Open Access, Peer-reviewed
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    Pediatr Gastroenterol Hepatol Nutr. 2022 Sep;25(5):376-386. English.
    Published online Sep 05, 2022.
    https://doi.org/10.5223/pghn.2022.25.5.376
    Copyright © 2022 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition
    Original Article

    Functional Gastrointestinal Disorders in Neonates and Toddlers According to the Rome IV Criteria: A Systematic Review and Meta-Analysis

    Carlos Alberto Velasco-Benítez,1 Laura Isabel Collazos-Saa,1 and Herney Andres García-Perdomo2
      • 1Department of Pediatrics, Universidad del Valle, Cali, Colombia.
      • 2Section of Urology, Universidad del Valle, Cali, Colombia.
    • Correspondence to Carlos Alberto Velasco-Benítez. Department of Pediatrics, Universidad del Valle, Cali 76001, Colombia. Email: carlos.velasco@correounivalle.edu.co
    Received February 06, 2022; Revised March 27, 2022; Accepted July 10, 2022.

    This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Functional gastrointestinal disorders (FGIDs) are classified as a combination of persistent gastrointestinal symptoms. The Rome IV criteria can elucidate several factors in the pathogenesis of FGIDs. The frequency of FGIDs can differ between clinical and nonclinical settings and between geographic regions. To determine the global prevalence of FGIDs in neonates and toddlers according to the Rome IV criteria. We included cohort and descriptive observational studies reporting the prevalence of FGIDs according to the Rome IV criteria in children aged 0–48 months. We searched the Medline, Embase, Lilacs, and CENTRAL databases from May 2016 to the present day. Furthermore, unpublished literature was searched to supplement this information. The Strengthening the Reporting of Observational Studies in Epidemiology statement was used to evaluate the risk of bias. A meta-analysis of the proportions was performed using MetaProp in R. The results are reported in forest plots. We identified and analyzed 15 studies comprising 48,325 participants. Six studies were conducted in Europe, three in Latin America, two in North America, and four in Asia. Most participants were 12–48 months old (61.0%) and were recruited from the community. The global prevalence of FGIDs was 22.0% (95% confidence interval, 15–31%). The most common disorder was functional constipation (9.0%), followed by infant regurgitation syndrome (8.0%). Its prevalence was higher in the Americas (28.0%). FGIDs, as defined by the Rome IV criteria, are present in 22% of children, and the most common primary disorder is functional constipation. A higher prevalence of FGIDs has been reported in America.

    Keywords
    Gastrointestinal diseases; Infant; Preschool

    INTRODUCTION

    Functional gastrointestinal disorders (FGIDs) are defined as a combination of gastrointestinal symptoms that present in a persistent fashion, which cannot be better explained by other medical conditions [1]. Although the underlying physiopathology remains elusive, some authors state that FGIDs are caused by disturbances of the gut-brain interaction related to motility disturbance, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system processing [2]. The fourth version of the Rome criteria, published in 2016, reinforced clinical examination as the main diagnostic tool, introduced new syndromes, updated the definitions of previously existing disorders, and explored new perceptions in the neurobiology of pain, the brain-gut axis, and the intestinal microbiome, leading to a better understanding of the underlying physiopathology [3]. Currently, no unique laboratory marker can be used to confirm the presence of FGIDs; therefore, clinical examination remains the basis for diagnosis [3].

    The relevance of the Rome IV criteria for the pediatric population lies in the more profound understanding of the role of internal and external factors in the pathogenesis of FGIDs in acknowledging these disorders, developing prevention strategies, and encouraging early identification and treatment to improve personal and family quality of life [4]. Even though FGIDs are common in the pediatric population, their frequency can differ between clinical and nonclinical settings, as well as across the world; for instance, in 2016, Ferreira-Maia et al. [5] reported a prevalence of FGIDs in neonates and toddlers between 27.1% and 38.0% according to the Rome II and III criteria.

    Multiple studies and systematic reviews have addressed the identification of FGIDs using the Rome II and Rome III criteria in the pediatric population [5]. However, a meta-analysis of FGIDs in the pediatric population according to the Rome IV criteria has not been published.

    This study aimed to determine the global prevalence of FGIDs in neonates and toddlers aged 0–48 months, according to the Rome IV criteria.

    MATERIALS AND METHODS

    This review was performed according to the Cochrane Collaboration recommendations [6], and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [7].

    Eligibility criteria

    1. Study designs

    We included cohort and descriptive observational studies.

    2. Participants

    All studies must involve 1) both male and female children aged 0–48 months; 2) the identification of FGIDs according to only the Pediatric Rome IV criteria, based on the Questionnaire on Pediatric Gastrointestinal Symptoms ROME IV version (QPGS-RIV, parental and/or self-report form), medical records, or clinical evaluation in a clinical or nonclinical setting; and 3) reports of epidemiological data (prevalence) concerning FGIDs.

    3. Primary outcome

    Prevalence of FGIDs in children aged 0–48 months according to the Rome IV criteria.

    4. Exclusion criteria

    Studies with no specific data for age groups, including patients with organic diseases (cow milk protein allergy, bronchopulmonary dysplasia, organic constipation, lactose intolerance, laryngomalacia, and gastroesophageal reflux disease).

    Information sources

    We searched the Medline (OVID), Embase, Lilacs, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from May 2016 to the present. To ensure literature saturation, references from relevant articles identified through the search, conferences, thesis databases, Open Grey, and Google Scholar were scanned. We contacted the authors by e-mail in the case of missing information. No language restrictions were applied.

    Data collection

    Two researchers reviewed each reference by title, abstract, and full-text. They then applied pre-specified inclusion and exclusion criteria. Disagreements were resolved by consensus, and disagreements that could not be resolved were resolved by a third reviewer.

    Two trained reviewers used a standardized form to extract the following information from each article: study design, geographic location, authors’ names, title, objectives, inclusion and exclusion criteria, number of patients included, timing, definitions of outcomes, outcomes, association measures, and funding sources.

    Data analysis/synthesis of results

    Statistical analyses were performed using R software (R Core Team 2020, Vienna, Austria). We performed a meta-analysis of proportions using the command MetaProp and the inverse method (logit-transformed proportions). Information was pooled using a random-effects meta-analysis according to the expected heterogeneity. Additionally, the estimated effects of the included studies were reported in forest plots with 95% confidence intervals (95% CIs). Heterogeneity was evaluated using the I2 test. For interpretation, we determined that values of <50% and >50% for the I2 test corresponded to low and high levels of heterogeneity, respectively.

    Publication bias

    An evaluation was conducted to identify reporting or publication biases using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [8].

    Sensitivity analysis

    We performed a sensitivity analysis, extracted weighted studies, and ran an estimated effect to identify differences.

    Subgroup analysis

    We performed a subgroup analysis based on continent (America, Asia, Europe, Africa, and Oceania) and each FGID according to the Rome IV criteria.

    RESULTS

    Study selection

    We identified 8,140 studies using database searches (Fig. 1). After exclusion, a total of 15 studies, including children aged 0–48 months, fulfilled the inclusion criteria [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23].

    Fig. 1
    Flow chart showing the study selection.

    Characteristics of included studies

    The total sample size ranged from 65 [11] to 20,932 [23] participants. The studies by Chanis and Velasco-Benitez [11], Beser et al. [14], Campeotto et al. [16], Ozdemir and Beser [18], and Chew et al. [21] only included children younger than 12 months; while that of Russo et al. [17] included children aged 0–17 years. For this analysis, we included only children aged 0–4 years.

    Six studies were conducted in Europe (Russia, Croatia, Romania, France, Italy, Belgium, and the Netherlands), three in Latin America (Colombia, El Salvador, and Panama), two in North America (the United States), and four in Asia (Turkey, Malaysia, and China). The majority of patient data were obtained from Asian studies, especially from China. Almost all studies were conducted in a single country, with the exception of the study by Steutel et al. [20], who performed a multicenter study in Italy, Belgium, and the Netherlands.

    Five studies [11, 12, 16, 20, 21] focused on primary care, while four used a community-based setting, four used third-level hospitals, and two used online community panels. Assessments of FGIDs were mainly based on parental reports using the QPGS-IV (n=12), whereas Beser et al. [14] and Campeotto et al. [16] assessed FGIDs using clinical evaluation, and Milošić et al. [13] used medical records for diagnosis.

    Based on the reported data, most participants were female (n=2,021); however, only Velasco-Benítez et al. [9], Robin et al. [19], Chew et al. [21], and Zwiener et al. [22] provided an accurate depiction of the races and ethnicities of their participants, with the white race being the most common (n=1,155), followed by mixed-race children (n=775) (Table 1).

    Table 1
    Characteristics of patients in the included studies

    Risk of bias assessment

    The study by Robin et al. [19] achieved twenty-six points, whereas that by Steutel et al. [20] achieved only 12 points; the median score for all the included studies was 16 points. All studies provided information on the background, study design, methodology for the setting, follow-up time, assessment of variables, designated outcomes, number of participants, outcome events, and a good summary of their findings. However, only Russo et al. [17], Robin et al. [19], and Chew et al. [21] addressed potential biases. No study reported sensitivity analyses, boundaries for continuous variables, or absolute risks in their results (Table 2).

    Table 2
    Risk of bias assessment

    Prevalence of functional gastrointestinal disorders

    The overall prevalence of FGIDs was 22% (95% CI, 15-31%, I2=99%) (Fig. 2). The analysis for each FGID showed a higher prevalence of functional constipation (9%; 95% CI, 6–13%), followed by infant regurgitation syndrome (8%; 95% CI, 5–13%), and infant colic (3%; 95% CI, 1–6%) (Fig. 2).

    Fig. 2
    Random effect meta-analysis for the global prevalence of FGIDs in neonates and toddlers.
    CI: confidence interval, FGID: functional gastrointestinal disorders.

    Global distribution of functional gastrointestinal disorders

    We found a higher prevalence of FGIDs among American countries (28.70%; 95% CI, 24.38–33.44%; I2=73.1%), followed by European (21.39%; 95% CI, 6.38–52.07%, I2=99.7%), and Asian (16.72%; 95% CI, 10.10–26.40%, I2=99.2%) countries.

    DISCUSSION

    FGIDs are a common cause of gastrointestinal complaints among infants and toddlers [9, 19]. Based on data from 15 countries worldwide, we found a global prevalence of FGIDs of 22% in children younger than four years according to the Rome IV criteria; this frequency is lower than that reported by Ferreira-Maia et al. [5], using the previous Rome criteria (27.1–38.0%). We also found that functional constipation and infant regurgitation were the most common forms of FGIDs. For the remaining FGIDs, we found a prevalence between 1% and 3%. This result differed from those of Ferreira-Maia et al. [5], which may be due to the diagnostic update of the Rome IV criteria. For colic, its description was determined by both the clinician and the researcher; in rumination, the accepted evolution of symptoms was for at least two months, cyclical vomiting was present for at least six months, and functional diarrhea was accepted as occurring up to four times per day. Additionally, dyschezia, which occurs in children up to nine months, and functional constipation differs between children with and without toilet training [1].

    High statistical heterogeneity was observed in this analysis (I2=99%), possibly reflecting the variety of population characteristics, sample sizes, FGID assessments, and sampling methods among the studies. However, in clinical practice and previous studies using the Rome III criteria, a significant variation in prevalence was reported by van Tilburg et al. [24] (27%) and Chogle et al. [25] (40.5%), and therefore could be expected.

    Despite the existence of a standardized definition of FGIDs, multiple assessment methods are currently available, as shown in this research.

    The prevalence of FGIDs in the Americas was the highest among all continents. On this continent, migration and colonization have resulted in racially heterogeneous populations with similar cultural backgrounds in the same region. This result can also explain the high heterogeneity observed among studies in this region. Moreover, social, psychological, and biological aspects are known to influence the perception and interpretation of symptoms such as pain [26]. For instance, lower pain tolerance has been reported in African American adults [27].

    In contrast, the Hispanic population exhibited a lower prevalence of chronic pain; however, this population reported a higher severity of symptoms with more sensitivity and less tolerance to a painful stimulus [28] than those reported by non-Hispanic white adults. The cultural interpretation of illness in some Hispanic populations as divine punishment or proving faith led to individuals seeking religion or traditional medicine [29] as a coping mechanism, and possibly delayed the search for Western medical care.

    Language can also influence specific medical terms, especially FGIDs, where the symptoms are vague and susceptible to subjective interpretation. Additionally, the use of colloquial expressions increases the number of terms that describe a symptom, and these terms can differ in meaning or cannot be understood at all, even in the same region [30]. Translations can also limit the assessment of symptoms, especially in questionnaires in other languages; for example, the term ‘fussy baby’ does not translate literally in Spanish and requires a strict interpretation from a translator to capture the essence of the phrase.

    Strengths and limitations

    This meta-analysis provides new insights into FGIDs in neonates and toddlers, using the most recent criteria developed for this purpose. The findings remain consistent with previous studies, reassuring that the Rome IV criteria are consistent across settings and populations. The use of PRISMA, Cochrane Collaboration, and STROBE strategies following a standardized method ensures proper search and qualitative analysis.

    Although all studies had a similar weight in the analysis, the high heterogeneity among the studies raises the question of whether other variables or confounders played a role. The variation in prevalence rates reflects sampling methods and population characteristics. Cross-sectional studies, such as those included in this research, are not ideal for prevalence assessment; however, they can be easier to set up and still help to determine the prevalence in a specific population and time, allowing data extraction and extrapolation, although at the cost of being less valid for examining cause-effect relationships, and having methodological deficiencies such as sample size, setting, and possible bias. However, the recruitment of patients in primary care and third-level hospitals could lead to an increased prevalence of

    GI symptoms, constituting a selection bias. Other biases related to a delay in publication (file drawer bias) and language differences must be accounted for; however, an active search for gray literature and nonpublished data was performed to ensure an exhaustive literature search, including various languages and settings.

    Conclusions

    FGIDs, as defined by the Rome IV criteria, are present in 22% of children, and the most common primary disorder is functional constipation. A higher prevalence of FGIDs was reported in America. It is necessary to conduct more studies with high methodological quality to ensure proper bias assessment and external validity. We suggest that multicenter research with standardized conditions, including children from all continents, should be conducted to properly characterize FGIDs worldwide.

    Notes

    Conflict of Interest:The authors have no financial conflicts of interest.

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    MeSH Terms
    Americas
    Asia
    Bias
    Child
    Cohort Studies
    Constipation
    Epidemiology
    Europe
    Forests
    Gastrointestinal Diseases*
    Humans
    Infant
    Infant, Newborn*
    Latin America
    North America
    Prevalence
    Systematic Review*
    Metrics
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