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Paediatric functional abdominal pain disorders

Nature Reviews Disease Primers volume 6, Article number: 89 (2020) Cite this article

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Abstract

Paediatric functional abdominal pain disorders, currently referred to as disorders of gut–brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3–16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota–gut–brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.

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Fig. 1: Summary of the aetiopathogenesis and pathophysiology of FAPDs.
Fig. 2: IBS prevalence in children.
Fig. 3: Aetiopathogenesis of hypersensitivity in FAPDs.
Fig. 4: Rome IV diagnostic workflow of FAPDs.
Fig. 5: Therapeutic algorithm for IBS in children.

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References

  1. Robin, S. G. et al. Prevalence of pediatric functional gastrointestinal disorders utilizing the Rome IV criteria. J. Pediatr. 195, 134–139 (2018). A large study collecting data on the prevalence of functional gastrointestinal disorders from families from the 50 states of the USA.

    Google Scholar 

  2. Drossman, D. A. Functional gastrointestinal disorders: history, pathophysiology, clinical features and Rome IV. Gastroenterology 150, 1262–1279 (2016).

    Google Scholar 

  3. Benninga, M. A. et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology https://doi.org/10.1053/j.gastro.2016.02.016 (2016).

    Article  Google Scholar 

  4. Hyams, J. S. et al. Functional disorders: children and adolescents. Gastroenterology https://doi.org/10.1053/j.gastro.2016.02.015 (2016). This paper finally brought together the different definitions of functional disorders in children under one umbrella definition (Rome IV).

    Article  Google Scholar 

  5. Rajindrajith, S. & Devanarayana, N. M. Subtypes and symptomatology of irritable bowel syndrome in children and adolescents: a school-based survey using Rome III criteria. J. Neurogastroenterol. Motil. 18, 298–304 (2012).

    Google Scholar 

  6. Turco, R. et al. Do distinct functional dyspepsia subtypes exist in children? J. Pediatr. Gastroenterol. Nutr. 62, 387–392 (2016).

    Google Scholar 

  7. Schurman, J. V. et al. Diagnostic utility of the water load test in children with chronic abdominal pain. J. Pediatr. Gastroenterol. Nutr. 44, 51–57 (2007).

    Google Scholar 

  8. Edwards, T., Friesen, C. & Schurman, J. V. Classification of pediatric functional gastrointestinal disorders related to abdominal pain using Rome III vs. Rome IV criterions. BMC Gastroenterol. 18, 41 (2018).

    Google Scholar 

  9. Rasquin, A. et al. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology 130, 1527–1537 (2006).

    Google Scholar 

  10. Diederen, K. et al. The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity. Aliment. Pharmacol. Ther. 44, 181–188 (2016).

    CAS  Google Scholar 

  11. Watson, K. L. Jr, Kim, S. C., Boyle, B. M. & Saps, M. Prevalence and impact of functional abdominal pain disorders in children with inflammatory bowel diseases (IBD-FAPD). J. Pediatr. Gastroenterol. Nutr. 65, 212–217 (2017).

    Google Scholar 

  12. Youssef, N. N., Murphy, T. G., Langseder, A. L. & Rosh, J. R. Quality of life for children with functional abdominal pain: a comparison study of patients’ and parents’ perceptions. Pediatrics 117, 54–59 (2006).

    Google Scholar 

  13. Varni, J. W. et al. Health-related quality of life in pediatric patients with irritable bowel syndrome: a comparative analysis. J. Dev. Behav. Pediatr. 27, 451–458 (2006).

    Google Scholar 

  14. Rasquin-Weber, A. et al. Childhood functional gastrointestinal disorders. Gut 45 (Suppl. 2), II60–II68 (1999).

    Google Scholar 

  15. Saps, M. & Di Lorenzo, C. Interobserver and intraobserver reliability of the Rome II criteria in children. Am. J. Gastroenterol. 100, 2079–2082 (2005).

    Google Scholar 

  16. Chogle, A., Dhroove, G., Sztainberg, M., Di Lorenzo, C. & Saps, M. How reliable are the Rome III criteria for the assessment of functional gastrointestinal disorders in children? Am. J. Gastroenterol. 105, 2697–2701 (2010).

    Google Scholar 

  17. Chogle, A. et al. Accuracy of pain recall in children. J. Pediatr. Gastroenterol. Nutr. 55, 288–291 (2012).

    Google Scholar 

  18. van der Plas, R. N., Benninga, M. A., Redekop, W. K., Taminiau, J. A. & Büller, H. A. How accurate is the recall of bowel habits in children with defaecation disorders? Eur. J. Pediatr. 156, 178–181 (1997).

    Google Scholar 

  19. Koppen, I. J. N., Velasco-Benitez, C. A., Benninga, M. A., Di Lorenzo, C. & Saps, M. Using the Bristol stool scale and parental report of stool consistency as part of the Rome III criteria for functional constipation in infants and toddlers. J. Pediatr. 177, 44–48.e41 (2016).

    Google Scholar 

  20. Sjölund, J. et al. Prevalence and progression of recurrent abdominal pain, from early childhood to adolescence. Clin. Gastroenterol. Hepatol. https://doi.org/10.1016/j.cgh.2020.04.047 (2020).

    Article  Google Scholar 

  21. Saps, M., Velasco-Benitez, C. A., Langshaw, A. H. & Ramirez-Hernandez, C. R. Prevalence of functional gastrointestinal disorders in children and adolescents: comparison between Rome III and Rome IV criteria. J. Pediatr. 199, 212–216 (2018).

    Google Scholar 

  22. Devanarayana, N. M., Adhikari, C., Pannala, W. & Rajindrajith, S. Prevalence of functional gastrointestinal diseases in a cohort of Sri Lankan adolescents: comparison between Rome II and Rome III criteria. J. Trop. Pediatr. 57, 34–39 (2011).

    Google Scholar 

  23. Korterink, J. J., Diederen, K., Benninga, M. A. & Tabbers, M. M. Epidemiology of pediatric functional abdominal pain disorders: a meta-analysis. PLoS ONE 10, e0126982 (2015). This paper is the best worldwide survey of prevalence or incidence of functional bowel disorder in children and adolescents, irrespective of the underlying definitions and using a large variety of methods.

    Google Scholar 

  24. Lewis, M. L., Palsson, O. S., Whitehead, W. E. & van Tilburg, M. A. L. Prevalence of functional gastrointestinal disorders in children and adolescents. J. Pediatr. 177, 39–43.e3 (2016).

    Google Scholar 

  25. Udoh, E., Devanarayana, N. M., Rajindrajith, S., Meremikwu, M. & Benninga, M. A. Abdominal pain-predominant functional gastrointestinal disorders in adolescent Nigerians. J. Pediatr. Gastroenterol. Nutr. 62, 588–593 (2016).

    Google Scholar 

  26. Gulewitsch, M. D., Enck, P., Schwille-Kiuntke, J., Weimer, K. & Schlarb, A. A. Rome III criteria in parents’ hands: pain-related functional gastrointestinal disorders in community children and associations with somatic complaints and mental health. Eur. J. Gastroenterol. Hepatol. 25, 1223–1229 (2013).

    Google Scholar 

  27. Sagawa, T. et al. Functional gastrointestinal disorders in adolescents and quality of school life. J. Gastroenterol. Hepatol. 28, 285–290 (2013).

    Google Scholar 

  28. Adeniyi, O. F., Lesi, O. A., Olatona, F. A., Esezobor, C. I. & Ikobah, J. M. Irritable bowel syndrome in adolescents in Lagos. Pan Afr. Med. J. 28, 93 (2017).

    Google Scholar 

  29. Carson, L. et al. Abdominal migraine: an under-diagnosed cause of recurrent abdominal pain in children. Headache 51, 707–712 (2011).

    Google Scholar 

  30. Mortimer, M. J., Kay, J. & Jaron, A. Clinical epidemiology of childhood abdominal migraine in an urban general practice. Dev. Med. Child Neurol. 35, 243–248 (1993).

    CAS  Google Scholar 

  31. Dahl-Larsen, R., Buhl, S. B., Husby, S. & Qvist, N. Recurrent abdominal pain, dyspepsia and constipation in children aged 9–13. A questionnaire investigation[Danish]. Ugeskr. Laeger 167, 1848–1851 (2005).

    Google Scholar 

  32. Newton, E., Schosheim, A., Patel, S., Chitkara, D. K. & van Tilburg, M. A. L. The role of psychological factors in pediatric functional abdominal pain disorders. Neurogastroenterol. Motil. 31, e13538 (2019).

    Google Scholar 

  33. Zernikow, B. et al. Characteristics of highly impaired children with severe chronic pain: a 5-year retrospective study on 2249 pediatric pain patients. BMC Pediatr. 12, 54 (2012).

    Google Scholar 

  34. Levy, R. L. et al. Increased somatic complaints and health-care utilization in children: effects of parent IBS status and parent response to gastrointestinal symptoms. Am. J. Gastroenterol. 99, 2442–2451 (2004).

    Google Scholar 

  35. Sherman, A. L., Bruehl, S., Smith, C. A. & Walker, L. S. Individual and additive effects of mothers’ and fathers’ chronic pain on health outcomes in young adults with a childhood history of functional abdominal pain. J. Pediatr. Psychol. 38, 365–375 (2013).

    Google Scholar 

  36. Levy, R. L. Exploring the intergenerational transmission of illness behavior: from observations to experimental intervention. Ann. Behav. Med. 41, 174–182 (2011).

    Google Scholar 

  37. Stone, A. L., Bruehl, S., Smith, C. A., Garber, J. & Walker, L. S. Social learning pathways in the relation between parental chronic pain and daily pain severity and functional impairment in adolescents with functional abdominal pain. Pain 159, 298–305 (2018).

    Google Scholar 

  38. Craig, K. D. Social communication model of pain. Pain 156, 1198–1199 (2015).

    Google Scholar 

  39. Van Der Veek, S. M. et al. Do parents maintain or exacerbate pediatric functional abdominal pain? A systematic review and meta-analysis. J. Health Psychol. 17, 258–272 (2012).

    Google Scholar 

  40. Dong, Y.-Y. Prevalence of irritable bowel syndrome in Chinese college and university students assessed using Rome III criteria. World J. Gastroenterol. 16, 4221 (2010).

    Google Scholar 

  41. Son, Y. J., Jun, E. Y. & Park, J. H. Prevalence and risk factors of irritable bowel syndrome in Korean adolescent girls: a school-based study. Int. J. Nurs. Stud. 46, 76–84 (2009).

    Google Scholar 

  42. Bonilla, S. & Saps, M. Early life events predispose the onset of childhood functional gastrointestinal disorders. Rev. Gastroenterol. Mex. 78, 82–91 (2013).

    CAS  Google Scholar 

  43. Levy, R. L. et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 121, 799–804 (2001).

    CAS  Google Scholar 

  44. van Tilburg, M. A., Zaki, E. A., Venkatesan, T. & Boles, R. G. Irritable bowel syndrome may be associated with maternal inheritance and mitochondrial DNA control region sequence variants. Dig. Dis. Sci. 59, 1392–1397 (2014).

    Google Scholar 

  45. Faure, C. & Grunder, F. R. in Pediatric Neurogastroenterology (eds Faure, C.; Thapar, N. & Di Lorenzo, C.) 39–52 (Springer, 2017).

  46. Halac, U., Noble, A. & Faure, C. Rectal sensory threshold for pain is a diagnostic marker of irritable bowel syndrome and functional abdominal pain in children. J. Pediatr. 156, 60–65.e1 (2010).

    Google Scholar 

  47. Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–S15 (2011).

    Google Scholar 

  48. Pas, R. et al. Hyperexcitability of the central nervous system in children with chronic pain: a systematic review. Pain Med. 19, 2504–2514 (2018).

    Google Scholar 

  49. Sherman, A. L., Morris, M. C., Bruehl, S., Westbrook, T. D. & Walker, L. S. Heightened temporal summation of pain in patients with functional gastrointestinal disorders and history of trauma. Ann. Behav. Med. 49, 785–792 (2015).

    Google Scholar 

  50. Liu, X. et al. Excessive coupling of the salience network with intrinsic neurocognitive brain networks during rectal distension in adolescents with irritable bowel syndrome: a preliminary report. Neurogastroenterol. Motil. 28, 43–53 (2016).

    CAS  Google Scholar 

  51. Langley-Evans, S. C. Nutrition in early life and the programming of adult disease: a review. J. Hum. Nutr. Diet. 28 (Suppl. 1), 1–14 (2015).

    Google Scholar 

  52. Rosen, J. M., Adams, P. N. & Saps, M. Umbilical hernia repair increases the rate of functional gastrointestinal disorders in children. J. Pediatr. 163, 1065–1068 (2013).

    Google Scholar 

  53. Saps, M. & Bonilla, S. Early life events: infants with pyloric stenosis have a higher risk of developing chronic abdominal pain in childhood. J. Pediatr. 159, 551–554.e1 (2011).

    Google Scholar 

  54. Saps, M. et al. Post-infectious functional gastrointestinal disorders in children. J. Pediatr. 152, 812–816 (2008).

    Google Scholar 

  55. Thabane, M. et al. An outbreak of acute bacterial gastroenteritis is associated with an increased incidence of irritable bowel syndrome in children. Am. J. Gastroenterol. 105, 933–939 (2010).

    Google Scholar 

  56. Cremon, C. et al. Salmonella gastroenteritis during childhood is a risk factor for irritable bowel syndrome in adulthood. Gastroenterology 147, 69–77 (2014). This study documents the existence of post-infection IBS in adults after an exposure to a bacteria (Salmonella) during childhood, nearly 25 years before the outbreak, although exposed adults did not report higher incidence of IBS than controls without such exposure.

    Google Scholar 

  57. Saps, M., Adams, P., Bonilla, S., Chogle, A. & Nichols-Vinueza, D. Parental report of abdominal pain and abdominal pain-related functional gastrointestinal disorders from a community survey. J. Pediatr. Gastroenterol. Nutr. 55, 707–710 (2012).

    Google Scholar 

  58. Saps, M., Dhroove, G. & Chogle, A. Henoch-Schonlein purpura leads to functional gastrointestinal disorders. Dig. Dis. Sci. 56, 1789–1793 (2011).

    Google Scholar 

  59. Anand, K. J., Runeson, B. & Jacobson, B. Gastric suction at birth associated with long-term risk for functional intestinal disorders in later life. J. Pediatr. 144, 449–454 (2004).

    CAS  Google Scholar 

  60. Saps, M., Lu, P. & Bonilla, S. Cow’s-milk allergy is a risk factor for the development of FGIDs in children. J. Pediatr. Gastroenterol. Nutr. 52, 166–169 (2011).

    Google Scholar 

  61. Uusijarvi, A. et al. Use of antibiotics in infancy and childhood and risk of recurrent abdominal pain — a Swedish birth cohort study. Neurogastroenterol. Motil. 26, 841–850 (2014).

    CAS  Google Scholar 

  62. Barreau, F., Salvador-Cartier, C., Houdeau, E., Bueno, L. & Fioramonti, J. Long-term alterations of colonic nerve-mast cell interactions induced by neonatal maternal deprivation in rats. Gut 57, 582–590 (2008).

    CAS  Google Scholar 

  63. Nurgali, K. et al. Morphological and functional changes in guinea-pig neurons projecting to the ileal mucosa at early stages after inflammatory damage. J. Physiol. 589, 325–339 (2011).

    CAS  Google Scholar 

  64. Collins, J., Borojevic, R., Verdu, E. F., Huizinga, J. D. & Ratcliffe, E. M. Intestinal microbiota influence the early postnatal development of the enteric nervous system. Neurogastroenterol. Motil. 26, 98–107 (2014).

    CAS  Google Scholar 

  65. Di Nardo, G. et al. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS. Neurogastroenterol. Motil. 26, 196–204 (2014).

    Google Scholar 

  66. Friesen, C. A. et al. Antral inflammatory cells, gastric emptying, and electrogastrography in pediatric functional dyspepsia. Dig. Dis. Sci. 53, 2634–2640 (2008).

    Google Scholar 

  67. Wauters, L., Nightingale, S., Talley, N. J., Sulaiman, B. & Walker, M. M. Functional dyspepsia is associated with duodenal eosinophilia in an Australian paediatric cohort. Aliment. Pharmacol. Ther. 45, 1358–1364 (2017).

    CAS  Google Scholar 

  68. Schappi, M. G. et al. Mast cell-nerve interactions in children with functional dyspepsia. J. Pediatr. Gastroenterol. Nutr. 47, 472–480 (2008).

    Google Scholar 

  69. Karunanayake, A., Rajindrajith, S., de Silva, H. A., Gunawardena, S. & Devanarayana, N. M. Autonomic functions and gastric motility in children with functional abdominal pain disorders. World J. Gastroenterol. 25, 95–106 (2019).

    Google Scholar 

  70. Friesen, C. A. et al. Electrogastrography in pediatric functional dyspepsia: relationship to gastric emptying and symptom severity. J. Pediatr. Gastroenterol. Nutr. 42, 265–269 (2006).

    Google Scholar 

  71. Vargas-Luna, F. M. et al. Electrogastrographic and autonomic nervous system responses to solid and liquid meals in youth with functional dyspepsia. Neurogastroenterol. Motil. 32, e13785 (2020).

    Google Scholar 

  72. Jericho, H., Adams, P., Zhang, G., Rychlik, K. & Saps, M. Nausea predicts delayed gastric emptying in children. J. Pediatr. 164, 89–92 (2014).

    Google Scholar 

  73. Riezzo, G., Russo, F. & Indrio, F. Electrogastrography in adults and children: the strength, pitfalls, and clinical significance of the cutaneous recording of the gastric electrical activity. Biomed. Res. Int. 2013, 282757 (2013).

    Google Scholar 

  74. Hoffman, I. & Tack, J. Assessment of gastric motor function in childhood functional dyspepsia and obesity. Neurogastroenterol. Motil. 24, 108–112, e81 (2012).

    CAS  Google Scholar 

  75. Di Lorenzo, C. et al. Visceral hyperalgesia in children with functional abdominal pain. J. Pediatr. 139, 838–843 (2001).

    Google Scholar 

  76. Kovacic, K. & Di Lorenzo, C. Functional nausea in children. J. Pediatr. Gastroenterol. Nutr. 62, 365–371 (2016).

    Google Scholar 

  77. Wang, X. J. & Camilleri, M. Personalized medicine in functional gastrointestinal disorders: understanding pathogenesis to increase diagnostic and treatment efficacy. World J. Gastroenterol. 25, 1185–1196 (2019).

    CAS  Google Scholar 

  78. DuPont, A. W. et al. Motility abnormalities in irritable bowel syndrome. Digestion 89, 119–123 (2014).

    CAS  Google Scholar 

  79. Camilleri, M. et al. Prospective study of motor, sensory, psychologic, and autonomic functions in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 6, 772–781 (2008).

    Google Scholar 

  80. Benninga, M. A. et al. Defaecation disorders in children, colonic transit time versus the Barr-score. Eur. J. Pediatr. 154, 277–284 (1995).

    CAS  Google Scholar 

  81. Rodriguez, L., Sood, M., Di Lorenzo, C. & Saps, M. An ANMS-NASPGHAN consensus document on anorectal and colonic manometry in children. Neurogastroenterol. Motil. https://doi.org/10.1111/nmo.12944 (2017).

    Article  Google Scholar 

  82. Van Ginkel, R., Voskuijl, W. P., Benninga, M. A., Taminiau, J. A. & Boeckxstaens, G. E. Alterations in rectal sensitivity and motility in childhood irritable bowel syndrome. Gastroenterology 120, 31–38 (2001).

    Google Scholar 

  83. Devanarayana, N. M. & Rajindrajith, S. Irritable bowel syndrome in children: current knowledge, challenges and opportunities. World J. Gastroenterol. 24, 2211–2235 (2018).

    Google Scholar 

  84. Enck, P. & Mazurak, N. Dysbiosis in functional bowel disorders. Ann. Nutr. Metab. 72, 296–306 (2018).

    CAS  Google Scholar 

  85. Enck, P. et al. Irritable bowel syndrome. Nat. Rev. Dis. Primers 2, 16014 (2016).

    Google Scholar 

  86. Pittayanon, R. et al. Gut microbiota in patients with irritable bowel syndrome-a systematic review. Gastroenterology 157, 97–108 (2019). This systematic review emphasizes inconsistencies in methodology, analyses and findings between studies and the heterogeneity of microbiota in subjects with IBS.

    Google Scholar 

  87. Miquel, S. et al. Faecalibacterium prausnitzii and human intestinal health. Curr. Opin. Microbiol. 16, 255–261 (2013).

    CAS  Google Scholar 

  88. Chumpitazi, B. P. et al. Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. Aliment. Pharmacol. Ther. 42, 418–427 (2015).

    CAS  Google Scholar 

  89. Rossi, M. et al. Volatile organic compounds in feces associate with response to dietary intervention in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 16, 385–391.e1 (2018).

    CAS  Google Scholar 

  90. Dong, T. S. & Gupta, A. Influence of early life, diet, and the environment on the microbiome. Clin. Gastroenterol. Hepatol. 17, 231–242 (2019).

    Google Scholar 

  91. Carding, S. R., Davis, N. & Hoyles, L. Review article: the human intestinal virome in health and disease. Aliment. Pharmacol. Ther. 46, 800–815 (2017).

    CAS  Google Scholar 

  92. Mukhopadhya, I., Segal, J. P., Carding, S. R., Hart, A. L. & Hold, G. L. The gut virome: the ‘missing link’ between gut bacteria and host immunity? Ther. Adv. Gastroenterol. 12, 1756284819836620 (2019).

    CAS  Google Scholar 

  93. Botschuijver, S. et al. Intestinal fungal dysbiosis is associated with visceral hypersensitivity in patients with irritable bowel syndrome and rats. Gastroenterology 153, 1026–1039 (2017).

    Google Scholar 

  94. Sokol, H. et al. Fungal microbiota dysbiosis in IBD. Gut 66, 1039–1048 (2017).

    CAS  Google Scholar 

  95. Carlson, M. J., Moore, C. E., Tsai, C. M., Shulman, R. J. & Chumpitazi, B. P. Child and parent perceived food-induced gastrointestinal symptoms and quality of life in children with functional gastrointestinal disorders. J. Acad. Nutr. Diet. 114, 403–413 (2014).

    Google Scholar 

  96. Chumpitazi, B. P., Weidler, E. M., Lu, D. Y., Tsai, C. M. & Shulman, R. J. Self-perceived food intolerances are common and associated with clinical severity in childhood irritable bowel syndrome. J. Acad. Nutr. Diet. 116, 1458–1464 (2016).

    Google Scholar 

  97. Reed-Knight, B., Squires, M., Chitkara, D. K. & van Tilburg, M. A. Adolescents with irritable bowel syndrome report increased eating-associated symptoms, changes in dietary composition, and altered eating behaviors: a pilot comparison study to healthy adolescents. Neurogastroenterol. Motil. 28, 1915–1920 (2016).

    CAS  Google Scholar 

  98. Mouchli, M. A. et al. Evaluating the safety and the effects on colonic compliance of neostigmine during motility testing in patients with chronic constipation. Neurogastroenterol. Motil. 28, 871–878 (2016).

    CAS  Google Scholar 

  99. Pawlowska, K., Umlawska, W. & Iwanczak, B. A link between nutritional and growth states in pediatric patients with functional gastrointestinal disorders. J. Pediatr. 199, 171–177 (2018).

    Google Scholar 

  100. Bohn, L., Storsrud, S. & Simren, M. Nutrient intake in patients with irritable bowel syndrome compared with the general population. Neurogastroenterol. Motil. 25, 23–30.e1 (2013).

    CAS  Google Scholar 

  101. Murray, K. et al. Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am. J. Gastroenterol. 109, 110–119 (2014).

    CAS  Google Scholar 

  102. van Tilburg, M. A. L. In: Neurogastroenterology: Gastrointestinal motility and functional disorders in children (eds Faure, C., Thapar, N., & Di Lorenzo, C.), 71–80 (Springer, 2017).

  103. Kennedy, P. J., Cryan, J. F., Dinan, T. G. & Clarke, G. Irritable bowel syndrome: a microbiome-gut-brain axis disorder? World J. Gastroenterol. 20, 14105–14125 (2014).

    Google Scholar 

  104. Wang, H., Lee, I. S., Braun, C. & Enck, P. Effect of probiotics on central nervous system functions in animals and humans - a systematic review. J. Neurogastroenterol. Motil. 22, 589–605 (2016).

    CAS  Google Scholar 

  105. Dinan, T. G. & Cryan, J. F. The microbiome-gut-brain axis in health and disease. Gastroenterol. Clin. North. Am. 46, 77–89 (2017).

    Google Scholar 

  106. Pinto-Sanchez, M. I. et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459.e8 (2017).

    Google Scholar 

  107. Ranasinghe, N., Devanarayana, N. M., Benninga, M. A., van Dijk, M. & Rajindrajith, S. Psychological maladjustment and quality of life in adolescents with constipation. Arch. Dis. Child. 102, 268–273 (2017).

    Google Scholar 

  108. Koloski, N. A., Jones, M. & Talley, N. J. Evidence that independent gut-to-brain and brain-to-gut pathways operate in the irritable bowel syndrome and functional dyspepsia: a 1-year population-based prospective study. Aliment. Pharmacol. Ther. 44, 592–600 (2016).

    CAS  Google Scholar 

  109. van Tilburg, M. A. L. & Carter, C. A. Integration of biomedical and psychosocial treatments in pediatrics functional gastrointestinal disorders. Gastroenterol. Clin. North. Am. 47, 863–875 (2018).

    Google Scholar 

  110. Hollier, J. M. et al. Multiple psychological factors predict abdominal pain severity in children with irritable bowel syndrome. Neurogastroenterol. Motil. 31, e13509 (2019).

    Google Scholar 

  111. Levy, R. L. et al. Cognitive mediators of treatment outcomes in pediatric functional abdominal pain. Clin. J. Pain 30, 1033–1043 (2014). This randomized controlled trial of psychological treatment found no role of anxiety on pain; instead, child pain catastrophizing and parent-perceived threat regarding their child’s pain predicted reductions in child abdominal pain.

    Google Scholar 

  112. Bonnert, M. et al. The role of avoidance behavior in the treatment of adolescents with irritable bowel syndrome: a mediation analysis. Behav. Res. Ther. 105, 27–35 (2018).

    Google Scholar 

  113. Siawash, M. et al. Abdominal wall pain or irritable bowel syndrome: validation of a pediatric questionnaire. J. Pediatr. Gastroenterol. Nutr. 69, e65–e69 (2019).

    Google Scholar 

  114. Lane, M. M., Weidler, E. M., Czyzewski, D. I. & Shulman, R. J. Pain symptoms and stooling patterns do not drive diagnostic costs for children with functional abdominal pain and irritable bowel syndrome in primary or tertiary care. Pediatrics 123, 758–764 (2009).

    Google Scholar 

  115. Turco, R. et al. The association of coeliac disease in childhood with functional gastrointestinal disorders: a prospective study in patients fulfilling Rome III criteria. Aliment. Pharmacol. Ther. 34, 783–789 (2011).

    CAS  Google Scholar 

  116. Saps, M. et al. Abdominal pain-associated functional gastrointestinal disorder prevalence in children and adolescents with celiac disease on gluten-free diet: a multinational study. J. Pediatr. 182, 150–154 (2017).

    Google Scholar 

  117. Heida, A., Holtman, G. A., Lisman-van Leeuwen, Y., Berger, M. Y. & van Rheenen, P. F. Avoid endoscopy in children with suspected inflammatory bowel disease who have normal calprotectin levels. J. Pediatr. Gastroenterol. Nutr. 62, 47–49 (2016).

    CAS  Google Scholar 

  118. Macarthur, C. Helicobacter pylori infection and childhood recurrent abdominal pain: lack of evidence for a cause and effect relationship. Can. J. Gastroenterol. 13, 607–610 (1999).

    CAS  Google Scholar 

  119. Trivic, I. & Hojsak, I. Initial diagnosis of functional gastrointestinal disorders in children increases a chance for resolution of symptoms. Pediatr. Gastroenterol. Hepatol. Nutr. 21, 264–270 (2018). An important observational study, which implies that a prompt diagnosis (at the first visit) based on symptoms and clinical history leads to a sufficient outcome in children presenting with a functional gastrointestinal disorder. It implies that testing is often unnecessary to establish a firm diagnosis.

    Google Scholar 

  120. Bonilla, S., Deli, W. & Saps, M. The prognostic value of obtaining a negative endoscopy in children with functional gastrointestinal disorders. Clin. Pediatr. 50, 396–401 (2011).

    Google Scholar 

  121. Freedman, S. B. et al. Delayed diagnoses in children with constipation: multicenter retrospective cohort study. J. Pediatr. 186, 87–94.e16 (2017).

    Google Scholar 

  122. van Tilburg, M. A. et al. Parents’ worries about recurrent abdominal pain in children. Gastroenterol. Nurs. 29, 50–55 (2006).

    Google Scholar 

  123. Santucci, N. R., Saps, M. & van Tilburg, M. A. New advances in the treatment of paediatric functional abdominal pain disorders. Lancet Gastroenterol. Hepatol. 5, 316–328 (2020).

    Google Scholar 

  124. Alfaro Cruz, L., Minard, C., Guffey, D., Chumpitazi, B. P. & Shulman, R. J. Does a minority of children with functional gastrointestinal disorders receive formal diet advice? JPEN J. Parenter. Enter. Nutr. https://doi.org/10.1002/jpen.1771 (2020).

    Article  Google Scholar 

  125. Duncanson, K. R., Talley, N. J., Walker, M. M. & Burrows, T. L. Food and functional dyspepsia: a systematic review. J. Hum. Nutr. Diet. 31, 390–407 (2018).

    CAS  Google Scholar 

  126. Duboc, H., Latrache, S., Nebunu, N. & Coffin, B. The role of diet in functional dyspepsia management. Front. Psychiatry 11, 23 (2020).

    Google Scholar 

  127. Barrett, J. S. & Gibson, P. R. Clinical ramifications of malabsorption of fructose and other short-chain carbohydrates. Pract. Gastroenterol. 31, 51–65 (2007).

    Google Scholar 

  128. Halmos, E. P., Power, V. A., Shepherd, S. J., Gibson, P. R. & Muir, J. G. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 146, 67–75.e5 (2014).

    CAS  Google Scholar 

  129. Chumpitazi, B. P. et al. Fructans exacerbate symptoms in a subset of children with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 16, 219–225.e1 (2018).

    CAS  Google Scholar 

  130. Shepherd, S. J., Parker, F. C., Muir, J. G. & Gibson, P. R. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin. Gastroenterol. Hepatol. 6, 765–771 (2008).

    CAS  Google Scholar 

  131. Major, G. et al. Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome. Gastroenterology 152, 124–133.e2 (2017). This study underscores how certain foods may induce symptoms in patients with IBS by causing visceral hypersensitivity that can be activated by distention and, based on other studies, by food-induced inflammation.

    Google Scholar 

  132. Yang, J. et al. Lactose intolerance in irritable bowel syndrome patients with diarrhoea: the roles of anxiety, activation of the innate mucosal immune system and visceral sensitivity. Aliment. Pharmacol. Ther. 39, 302–311 (2014).

    CAS  Google Scholar 

  133. Zhou, S. Y. et al. FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction. J. Clin. Invest. 128, 267–280 (2018).

    Google Scholar 

  134. Halmos, E. P. & Gibson, P. R. Controversies and reality of the FODMAP diet for patients with irritable bowel syndrome. J. Gastroenterol. Hepatol. 34, 1134–1142 (2019).

    Google Scholar 

  135. Wilder-Smith, C. H., Olesen, S. S., Materna, A. & Drewes, A. M. Predictors of response to a low-FODMAP diet in patients with functional gastrointestinal disorders and lactose or fructose intolerance. Aliment. Pharmacol. Ther. 45, 1094–1106 (2017).

    CAS  Google Scholar 

  136. Bellini, M. et al. Low FODMAP diet: evidence, doubts, and hopes. Nutrients 12, 148 (2020).

    Google Scholar 

  137. Lebenthal, E., Rossi, T. M., Nord, S. K. & Branski, D. Recurrent abdominal pain and lactose absorption in children. Pediatrics 67, 828–832 (1981).

    CAS  Google Scholar 

  138. Dearlove, J., Dearlove, B., Pearl, K. & Primavesi, R. Dietary lactose and the child with abdominal pain. Br. Med. J. 286, 1936–1936 (1983).

    CAS  Google Scholar 

  139. Garcia-Etxebarria, K. et al. Increased prevalence of rare sucrase-isomaltase pathogenic variants in irritable bowel syndrome patients. Clin. Gastroenterol. Hepatol. 16, 1673–1676 (2018).

    CAS  Google Scholar 

  140. Gericke, B., Amiri, M., Scott, C. R. & Naim, H. Y. Molecular pathogenicity of novel sucrase-isomaltase mutations found in congenital sucrase-isomaltase deficiency patients. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 817–826 (2017).

    CAS  Google Scholar 

  141. Zheng, T. et al. Reduced efficacy of low FODMAPs diet in patients with IBS-D carrying sucrase-isomaltase (SI) hypomorphic variants. Gut 69, 397–398 (2019).

    Google Scholar 

  142. Fritscher-Ravens, A. et al. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 147, 1012–1020.e4 (2014).

    Google Scholar 

  143. Fritscher-Ravens, A. et al. Many patients with irritable bowel syndrome have atypical food allergies not associated with immunoglobulin E. Gastroenterology 157, 109–118.e5 (2019).

    Google Scholar 

  144. Boyce, J. A. et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored expert panel report. Nutr. Res. 31, 61–75 (2011).

    CAS  Google Scholar 

  145. Azcarate-Peril, M. A. et al. Impact of short-chain galactooligosaccharides on the gut microbiome of lactose-intolerant individuals. Proc. Natl Acad. Sci. USA 114, E367–E375 (2017).

    CAS  Google Scholar 

  146. Huaman, J. W. et al. Effects of prebiotics vs a diet low in FODMAPs in patients with functional gut disorders. Gastroenterology 155, 1004–1007 (2018).

    CAS  Google Scholar 

  147. Medow, M. S. et al. Beta-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am. J. Dis. Child. 144, 1261–1264 (1990).

    CAS  Google Scholar 

  148. Treem, W. R. Clinical aspects and treatment of congenital sucrase-isomaltase deficiency. J. Pediatr. Gastroenterol. Nutr. 55 (Suppl. 2), S7–S13 (2012).

    Google Scholar 

  149. Komericki, P. et al. Oral xylose isomerase decreases breath hydrogen excretion and improves gastrointestinal symptoms in fructose malabsorption - a double-blind, placebo-controlled study. Aliment. Pharmacol. Ther. 36, 980–987 (2012).

    CAS  Google Scholar 

  150. Tuck, C. J., Taylor, K. M., Gibson, P. R., Barrett, J. S. & Muir, J. G. Increasing symptoms in irritable bowel symptoms with ingestion of galacto-oligosaccharides are mitigated by alpha-galactosidase treatment. Am. J. Gastroenterol. 113, 124–134 (2018).

    CAS  Google Scholar 

  151. Huang, R. C., Palmer, L. J. & Forbes, D. A. Prevalence and pattern of childhood abdominal pain in an Australian general practice. J. Paediatr. Child. Health 36, 349–353 (2000).

    CAS  Google Scholar 

  152. Paulo, A. Z., Amancio, O. M., de Morais, M. B. & Tabacow, K. M. Low-dietary fiber intake as a risk factor for recurrent abdominal pain in children. Eur. J. Clin. Nutr. 60, 823–827 (2006).

    CAS  Google Scholar 

  153. Moayyedi, P. et al. The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis. Am. J. Gastroenterol. 109, 1367–1374 (2014).

    CAS  Google Scholar 

  154. Nagarajan, N. et al. The role of fiber supplementation in the treatment of irritable bowel syndrome: a systematic review and meta-analysis. Eur. J. Gastroenterol. Hepatol. 27, 1002–1010 (2015).

    CAS  Google Scholar 

  155. Eswaran, S., Muir, J. & Chey, W. D. Fiber and functional gastrointestinal disorders. Am. J. Gastroenterol. 108, 718–727 (2013).

    CAS  Google Scholar 

  156. Shulman, R. J. et al. Psyllium fiber reduces abdominal pain in children with irritable bowel syndrome in a randomized, double-blind trial. Clin. Gastroenterol. Hepatol. 15, 1915–1920.e4 (2017).

    Google Scholar 

  157. Ford, A. C., Harris, L. A., Lacy, B. E., Quigley, E. M. M. & Moayyedi, P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment. Pharmacol. Ther. 48, 1044–1060 (2018).

    Google Scholar 

  158. Wegh, C. A. M., Benninga, M. A. & Tabbers, M. M. Effectiveness of probiotics in children with functional abdominal pain disorders and functional constipation: a systematic review. J. Clin. Gastroenterol. 52, (Suppl. 1), S10–S26 (2018).

    Google Scholar 

  159. Cheung, W. Y. et al. The economic impact of the transition from branded to generic oncology drugs. Curr. Oncol. 26, 89–93 (2019).

    CAS  Google Scholar 

  160. Romano, C. et al. Lactobacillus reuteri in children with functional abdominal pain (FAP). J. Paediatr. Child. Health 50, E68–E71 (2014).

    Google Scholar 

  161. 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. https://doi.org/10.1016/j.jpeds.2016.04.003 (2016).

    Article  Google Scholar 

  162. Jadresin, O. et al. Lactobacillus reuteri DSM 17938 in the treatment of functional abdominal pain in children - RCT study. J. Pediatr. Gastroenterol. Nutr. 64, 925–929 (2017).

    CAS  Google Scholar 

  163. Maragkoudaki, M. et al. Lactobacillus reuteri DSM 17938 and a placebo both significantly reduced symptoms in children with functional abdominal pain. Acta Paediatr. 106, 1857–1862 (2017).

    CAS  Google Scholar 

  164. Eftekhari, K., Vahedi, Z., Kamali Aghdam, M. & Diaz, D. N. A randomized double-blind placebo-controlled trial of lactobacillus reuteri for chronic functional abdominal pain in children. Iran. J. Pediatr. 25, e2616 (2015).

    Google Scholar 

  165. Francavilla, R. et al. A randomized controlled trial of Lactobacillus GG in children with functional abdominal pain. Pediatrics 126, e1445–e1452 (2010).

    Google Scholar 

  166. Gawronska, A., Dziechciarz, P., Horvath, A. & Szajewska, H. A randomized double-blind placebo-controlled trial of Lactobacillus GG for abdominal pain disorders in children. Aliment. Pharmacol. Ther. 25, 177–184 (2007).

    CAS  Google Scholar 

  167. Guandalini, S. 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. 51, 24–30 (2010).

    Google Scholar 

  168. Lackner, J. M. et al. Durability and decay of treatment benefit of cognitive behavioral therapy for irritable bowel syndrome: 12-month follow-up. Am. J. Gastroenterol. 114, 330–338 (2019).

    Google Scholar 

  169. Lackner, J. M. et al. Improvement in gastrointestinal symptoms after cognitive behavior therapy for refractory irritable bowel syndrome. Gastroenterology 155, 47–57 (2018).

    Google Scholar 

  170. Rutten, J. M. T. M., Korterink, J. J., Venmans, L. M. A. J., Benninga, M. A. & Tabbers, M. M. Nonpharmacologic treatment of functional abdominal pain disorders: a systematic review. Pediatrics 135, 522–535 (2015). A large randomized controlled trial showing the (long-term) efficacy of hypnotherapy by a therapist and by home-based hypnotherapy self-exercises. The home-based hypnotherapy is cheap and may be available in many languages in the near future.

    Google Scholar 

  171. Abbott, R. A. et al. Recurrent abdominal pain in children: summary evidence from 3 systematic reviews of treatment effectiveness. J. Pediatr. Gastroenterol. Nutr. 67, 23–33 (2018).

    Google Scholar 

  172. Levy, R. L. et al. Cognitive-behavioral therapy for children with functional abdominal pain and their parents decreases pain and other symptoms. Am. J. Gastroenterol. 105, 946–956 (2010).

    Google Scholar 

  173. Levy, R. L. et al. Twelve-month follow-up of cognitive behavioral therapy for children with functional abdominal pain. JAMA Pediatr. 167, 178–184 (2013).

    Google Scholar 

  174. Lalouni, M. et al. Clinical and cost effectiveness of online cognitive behavioral therapy in children with functional abdominal pain disorders. Clin. Gastroenterol. Hepatol. 17, 2236–2244.e11 (2019).

    Google Scholar 

  175. Levy, R. L. et al. Brief telephone-delivered cognitive behavioral therapy targeted to parents of children with functional abdominal pain: a randomized controlled trial. Pain 158, 618–628 (2017).

    Google Scholar 

  176. Bonnert, M. et al. Internet-delivered cognitive behavior therapy for adolescents with irritable bowel syndrome: a randomized controlled trial. Am. J. Gastroenterol. 112, 152–162 (2017).

    Google Scholar 

  177. Sampaio, F. et al. Cost-effectiveness of internet-delivered cognitive-behavioural therapy for adolescents with irritable bowel syndrome. BMJ Open 9, e023881 (2019).

    Google Scholar 

  178. Reed-Knight, B., Claar, R. L., Schurman, J. V. & van Tilburg, M. A. Implementing psychological therapies for functional GI disorders in children and adults. Expert. Rev. Gastroenterol. Hepatol. 10, 981–984 (2016).

    CAS  Google Scholar 

  179. Prior, A., Colgan, S. M. & Whorwell, P. J. Changes in rectal sensitivity after hypnotherapy in patients with irritable bowel syndrome. Gut 31, 896–898 (1990).

    CAS  Google Scholar 

  180. Whorwell, P. J., Houghton, L. A., Taylor, E. E. & Maxton, D. G. Physiological effects of emotion: assessment via hypnosis. Lancet 340, 69–72 (1992).

    CAS  Google Scholar 

  181. Palsson, O. S., Turner, M. J., Johnson, D. A., Burnett, C. K. & Whitehead, W. E. Hypnosis treatment for severe irritable bowel syndrome: investigation of mechanism and effects on symptoms. Dig. Dis. Sci. 47, 2605–2614 (2002).

    Google Scholar 

  182. Vlieger, A. M. et al. No change in rectal sensitivity after gut-directed hypnotherapy in children with functional abdominal pain or irritable bowel syndrome. Am. J. Gastroenterol. 105, 213–218 (2010).

    CAS  Google Scholar 

  183. Vlieger, A. M., Rutten, J. M., Govers, A. M., Frankenhuis, C. & Benninga, M. A. Long-term follow-up of gut-directed hypnotherapy vs. standard care in children with functional abdominal pain or irritable bowel syndrome. Am. J. Gastroenterol. 107, 627–631 (2012).

    Google Scholar 

  184. Rutten, J. et al. Home-based hypnotherapy self-exercises vs individual hypnotherapy with a therapist for treatment of pediatric irritable bowel syndrome, functional abdominal pain, or functional abdominal pain syndrome: a randomized clinical trial. JAMA Pediatr. 171, 470–477 (2017).

    Google Scholar 

  185. Korterink, J. J., Ockeloen, L. E., Hilbink, M., Benninga, M. A. & Deckers-Kocken, J. M. Yoga therapy for abdominal pain-related functional gastrointestinal disorders in children: a randomized controlled trial. J. Pediatr. Gastroenterol. Nutr. 63, 481–487 (2016).

    Google Scholar 

  186. Bittar, R. G. et al. Deep brain stimulation for pain relief: a meta-analysis. J. Clin. Neurosci. 12, 515–519 (2005).

    Google Scholar 

  187. Babygirija, R., Sood, M., Kannampalli, P., Sengupta, J. N. & Miranda, A. Percutaneous electrical nerve field stimulation modulates central pain pathways and attenuates post-inflammatory visceral and somatic hyperalgesia in rats. Neuroscience 356, 11–21 (2017).

    CAS  Google Scholar 

  188. Kovacic, K. et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol. Hepatol. 2, 727–737 (2017).

    Google Scholar 

  189. Day, A. S. Use of complementary and alternative therapies and probiotic agents by children attending gastroenterology outpatient clinics. J. Paediatr. Child. Health 38, 343–346 (2002).

    CAS  Google Scholar 

  190. Vlieger, A. M., Blink, M., Tromp, E. & Benninga, M. A. Use of complementary and alternative medicine by pediatric patients with functional and organic gastrointestinal diseases: results from a multicenter survey. Pediatrics 122, e446–e451 (2008).

    Google Scholar 

  191. Korterink, J. J., Rutten, J. M., Venmans, L., Benninga, M. A. & Tabbers, M. M. Pharmacologic treatment in pediatric functional abdominal pain disorders: a systematic review. J. Pediatr. 166, 424–431.e6 (2015).

    CAS  Google Scholar 

  192. Elsenbruch, S. & Enck, P. Placebo effects and their determinants in gastrointestinal disorders. Nat. Rev. Gastroenterol. Hepatol. 12, 472–485 (2015).

    Google Scholar 

  193. Weimer, K. et al. Placebo effects in children: a review. Pediatr. Res. 74, 96–102 (2013).

    Google Scholar 

  194. Czerniak, E., Oberlander, T. F., Weimer, K., Kossowsky, J. & Enck, P. “Placebo by proxy” and “Nocebo by proxy” in children: a review of parents’ role in treatment outcomes. Front. Psychiatry 11, 169 (2020).

    Google Scholar 

  195. Rome Foundation. GI genius interactive clinical decision toolkit. Rome Foundation https://romeonline.org/product/rome-iv-interactive-clinical-decision-toolkit-logicnets (2020).

  196. Kline, R. M., Kline, J. J., Di Palma, J. & Barbero, G. J. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J. Pediatr. 138, 125–128 (2001).

    CAS  Google Scholar 

  197. Saps, M., Miranda, A. in Gastrointestinal Pharmacology Vol. 239 (ed. Greenwood-Van Meerveld, B.) 147–176 (Springer, 2017).

  198. Karabulut, G. S. et al. The incidence of irritable bowel syndrome in children using the Rome III criteria and the effect of trimebutine treatment. J. Neurogastroenterol. Motil. 19, 90–93 (2013).

    Google Scholar 

  199. Pourmoghaddas, Z., Saneian, H., Roohafza, H. & Gholamrezaei, A. Mebeverine for pediatric functional abdominal pain: a randomized, placebo-controlled trial. Biomed. Res. Int. 2014, 191026 (2014).

    Google Scholar 

  200. Narang, M., Shah, D. & Akhtar, H. Efficacy and safety of drotaverine hydrochloride in children with recurrent abdominal pain: a randomized placebo controlled trial. Indian Pediatr. 52, 847–851 (2015).

    Google Scholar 

  201. Scarpellini, E. et al. Rifaximin treatment for small intestinal bacterial overgrowth in children with irritable bowel syndrome. Eur. Rev. Med. Pharmacol. Sci. 17, 1314–1320 (2013).

    CAS  Google Scholar 

  202. Collins, B. S. & Lin, H. C. Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain. J. Pediatr. Gastroenterol. Nutr. 52, 382–386 (2011).

    CAS  Google Scholar 

  203. Bahar, R. J., Collins, B. S., Steinmetz, B. & Ament, M. E. Double-blind placebo-controlled trial of amitriptyline for the treatment of irritable bowel syndrome in adolescents. J. Pediatr. 152, 685–689 (2008).

    CAS  Google Scholar 

  204. Saps, M. et al. Multicenter, randomized, placebo-controlled trial of amitriptyline in children with functional gastrointestinal disorders. Gastroenterology 137, 1261–1269 (2009).

    CAS  Google Scholar 

  205. Campo, J. V. et al. Citalopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders: an exploratory study. J. Am. Acad. Child. Adolesc. Psychiatry 43, 1234–1242 (2004).

    Google Scholar 

  206. Roohafza, H., Pourmoghaddas, Z., Saneian, H. & Gholamrezaei, A. Citalopram for pediatric functional abdominal pain: a randomized, placebo-controlled trial. Neurogastroenterol. Motil. 26, 1642–1650 (2014).

    CAS  Google Scholar 

  207. Federal Drug Administration (FDA). Suicidality in children and adolescents being treated with antidepressant medications. FDA https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications (2018).

  208. Lee, K. J., Kim, J. H. & Cho, S. W. Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome. Aliment. Pharmacol. Ther. 22, 981–988 (2005).

    CAS  Google Scholar 

  209. Houghton, L. A. et al. Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut 56, 1218–1225 (2007).

    CAS  Google Scholar 

  210. Mugie, S. M. et al. Prucalopride is no more effective than placebo for children with functional constipation. Gastroenterology 147, 1285–1295.e1 (2014).

    CAS  Google Scholar 

  211. Benninga, M. et al. Efficacy and safety of lubiprostone in children with functional constipation: a multicenter, randomized, placebo-controlled, double-blind pivotal study. Gastroenterology 154, S559–S560 (2018).

    Google Scholar 

  212. Lisman-van Leeuwen, Y., Spee, L. A. A., Benninga, M. A., Bierma-Zeinstra, S. M. A. & Berger, M. Y. Prognosis of abdominal pain in children in primary care–a prospective cohort study. Ann. Fam. Med. 11, 238–244 (2013).

    Google Scholar 

  213. Saps, M. et al. Recommendations for pharmacological clinical trials in children with irritable bowel syndrome: the Rome foundation pediatric subcommittee on clinical trials. Neurogastroenterol. Motil. 28, 1619–1631 (2016).

    CAS  Google Scholar 

  214. Federal Drug Administration (FDA). Gastroenterology regulatory endpoints and the advancement of therapeutics for alcoholic hepatitis and alcohol associated liver disease and pediatric irritable bowel syndrome and pediatric functional constipation workshop. FDA https://www.fda.gov/drugs/news-events-human-drugs/gastroenterology-regulatory-endpoints-and-advancement-therapeutics-alcoholic-hepatitis-and-alcohol (2020).

  215. Federal Drug Administration (FDA). Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. (US Department of Health and Human Services, 2009).

  216. Riley, A. W. Evidence that school-age children can self-report on their health. Ambul. Pediatr. 4, 371–376 (2004).

    Google Scholar 

  217. Varni, J. W. et al. Gastrointestinal symptoms predictors of health-related quality of life in pediatric patients with functional gastrointestinal disorders. Qual. Life Res. 26, 1015–1025 (2017).

    Google Scholar 

  218. Irwin, D. E. et al. Sampling plan and patient characteristics of the PROMIS pediatrics large-scale survey. Qual. Life Res. 19, 585–594 (2010).

    Google Scholar 

  219. Spiegel, B. M. et al. Development of the NIH patient-reported outcomes measurement information system (PROMIS) gastrointestinal symptom scales. Am. J. Gastroenterol. 109, 1804–1814 (2014).

    Google Scholar 

  220. Varni, J. W. The PedsQL (TM) measurement model for the pediatric quality of life inventory (TM). PedsQL http://www.pedsql.org (2020).

  221. Varni, J. W., Seid, M., Knight, T. S., Uzark, K. & Szer, I. S. The PedsQL 4.0 generic core scales: sensitivity, responsiveness, and impact on clinical decision-making. J. Behav. Med. 25, 175–193 (2002).

    Google Scholar 

  222. Varni, J. W., Seid, M. & Kurtin, P. S. PedsQL 4.0: reliability and validity of the pediatric quality of life inventory version 4.0 generic core scales in healthy and patient populations. Med. Care 39, 800–812 (2001).

    CAS  Google Scholar 

  223. Varni, J. W., Seid, M. & Rode, C. A. The PedsQL: measurement model for the pediatric quality of life inventory. Med. Care 37, 126–139 (1999).

    CAS  Google Scholar 

  224. Varni, J. W., Kay, M. T., Limbers, C. A., Franciosi, J. P. & Pohl, J. F. PedsQL gastrointestinal symptoms module item development: qualitative methods. J. Pediatr. Gastroenterol. Nutr. 54, 664–671 (2012).

    Google Scholar 

  225. Varni, J. W. et al. PedsQL gastrointestinal symptoms module: feasibility, reliability, and validity. J. Pediatr. Gastroenterol. Nutr. 59, 347–355 (2014).

    Google Scholar 

  226. Varni, J. W. et al. Health-related quality of life in pediatric patients with functional and organic gastrointestinal diseases. J. Pediatr. 166, 85–90 (2015).

    Google Scholar 

  227. Varni, J. W. et al. PedsQL gastrointestinal symptoms scales and gastrointestinal worry scales in pediatric patients with functional and organic gastrointestinal diseases in comparison to healthy controls. Qual. Life Res. 24, 363–378 (2015).

    Google Scholar 

  228. van Tilburg, M. A. & Murphy, T. B. Quality of life paradox in gastrointestinal disorders. J. Pediatr. 166, 11–14 (2015).

    Google Scholar 

  229. Walker, L. S. & Greene, J. W. The functional disability inventory: measuring a neglected dimension of child health status. J. Pediatr. Psychol. 16, 39–58 (1991).

    CAS  Google Scholar 

  230. Claar, R. L. & Walker, L. S. Functional assessment of pediatric pain patients: psychometric properties of the functional disability inventory. Pain 121, 77–84 (2006).

    Google Scholar 

  231. Russell, A. C., Stone, A. L. & Walker, L. S. Nausea in children with functional abdominal pain predicts poor health outcomes in young adulthood. Clin. Gastroenterol. Hepatol. 15, 706–711 (2017).

    Google Scholar 

  232. Campo, J. V. et al. Adult outcomes of pediatric recurrent abdominal pain: do they just grow out of it? Pediatrics 108, E1 (2001).

    CAS  Google Scholar 

  233. Shelby, G. D. et al. Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders. Pediatrics 132, 475–482 (2013).

    Google Scholar 

  234. Hoge, E. A., Pollack, M. H., Kaufman, R. E., Zak, P. J. & Simon, N. M. Oxytocin levels in social anxiety disorder. CNS Neurosci. Ther. 14, 165–170 (2008).

    CAS  Google Scholar 

  235. Gieteling, M. J., Bierma-Zeinstra, S. M., Passchier, J. & Berger, M. Y. Prognosis of chronic or recurrent abdominal pain in children. J. Pediatr. Gastroenterol. Nutr. 47, 316–326 (2008).

    Google Scholar 

  236. Horst, S. et al. Predicting persistence of functional abdominal pain from childhood into young adulthood. Clin. Gastroenterol. Hepatol. 12, 2026–2032 (2014).

    Google Scholar 

  237. Lindley, K. J., Glaser, D. & Milla, P. J. Consumerism in healthcare can be detrimental to child health: lessons from children with functional abdominal pain. Arch. Dis. Child. 90, 335–337 (2005).

    CAS  Google Scholar 

  238. Pace, F. et al. Family history of irritable bowel syndrome is the major determinant of persistent abdominal complaints in young adults with a history of pediatric recurrent abdominal pain. World J. Gastroenterol. 12, 3874–3877 (2006).

    Google Scholar 

  239. Dengler-Crish, C. M., Horst, S. N. & Walker, L. S. Somatic complaints in childhood functional abdominal pain are associated with functional gastrointestinal disorders in adolescence and adulthood. J. Pediatr. Gastroenterol. Nutr. 52, 162–165 (2011).

    Google Scholar 

  240. Feinle-Bisset, C. & Azpiroz, F. Dietary and lifestyle factors in functional dyspepsia. Nat. Rev. Gastroenterol. Hepatol. 10, 150–157 (2013).

    CAS  Google Scholar 

  241. Krasaelap, A. & Madani, S. Cyproheptadine: a potentially effective treatment for functional gastrointestinal disorders in children. Pediatr. Ann. 46, e120–e125 (2017).

    Google Scholar 

  242. Rodriguez, L., Diaz, J. & Nurko, S. Safety and efficacy of cyproheptadine for treating dyspeptic symptoms in children. J. Pediatr. 163, 261–267 (2013).

    CAS  Google Scholar 

  243. Li, J. et al. A combination of peppermint oil and caraway oil for the treatment of functional dyspepsia: a systematic review and meta-analysis. Evid. Based Complement. Altern. Med. 2019, 7654947 (2019).

    Google Scholar 

  244. Kim, Y. S., Kim, J.-W., Ha, N.-Y., Kim, J. & Ryu, H. S. Herbal therapies in functional gastrointestinal disorders: a narrative review and clinical implication. Front. Psychiatry 11, 601 (2020).

    Google Scholar 

  245. Browne, P. D., Nagelkerke, S. C. J., van Etten-Jamaludin, F. S., Benninga, M. A. & Tabbers, M. M. Pharmacological treatments for functional nausea and functional dyspepsia in children: a systematic review. Expert. Rev. Clin. Pharmacol. https://doi.org/10.1080/17512433.2018.1540298 (2018).

    Article  Google Scholar 

  246. Masuy, I., Van Oudenhove, L. & Tack, J. Review article: treatment options for functional dyspepsia. Aliment. Pharmacol. Ther. 49, 1134–1172 (2019).

    Google Scholar 

  247. Li, B. U. K. Managing cyclic vomiting syndrome in children: beyond the guidelines. Eur. J. Pediatr. 177, 1435–1442 (2018).

    CAS  Google Scholar 

  248. Beinvogl, B. et al. Multidisciplinary treatment reduces pain and increases function in children with functional gastrointestinal disorders. Clin. Gastroenterol. Hepatol. 17, 994–996 (2019).

    Google Scholar 

  249. Dehghani, S. M., Imanieh, M. H., Oboodi, R. & Haghighat, M. The comparative study of the effectiveness of cimetidine, ranitidine, famotidine, and omeprazole in treatment of children with dyspepsia. ISRN Pediatr. 2011, 219287 (2011).

    Google Scholar 

  250. KIDSCREEN. Health-related quality of life questionnaire for children and adolescents aged from 8 to 18 years. KIDSCREEN https://www.kidscreen.org/english/questionnaires (2020).

  251. KINDL. KINDL: revised questionnaire for CHILDREN and adolescents to record the health-related quality of life. KINDL https://www.kindl.org/ (2020).

  252. GCQ. Generic children’s quality of life measure. CORC https://www.corc.uk.net/outcome-experience-measures/generic-childrens-quality-of-life-measure/ (2020).

  253. HUInc. Health Utilities Inc: health-related quality-of-life. HUInc http://healthutilities.com (2020).

  254. HACHQ. Infant toddler quality of life questionnaire (ITQOL). Inspiring Impact https://www.inspiringimpact.org/resource-library/infant-toddler-quality-of-life-questionnaire-itqol/ (2020).

  255. Brugman, E. et al. TNO-AZL preschool children quality of life questionnaire (TAPQOL). ePROVIDE https://eprovide.mapi-trust.org/instruments/tno-azl-preschool-children-quality-of-life-questionnaire/ (2020).

  256. Fekkes, M. et al. TNO AZL children’s quality of life (TACQOL). ePROVIDE https://eprovide.mapi-trust.org/instruments/tno-azl-children-s-quality-of-life/ (2020).

  257. PROMIS. List of pediatric measures. HealthMeasures https://www.healthmeasures.net/explore-measurement-systems/promis/intro-to-promis/list-of-pediatric-measures/ (2020).

Download references

Acknowledgements

R.J.S. acknowledges the funding R01 NR013497 and R01 NR016786 from the National Institutes of Health, the USDA/ARS under Cooperative Agreement No. 58-3092-0-001, and P30 DK56338, which funds the Texas Medical Center Digestive Disease Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work is a publication of the USDA/ARS Children’s Nutrition Research Center, Department of Paediatrics, Baylor College of Medicine and Texas Children’s Hospital. The contents do not necessarily reflect the views or policies of the USDA nor does the mention of trade names, commercial products or organizations imply endorsement by the US Government.

Author information

Author notes

  1. Nikhil Thapar

    Present address: Queensland Children’s Hospital, Paediatric Gastroenterology, Hepatology and Liver Transplant, Brisbane, Australia

Authors and Affiliations

  1. Neurogastroenterology and Motility Unit, Department of Paediatric Gastroenterology, Great Ormond Street Hospital NHS Foundation Trust, London, UK

    Nikhil Thapar

  2. UCL Great Ormond Street Institute of Child Health, London, UK

    Nikhil Thapar

  3. Emma Children’s Hospital, Amsterdam University Medical Center, Amsterdam, Netherlands

    Marc A. Benninga

  4. Department of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA

    Michael D. Crowell

  5. Division of Pediatric Gastroenterology, Nationwide Children’s Hospital, Columbus, OH, USA

    Carlo Di Lorenzo

  6. University Hospital Tübingen, Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, Tübingen, Germany

    Isabelle Mack & Paul Enck

  7. Boston Children’s Hospital, Harvard medical School, Boston, MA, USA

    Samuel Nurko

  8. Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Miami, Miller School of Medicine, Miami, FL, USA

    Miguel Saps

  9. Children’s Nutrition Research Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Robert J. Shulman

  10. Department of Pediatrics, The Medical University of Warsaw, Warsaw, Poland

    Hania Szajewska

  11. College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, USA

    Miranda A. L. van Tilburg

  12. Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC, USA

    Miranda A. L. van Tilburg

  13. School of Social Work, University of Washington, Seattle, WA, USA

    Miranda A. L. van Tilburg

Authors
  1. Nikhil Thapar
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  2. Marc A. Benninga
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  3. Michael D. Crowell
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  4. Carlo Di Lorenzo
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Contributions

Introduction (P.E. and N.T.); Epidemiology (P.E., I.M. and N.T.); Mechanisms/pathophysiology (S.N., H.S., M.A.L.v.T. and N.T.); Diagnosis, screening and prevention (C.D.L. and M.A.L.v.T.); Management (M.A.B., M.S. and R.J.S.); Quality of life (M.D.C.); Outlook (N.T.); Overview of Primer (P.E. and N.T.).

Corresponding authors

Correspondence to Nikhil Thapar or Paul Enck.

Ethics declarations

Competing interests

N.T. has received grants, membership on advisory boards, speaker fees or travel support from Danone, Nutricia and Takeda. M.A.B. has received grants, membership on advisory boards, speaker fees or travel support from Abbott, Allergan, Coloplast, Danone, Friesland Campina, HIPP, Johnson & Johnson, Norgine, Shire, Sucampo and United Pharmaceuticals. C.D.L. has received grants, membership on advisory boards, speaker fees or travel support from Allergan, Mahana, Mallinckrodt, QOL, Sucampo and Takeda. M.S. has received grants, membership on advisory boards, speaker fees or travel support from Abbott, Allergan, Forest, QOL and Sucampo. H.S. has received grants, membership on advisory boards, speaker fees or travel support from Arla, Biocodex, Biogaia, Ch.Hansen, Danone, Merck, Nestlé and Nutricia. M.A.L.v.T. has received consultancy fees from Mahana. P.E. has received grants, membership on advisory boards, speaker fees or travel support from Alimentary Health, Aptinyx, Arena, Biocodex, CEMET, Danone, Genetic Analysis, Indigo, Merz, MDC, Sanofi, SymbioPharm and 4DPharma. All other authors declare no competing interests.

Additional information

Dedication

We dedicate this manuscript to the memory of Paul E. Hyman, MD, who passed away on 7 August 2020. Paul was a true pioneer and master of the field of functional gastrointestinal disorders and dedicated much of his career to caring for children suffering from such conditions. A great family man, friend, colleague, mentor and inspiration to so many.

Peer review information

Nature Reviews Disease Primers thanks Christopher Eccleston, Anne Lynch-Jordan, Emeran Mayer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Hyperalgesia

An abnormally heightened sensitivity to pain.

Postprandial fullness

Unpleasant sensation thought to emanate from the stomach for a considerable period after eating a meal giving the feeling of the persistence of food.

Aura

Temporary symptoms that typically develop prior to and signal a more serious symptom such as abdominal pain or migraine.

Social learning theory

A theory of learning that proposes that new behaviours can be acquired by observing and imitating others as well as learning through reinforcement of our behaviours by others.

Social communication model of pain

A model that describes pain as a social transaction between the child experiencing and expressing pain and the caregiver assessing and treating the pain.

Hypersensitivity

A heightened sensitivity to algogenic factors via lowering of the threshold of pain-sensing neurons.

Hypervigilance

An enhanced state of sensory sensitivity accompanied by an exaggerated intensity of behaviours such as increased alertness.

Secondary hyperalgesia

Centrally mediated condition characterized by increased pain sensitivity outside of the area of injury or inflammation as a result of continuous nociceptor input from the zone of primary hyperalgesia.

Henoch-Schönlein purpura

The most common form of systemic immune-mediated (specifically by IgA) small-vessel vasculitis in children, with a predilection for the skin, gastrointestinal tract, joints and kidneys.

Gastric emptying

Measure of how effectively stomach contents are moved into the intestine, displayed as t1/2 (time at which 50% of contents have emptied) or as the percentage of contents remaining within the stomach at pre-defined time intervals (1, 2 and 4 hours).

Gastric arrhythmia or dysrhythmia

Abnormal myoelectrical rhythms of the stomach, a normal rhythm is ~3 cycles per minute.

Gastric accommodation

Vagus nerve-mediated reflex associated with a reduction in gastric tone as well as with an increase in gastric volume and gastric compliance, which allows temporary storage of ingested food before controlled release into the intestine.

Tachygastria

Increased (>3 cycles per minute) rate of electrical pacemaker activity in the stomach.

Bradygastria

Decreased (<3 cycles per minute) rate of electrical pacemaker activity in the stomach.

Mixed dysrhythmia

Elements of both bradygastria and tachygastria present within an electrogastrography reading.

Somatization

The manifestation of psychological distress in the form of physical symptoms, for which medical help is often sought.

Catastrophizing

A cognitive distortion that results in the person assuming that things are worse than they are or will have a far worse outcome than is realistic and often characterized by a lack of confidence and control.

Disease threat

An increased perception of the duration, frequency and seriousness of the symptoms.

Avoidance behaviours

Any act or series of actions that enables an individual to anticipate or avoid unpleasant or painful situations, stimuli or events.

Arthralgias

Any discomfort or pain in the joints, although joint pain is not related to an inflammatory condition such as arthritis.

Myalgias

Muscle aches and pain, which can involve ligaments, tendons and fascia, that is, the soft tissues that connect muscles, bones and organs.

FODMAP

Fermentable, Oligosaccharides, Disaccharides, Monosaccharides and Polyols, which are short-chain carbohydrates that are believed to be either slowly absorbed or not digested in the small intestine.

Lactulose breath test

A test used to measure an increase in hydrogen and/or methane excreted in the breath, presumed to arise from the metabolism of ingested lactulose by intestinal bacteria. This test is used as a measure of small intestinal bacterial overgrowth or small bowel transit and to predict a patient’s response to a low FODMAP diet.

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Thapar, N., Benninga, M.A., Crowell, M.D. et al. Paediatric functional abdominal pain disorders. Nat Rev Dis Primers 6, 89 (2020). https://doi.org/10.1038/s41572-020-00222-5

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