic accuracy of pH-metry, pH-impedance, esophagogastroscopy, barium contrast study, scintigraphy, and empirical treatment as diagnostic tools. Quality was assessed according to Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews criteria. RESULTS: Of the 2178 studies found, 6 studies were included, containing 408 participants (age 1 month-13.6 years) and 145 controls (age 1 month-16.9 years). Studies included children with GERD symptoms; 1 included an atypical presentation. In all the studies, the diagnostic accuracy of pH-metry was investigated, and in 2 studies esophagogastroscopy was investigated as well. Sensitivity and specificity were calculated in 3 studies. The range of reported sensitivity and specificity was broad and unreliable because of poor methodological quality according to Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews criteria and inadequate study design. CONCLUSION: Diagnostic accuracy of tests in children suspected of GERD remains unclear and implications for practice are hard to give. There is an urgent need of well-designed randomized controlled trials where the effect of treatment according to specific signs and symptoms will be compared with the effect of treatment based on the results of additional diagnostic tests, for patient relevant outcomes.

Value of abdominal radiography, colonic transit time, and rectal ultrasound scanning in the diagnosis of idiopathic constipation in children: a systematic review.

OBJECTIVE: To perform a systematic review evaluating the value of abdominal radiography, colonic transit time (CTT), and rectal ultrasound scanning in the diagnosis of idiopathic constipation in children. STUDY DESIGN: Eligible studies were those assessing diagnostic accuracy of abdominal radiography, CTT, or rectal ultrasound scanning in children suspected for idiopathic constipation. Methodological quality of the included studies was assessed with the Quality Assessment of studies of Diagnostic Accuracy included in Systematic reviews checklist. RESULTS: One systematic review summarized 6 studies on abdominal radiography until 2004. The additional 9 studies evaluated abdominal radiography (n = 2), CTT (n = 3), and ultrasound scanning (n = 4). All studies except two used a case-control study design, which will lead to overestimation of test accuracy. Furthermore, none of the studies interpreted the results of the abdominal radiography, ultrasound scanning, or CTT without knowledge of the clinical diagnosis of constipation. The sensitivity of abdominal radiography, as studied in 6 studies, ranged from 80% (95% CI, 65-90) to 60% (95% CI, 46-72), and its specificity ranged from 99% (95% CI, 95-100) to 43% (95% CI, 18-71). Only one study presented test characteristics of CTT, and two studies presented test characteristics of ultrasonography. CONCLUSION: We found insufficient evidence for a diagnostic association between clinical symptoms of constipation and fecal loading on abdominal radiographs, CTT, and rectal diameter on ultrasound scanning in children.