Introduction
Functional Gastrointestinal Disorders (FGIDs), recently referred to as disorders of gut-brain interaction, are conditions that cannot be easily attributed to any structural, biochemical, or organic abnormalities.1 A child is not a miniature adult, and similarly, the FGID spectrum varies from infancy to adulthood. The ROME criteria, established in the late 20th century, have been updated periodically based on clinical experience and scientific evidence. The latest version, ROME IV, has been in use since 2016. Even within the pediatric age group, FGIDs are classified for both neonates/toddlers (< four years) and children/adolescents (four to 18 years).1,2 Infant regurgitation, infant rumination syndrome, cyclic vomiting syndrome, infant colic, functional diarrhea, infant dyschezia, and functional constipation constitute the neonate/toddler age group. Meanwhile, functional nausea and vomiting disorders (cyclic vomiting syndrome, functional nausea, functional vomiting, rumination syndrome, aerophagia), functional abdominal pain disorders (functional dyspepsia, irritable bowel syndrome, abdominal migraine, functional abdominal pain not otherwise specified), and functional defecation disorders (functional constipation, non-retentive fecal incontinence) constitute the children/adolescent age group.1,2 The inability of children to express the exact nature of their problem and the changing developmental factors make it challenging to diagnose, study, and treat pediatric FGIDs.3
Most pediatric FGIDs may evolve and continue into adulthood, contributing to significant morbidity, absenteeism, expenditure, and reduced quality of life.4–6 FGIDs significantly burden the healthcare system, contributing to both inpatient and emergency visits.7,8 They are also associated with various psychological problems such as low self-esteem, childhood trauma, anxiety, and depression.9–11 Health-related quality of life in pediatric FGID patients was lower in all domains compared to healthy children.12,13 A recent systematic review of 20 studies, including a total of 18,935 children, showed the median prevalence of FGID in children under four years to be up to 22.2%, and in those aged four to 18 years, up to 21.8%. Infant regurgitation dominated in the under 12 months age group, functional constipation, and cyclic vomiting dominated in the 13–48 month age group and functional constipation, functional dyspepsia and irritable bowel syndrome dominated in the over four years age group.13 Moreover, older children are more likely to qualify for FGIDs, especially functional dyspepsia, if their parents also qualify for the same.14 In this review, we discuss the latest advances in our understanding of the mechanisms and management of common pediatric FGIDs.
Diagnosis
Diagnosing FGIDs can be challenging, with physicians often going the extra mile to investigate for organic causes, leading to costly expenditures. The ROME IV criteria are predominantly symptom-based with less emphasis on investigations. Nonetheless, a detailed history and thorough clinical examination are essential, including an assessment of stressors, psychosocial factors, and past medical or drug history.15 It is crucial to be aware of red flag signs such as declining weight and height, delayed puberty, painful swallowing, bile-stained or persistent vomiting, bleeding, localized pain away from the umbilicus, fever, arthritis, perianal disease, and a family history of inflammatory bowel disease, or celiac disease, etc.16 Among the various lab tests available, fecal calprotectin and celiac markers are the most cost-effective investigations for a child presenting with an irritable bowel syndrome (IBS) phenotype, with the role of endoscopy being limited.17–19 Providing reassurance, acknowledging the symptoms, educating the parents, and guiding them to appropriate therapy forms the cornerstone of successful management. An earlier diagnosis, especially during the first visit, can significantly improve recovery outcomes for children (hazard ratio 2.1, 95% confidence interval 1.0 to 4.5).20
Neonate/Toddler FGID
Infant regurgitation
Involuntary movement of gastric contents into the mouth, nose, or esophagus is common in infants between three weeks and 12 months of age. It should occur at least twice per day for at least three weeks without any retching, failure to thrive, apnea, feeding difficulty, or posturing. The estimated prevalence is 41–67%.2
Infant rumination syndrome
This condition is rare compared to regurgitation. It involves effortless regurgitation of food, which is chewed and re-swallowed, accompanied by repetitive contractions of abdominal muscles, lasting for at least two months. Its estimated prevalence is 1.9%.2 The onset is between three to eight months of age, without any distress, and usually does not occur during sleep. It has been considered a self-stimulatory mechanism in a child with maternal emotional and sensory deprivation or neglect.21
Cyclic vomiting syndrome
This condition involves stereotypical and repetitive episodes of vomiting lasting hours to days, with episodes separated by weeks to months of return to baseline. For diagnosis, it must occur at least twice within six months. The estimated prevalence is 3.4%.2 Although it has a wide range of onset ages, an onset before two years of age might warrant metabolic, neurological, or anatomical testing for more serious conditions.22
Infant colic
This condition has an onset before five months of age and is characterized by recurrent and prolonged irritability, fussing, and crying without any obvious cause and no evidence of failure to thrive. These episodes should last for at least 3 h a day, three days a week, or in a 24-hour behavior diary record of 3 h of crying with fussing. About 5–19% of infants are thought to have infant colic.2
Functional diarrhea
Painless and recurrent passage of four or more well-formed stools, lasting for a minimum of four weeks without any failure to thrive in a child aged six months to 60 months, constitutes functional diarrhea. About 6–7% of infants have functional diarrhea.2
Infant dyschezia
This condition has an onset before nine months of age, without any other red flag signs, and involves at least 10 m of crying and straining before the passage of soft stools. The estimated prevalence is about 2.4%.2
Functional constipation
A child who is afraid of the unpleasant evacuation of the rectum voluntarily withholds feces, leading to overabsorption of water and hard stools that further cause painful defecation. This condition is called functional constipation.23 For children up to four years of age, it should include at least two of the following features: history of stool retention, hard painful bowel movements, larger diameter stools, fecal mass in the rectum, with two or fewer defecations per week. For a toilet-trained child, it can involve at least one episode of incontinence or large stools clogging the toilet. About 3–27% of children are found to have functional constipation.2
Child/Adolescent FGID
Cyclical vomiting
Diagnosing cyclical vomiting in older children is similar to that in younger children, with an emphasis on ruling out other medical conditions. The estimated prevalence is 0.2–1.0%.1
Rumination syndrome
One significant change for older children is that it can occur secretly without the parents’ knowledge. It does not occur during sleep and involves no retching, but begins as soon as food is taken. Eating disorders and other medical conditions need to be ruled out.1
Functional nausea and vomiting
Pediatric data is rare. It is characterized by bothersome nausea at least twice a week or one episode of non-self-induced vomiting per week, not explainable by any other medical condition.1
Aerophagia
Excessive air swallowing leading to belching, flatus, and abdominal distension lasting for at least two months and not explainable by another medical condition constitutes a diagnosis of aerophagia. It occurs in about 4.2–7.5% of children.1
Functional dyspepsia
Postprandial fullness, early satiety, or epigastric pain, all not explainable by other medical conditions, must be present for at least four days a month for two months. This can be further subclassified as postprandial distress syndrome or epigastric pain syndrome based on predominant symptoms. The estimated prevalence is about 1.4% in children and ranges from 5 to 10% in adolescents.1
IBS
IBS is classified as IBS with diarrhea, IBS with constipation, or IBS unspecified. Symptoms must include abdominal pain related to defecation, a change in stool frequency, or stool consistency, lasting for at least four days a month for a minimum of two months, and not explained by other medical conditions. About 1.2–5.4% of children are thought to have IBS.1 The presence of red flag signs like blood in stools or failure to thrive should prompt a thorough search for organic causes like celiac disease and inflammatory bowel disease.
Abdominal migraine
It is characterized by paroxysmal episodes of severe and diffuse abdominal pain that last for a minimum of 1 h, interfering with normal daily activities, and presenting a stereotypical pattern with at least two of the following six features: anorexia, nausea, vomiting, headache, photophobia, and pallor. there must be a minimum of two episodes separated by weeks or months within a 6-month period and possible medical conditions must be ruled out. The estimated prevalence is up to 23%.1 Cyclical vomiting, abdominal migraine, and migraine headache are all episodic, stereotypical conditions with symptom-free periods in between, often triggered by stress, fatigue, or travel, and likely share a common pathophysiology. These abdominal conditions can develop into migraine headaches in adulthood.
Functional abdominal pain not otherwise specified
This group includes conditions that involve abdominal pain for four days a month for at least two months without the classic features of IBS, dyspepsia, or abdominal migraine, and not explained by other medical conditions. An estimated 1.2–4% of children have this disorder.1
Functional constipation
As discussed in the toilet-trained children category above, the only change for older children is that constipation should last for at least one month, should not fulfill IBS criteria, and should not be explained by other medical conditions. The estimated prevalence is about 14%.1 In the absence of any red flag signs, routine testing for celiac disease, hypothyroidism, cow milk allergy, or radiography is not recommended. An X-ray can be considered if fecal impaction is suspected.
Non retentive fecal incontinence
A child older than four years should have at least a one-month history of defecation in inappropriate places with no evidence of fecal retention or other medical conditions. Around 0.8–4.1% of the children may have this disorder.1 It has been postulated to occur as a result of emotional disturbance and even sexual abuse in childhood.24
Mechanisms
The exact pathophysiology behind FGIDs is still poorly understood. Traditionally, early life factors (genetic and environmental), psychosocial factors, physiological factors (abnormal motility, visceral hypersensitivity, immune dysregulation, diet), and the gut-brain axis are known to play a role in FGIDs.15
Genetic and environment
An early life stressful event like physical injury or infection can cause persistent structural and functional disruption of the neural and enteral neural circuitry during a vulnerable developmental period.25,26 A meta-analysis showed girls have a higher risk (Odds ratio 1.5, 95% confidence interval 1.3–1.7) of developing functional abdominal pain compared to boys.27 The same study did not show any difference in the prevalence of functional abdominal pain disorders between those under 12 years and those older.27 Earlier studies on IBS have shown monozygotic twins to be at a higher risk than dizygotic twins (17.2% vs 8.4%) with subsequent studies estimating the heritability of FGIDs to be between 22% to 57%.28,29 A polygenic mode of inheritance influenced by environmental factors leading to epigenetic changes is widely accepted.29,30
Psychosocial factors
Psychosocial factors like somatization and ineffective coping mechanisms, alongside anxiety and depression, can lead to FGIDs. These maladaptations and negative emotions can increase colonic transit time. They are postulated to alter the gut mucosal barrier, affecting the gut-brain axis and creating a vicious bidirectional cycle.31
Altered gut physiology and immune dysregulation
Changes in visceral afferent processing mediated by infection, inflammation, or stress can lead to a state of hyperalgesia with changes in mucosal permeability, impaired barrier function, immune dysregulation, serotonin, and histamine release, activating nociceptors, leading to reduced thresholds for pain and distention response, with children being more susceptible.32,33 Central sensitization in the form of secondary hyperalgesia and altered cortical nociceptive processing has been shown in functional abdominal pain.34,35 Moreover, an increase in mast cells and eosinophils suggests a role of immune dysregulation in FGIDs.36 Both upper and lower gastric dysmotility, such as delayed gastric emptying, reduced gastric accommodation, delayed or accelerated colonic transit, and pelvic floor dyssynergia, have been postulated to be associated with FGIDs along with an increased inter-digestive migrating contraction, which has a housekeeping role in the gastrointestinal tract.37 The gut-brain axis has come under the scanner as of late as a popular theory for FGID causation.
Gut-brain axis
There is increasing evidence of gut microbiota dysbiosis, with a decrease in species with anti-inflammatory effects, such as Bifidobacterium and Faecalibacterium in FGIDs, especially IBS.38–40 A recent review showed stress, early life events, diet, and antibiotic therapy might alter the gut microbiota, and some probiotic strains can improve gastric emptying with potential improvement in FGIDs.41 However, there are marked heterogeneities among studies, and limited evidence exists regarding gut microbiota dysbiosis leading to FGIDs.42 To summarize, there may be a complex interplay between the viscera, central nervous system, and gut microbiota mediated via the vagus nerve, hypothalamus-pituitary axis, endocrine, and immune systems. Factors such as interleukins 1 and 6, neurotransmitters like gamma-aminobutyric acid, serotonin, acetylcholine, and metabolites such as short-chain fatty acids, contribute to visceral and central hypersensitivity involving cortical structures like the amygdala, prefrontal cortex, somatosensory cortex, insula, periaqueductal gray matter, anterior cingulate cortex, and thalamus.43 The simplified mechanism is shown in Figure 1.
Management
Most children with FGIDs require a multifaceted approach, combining medical, behavioral, and dietary methods. It is best if all these modalities are available under one roof, as a single modality rarely resolves FGIDs satisfactorily. Given the heterogeneity of FGIDs, one treatment algorithm cannot fit all patients. A biopsychosocial approach that identifies and addresses triggers educates parents with information sheets, and integrates multidisciplinary care forms the backbone of successful therapy.44 Up to 60–70% of children are known to recover from FGIDs over time but are at risk of developing migraine headaches, anxiety, and other disorders later in adulthood, necessitating proper transition of care and collaboration between pediatric and adult healthcare providers.4,45
Dietary methods
Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet (FODMAP)
High FODMAPs such as wheat, lentils, barley, rye, and asparagus can alter the gut microbiome and enhance visceral nociception.46 Although few studies showed a trend toward improvement in abdominal pain symptoms in children with a low FODMAP diet, overall results are conflicting.47,48
Lactose and gluten-free diet
Lactose intolerance and non-celiac gluten sensitivity symptoms might mimic those of IBS. The role of lactose elimination in FGID is controversial. Several randomized controlled trials (RCTs) have not shown promising results with lactose-restricted diets.49,50 Pediatric studies are lacking in the prevalence of non-celiac gluten sensitivity. Although a recent RCT showed promising results in reducing abdominal pain symptoms, the overall evidence is still not concrete.51,52
Fiber supplementation
Soluble dietary fibers that are viscous and moderately fermented improve IBS symptoms via laxative effect, increasing stool bulk and forming a gel-like covering. They also promote a beneficial gut microenvironment via short-chain fatty acids like butyrate and help regulate the gut-brain axis.53 Meta-analyses on predominantly adult populations have shown a proven role of soluble dietary fibers in IBS.54 Pediatric RCTs have also shown a greater reduction in pain and IBS severity scores with the use of psyllium.55,56
Probiotics
Probiotics, beneficial organisms that inhabit the gut, have a proven role in antibiotic-associated diarrhea, ulcerative colitis, and celiac.57–59 A systematic review in 2018 showed Lactobacillus rhamnosus GG reduces the intensity and frequency of IBS-related abdominal pain in children though evidence is unsatisfactory for functional constipation and functional abdominal pain disorder.60 An RCT on infants showed a 50% reduction in infant colic with L. reutreri.61
Nutraceuticals
Peppermint oil has shown some efficacy in relieving abdominal pain symptoms, though quality studies are lacking.62 Fennel, a medicinal herb with potential antioxidant, antispasmodic, and anti-inflammatory properties, seemed to reduce crying episodes in infants with colic.63 A meta-analysis on the role of vitamin D in IBS showed poor quality evidence for improvement in IBS severity scores but not in quality of life.64
Psychosocial methods
Cognitive behavioral therapy (CBT)
A Cochrane review done in 2017 of 18 RCTs, has shown CBT to be effective in addressing the anxiety and stress related to somatic sensations found in these patients.65 CBT can be delivered both via in person as well as telephonic means. Patient motivation and engagement are necessary.
Hypnotherapy
By inducing a deep state of relaxation, hypnotherapy helps in reducing pain outcomes in pediatric FGIDs.65 A recent RCT showed superior efficacy of hypnotherapy compared to medical treatment for functional nausea.66
Yoga therapy
Yoga improved physical and mental well-being, and multiple studies have shown the downregulation of the sympathetic and hypothalamic-pituitary axis.67 However the Cochrane review did not show any proven role of yoga therapy in IBS and it is not recommended as a routine treatment.65
Neuro-electrical stimulation
Gastric electrical stimulation and percutaneous electrical nerve field stimulation are examples of electrical neurostimulation therapies investigated in pediatric FGIDs. Gastric electrical stimulation significantly improved gastroparesis and chronic nausea, while percutaneous electrical nerve field stimulation reduced pain symptoms of IBS.68,69 More studies are needed to make a routine recommendation.
Fecal microbiota transplantation
This procedure involves manipulating the gut microbiota by administering an oral solution of fecal matter from a donor to confer a health benefit, such as treating Clostridium difficle.70 A recent study on 12 pediatric patients showed good responses in bloating, pain, and diarrheal symptoms, with evidence of positive manipulation of the recipient gut microbiota.71
Pharmacological methods
Being a functional disorder, the placebo response is much higher, making it difficult to assess whether there is an actual response to a drug.72 Antispasmodics, antibiotics, laxatives, antihistamines, anti-reflux drugs, analgesics, and antidepressants have all been tried in pediatric FGIDs. A systematic review done in 2015 with six studies on children above 4.5 years of age showed some evidence for peppermint oil polyethylene glycol, with tegaserod and cyproheptadine reducing pain intensity, while famotidine and amitriptyline improved the quality of life.73
Antispasmodics
Antispasmodics act on gastric smooth muscles leading to relaxation. Trimebutine, mebeverine, and drotaverine are the only drugs used in three RCTs in children. All three drugs improved abdominal pain and discomfort compared to the placebo.74–76
Antibiotics
Rifaximin, a poorly absorbed oral antibiotic, is known to control small intestinal bacterial overgrowth and regulate gut microbial dysbiosis. Rifaximin is even approved for adults with IBS.77 Pediatric studies are fewer and the results are conflicting, so it is not routinely recommended.78,79
Antidepressants
Antidepressants like amitriptyline can have anticholinergic side effects, QT prolongation, and increased suicidal thoughts.80 Nonetheless, they have been tried in those refractory cases.
RCTs have shown improvement in quality of life, anxiety, pain, and depression with the usage of amitriptyline and citalopram.81–83
Laxatives, prokinetics and antidiarrheals
Polyethylene glycol with tegaserod improved pain and stooling in IBS with constipation.84 Linaclotide, lubiprostone, and prucalopride have shown efficacy in adult studies, but quality pediatric studies are lacking, so they are not recommended for IBS.85 For functional constipation, disimpaction and maintenance regimens may be necessary. Osmotic laxatives like PEG, lactulose, sorbitol, and milk of magnesia, as well as stimulant laxatives like senna and bisacodyl, glycerin suppositories, rectal enemas, such as sodium phosphate and saline enema, and lubricants like mineral oil, are used to produce soft painless stools, and prevent re-impaction.86 Prokinetics like domperidone, a dopamine antagonist, have a beneficial role in adult dyspepsia. An RCT of 89 children using domperidone versus placebo showed it may be a safe and effective drug for reducing pain and overall feeling of improvement.87 Loperamide, though a first-line anti-diarrheal drug for the IBS-diarrhea type, has no RCT in children and is not recommended.88,89
The summary of the diagnosis, pathophysiology, and treatment is provided in Table 1.
Table 1Brief summary of FGIDs diagnosis, mechanism, and management
| S. No. | Topics | Summary |
|---|
| 1. | Diagnostic criteria | ROME IV |
| 2. | Neonatal/toddler FGIDs | Infant regurgitation, Infant rumination syndrome, Cyclic vomiting syndrome, Infant colic, Functional diarrhea, Infant dyschezia, Functional constipation |
| 3. | Child/Adolescent FGIDs | Cyclical vomiting, Rumination Syndrome, Functional nausea and vomiting, Aerophagia, Functional Dyspepsia, Irritable bowel syndrome, Abdominal migraine, Functional abdominal pain not otherwise specified, Functional constipation, Non-retentive fecal incontinence |
| 4. | Red flag signs | Declining weight and height, delayed puberty, painful swallowing, bile-stained vomiting or persistent vomiting, bleeding, localized pain away from the umbilicus, fever, arthritis, perianal disease, and family history of inflammatory bowel disease or celiac disease |
| 5. | Pathophysiology | Genetic and environmental, psychosocial factors, abnormal motility, visceral hypersensitivity, mucosal permeability, central sensitization, immune dysregulation, diet, and gut-brain axis |
| 6. | Management | |
| 1. Dietary | Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet (FODMAP), lactose-gluten free diet, fiber supplementation, probiotics, nutraceuticals |
| 2. Psychosocial | Cognitive behavioral therapy, hypnotherapy, yoga therapy, neuro-electrical stimulation, fecal microbiota transplantation |
| 3. Pharmacological | Antispasmodics, antibiotics, antidepressants, laxatives, prokinetics, antidiarrheals |
| 7. | Knowledge gained and application in clinical practice | FGIDs contribute to significant morbidity and reduced quality of life for both children and their caregivers; Different age groups can have their own unique manifestations; Despite several advancements the exact pathophysiology is poorly understood; Diagnosis does not need investigations and red flag signs should be watched out for; Early identification, parent education, and a combined multi-integrated biopsychosocial treatment modality can help in better outcomes. |
Conclusion
This review highlights the prevalence, economic and psychosocial burden, age-stratified ROME IV classification, pathophysiology, diagnosis, red flag signs, and pharmacological and non-pharmacological treatment modalities for pediatric FGIDs. Compared to adult studies, well-controlled RCTs are lacking in the pediatric age group, especially with respect to pharmacological treatment. There is a trend towards greater emphasis on the gut-brain axis and the role of prebiotics and probiotics in maintaining favorable gut microbiota in FGIDs. Having a multi-integrated, biopsychosocial approach with enriched parental knowledge is the current recommended modality of treatment. Early recognition and treatment initiation can prevent long-term morbidity and improve the quality of life for both parents and their children.
Declarations
Funding
None.
Conflict of interest
None.
Authors’ contributions
Study concept and design (AM, GK and SG), acquisition of data (AM, GK and SG), analysis and interpretation of data (AM, GK and SG), drafting of the manuscript (AM, GK and SG), critical revision of the manuscript for important intellectual content (AM, GK and SG), administrative, technical, or material support (SG), and study supervision (SG). All authors have made a significant contribution to this study and have approved the final manuscript.