Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Infant colic: mechanisms and management

Abstract

Infant colic is a commonly reported phenomenon of excessive crying in infancy with an enigmatic and distressing character. Despite its frequent occurrence, little agreement has been reached on the definition, pathogenesis or the optimal management strategy for infant colic. This Review aims to delineate the definitional entanglement with the Rome IV criteria, which were published in 2016, as the leading, most recent diagnostic criteria. Moreover, neurogenic, gastrointestinal, microbial and psychosocial factors that might contribute to the pathophysiology of infant colic are explored. This Review underlines that a comprehensive medical history and physical examination in the absence of alarm symptoms serve as guidance for the clinician to a positive diagnosis. It also highlights that an important aspect of the management of infant colic is parental education and reassurance. Management strategies, including behavioural, dietary, pharmacological and alternative interventions, are also discussed. Owing to a lack of large, high-quality randomized controlled trials, none of these therapies are strongly recommended. Finally, the behavioural and somatic sequelae of infant colic into childhood are summarized.

Key points

  • Infant colic is a common phenomenon in infancy with an enigmatic and distressing character.

  • Infant colic is most often defined according to the Wessel criteria or according to the Rome criteria.

  • The pathogenesis of infant colic remains unclear and is thought to be multifactorial; however, a growing body of evidence suggests that the gut microbiome contributes to development of the condition.

  • The cornerstones in the management of infant colic are parental reassurance and education.

  • Owing to a lack of large, high-quality randomized controlled trials, none of the behavioural, dietary, pharmacological or alternative interventions are strongly recommended.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Crying amounts and patterns from three North American studies4,6,7 illustrating absence of a secular trend.
Fig. 2: Possible pathophysiological mechanisms contributing to the pathogenesis of infant colic.
Fig. 3: Mechanisms through which bacterial dysbiosis can contribute to excessive crying in infant colic.
Fig. 4: Hypothesized mechanisms possibly leading to bacterial dysbiosis in infants.
Fig. 5: Suggested diagnostic algorithm for infant colic.
Fig. 6: The vicious circle of infant crying and maternal fatigue and adverse events.

Similar content being viewed by others

References

  1. Zeifman, D. M. An ethological analysis of human infant crying: answering Tinbergen’s four questions. Dev. Psychobiol. 39, 265–285 (2001).

    Article  PubMed  CAS  Google Scholar 

  2. deVries, M. W. Temperament and infant mortality among the Masai of East Africa. Am. J. Psychiatry 141, 1189–1194 (1984).

    Article  PubMed  CAS  Google Scholar 

  3. St James-Roberts, I. & Halil, T. Infant crying patterns in the first year: normal community and clinical findings. J. Child Psychol. Psychiatry 32, 951–968 (1991).

    Article  Google Scholar 

  4. Brazelton, T. B. Crying in infancy. Pediatrics 29, 579–588 (1962).

    PubMed  CAS  Google Scholar 

  5. Benninga, M. A. et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 150, 1443–1455.e2 (2016).

    Article  Google Scholar 

  6. Hunziker, U. A. & Barr, R. G. Increased carrying reduces infant crying: a randomized controlled trial. Pediatrics 77, 641–648 (1986).

    PubMed  CAS  Google Scholar 

  7. Kramer, M. S. et al. Pacifier use, early weaning, and cry/fuss behavior: a randomized controlled trial. JAMA 286, 322–326 (2001).

    Article  PubMed  CAS  Google Scholar 

  8. Wolke, D., Bilgin, A. & Samara, M. Systematic review and meta-analysis: fussing and crying durations and prevalence of colic in infants. J. Pediatr. 185, 55–61.e4 (2017).

    Article  PubMed  Google Scholar 

  9. Barr, R. The normal crying curve: what do we really know? Dev. Med. Child Neurol. 32, 356–362 (1990).

    Article  PubMed  CAS  Google Scholar 

  10. Wessel, M. A., Cobb, J. C., Jackson, E. B., Harris, G. S. & Detwiler, A. C. Paroxysmal fussing in infancy, sometimes called colic. Pediatrics 14, 421–435 (1954).

    PubMed  CAS  Google Scholar 

  11. Emde, R. N., Gaensbauer, T. J. & Harmon, R. J. Emotional expression in infancy; a biobehavioral study. Psychol. Issues 10, 1–200 (1976).

    PubMed  CAS  Google Scholar 

  12. Bell, S. M. & Ainsworth, M. D. Infant crying and maternal responsiveness. Child Dev. 43, 1171–1190 (1972).

    Article  PubMed  CAS  Google Scholar 

  13. James-Roberts, I. S. in New Evidence on Unexplained Early Infant Crying: Its Origins, Nature and Management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 5–24 (Johnson & Johnson Pediatric Institute, Skillman, New Jersey, 2001).

  14. Forsyth, B. W. & Canny, P. F. Perceptions of vulnerability 3 1/2 years after problems of feeding and crying behavior in early infancy. Pediatrics 88, 757–763 (1991).

    PubMed  CAS  Google Scholar 

  15. Lehtonen, L. A. in New Evidence on Unexplained Early Infant Crying: Its Origins, Nature and Management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 259–271 (Johnson & Johnson Pediatric Institute, Skillman, New Jersey, 2001).

  16. Reijneveld, S. A., Brugman, E. & Hirasing, R. A. Excessive infant crying: the impact of varying definitions. Pediatrics 108, 893–897 (2001).

    Article  PubMed  CAS  Google Scholar 

  17. Steutel, N. F., Benninga, M. A., Langendam, M. W., de Kruijff, I. & Tabbers, M. M. Reporting outcome measures in trials of infant colic. J. Pediatr. Gastroenterol. Nutr. 59, 341–346 (2014).

    Article  PubMed  Google Scholar 

  18. Hyman, P. E. et al. Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 130, 1519–1526 (2006).

    Article  PubMed  Google Scholar 

  19. Gormally, S. M. & Barr, R. G. Of clinical pies and clinical clues: proposal for a clinical approach to complaints of early crying and colic. Ambulatory Child Health. 2, 137–153 (1997).

    Google Scholar 

  20. Wolke, D. in New Evidence on Unexplained Early Infant Crying: Its Origins, Nature and Management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 187–208 (Johnson & Johnson Pediatric Institute, Skillman, New Jersey, 2001).

  21. Barr, R. in Handbook of Development Psychopathology (eds Sameroff, A. J., Lewis, M. & Miller, S. M.) 327–350 (Kluwer Academic/Plenum Publishers, New York, 2000).

  22. Fujiwara, T., Barr, R. G., Brant, R. & Barr, M. Infant distress at five weeks of age and caregiver frustration. J. Pediatr. 159, 425–430.e2 (2011).

    Article  PubMed  Google Scholar 

  23. Gustafson, G., Wood, R. & Green, J. A. in Crying as a Sign, a Symptom, and a Signal. (eds Barr, R. G., Hopkins, B. & Green, J. A.) 8–22 (Mac Keith Press, London, 2000).

  24. James-Roberts, I. S., Conroy, S. & Wilsher, K. Bases for maternal perceptions of infant crying and colic behaviour. Arch. Dis. Child. 75, 375–384 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Barr, R. G., Rotman, A., Yaremko, J., Leduc, D. & Francoeur, T. E. The crying of infants with colic: a controlled empirical description. Pediatrics 90, 14–21 (1992).

    PubMed  CAS  Google Scholar 

  26. St James-Roberts, I., Hurry, J. & Bowyer, J. Objective confirmation of crying durations in infants referred for excessive crying. Arch. Dis. Child. 68, 82–84 (1993).

    Article  Google Scholar 

  27. Räihä, H., Lehtonen, L. & Korvenranta, H. Family context of infantile colic. Infant Ment. Health J. 16, 206–217 (1995).

    Article  Google Scholar 

  28. Lehtonen, L. & Korvenranta, H. Infantile colic. Seasonal incidence and crying profiles. Arch. Pediatr. Adolesc. Med. 149, 533–536 (1995).

    Article  PubMed  CAS  Google Scholar 

  29. Lucassen, P. L. et al. Systematic review of the occurrence of infantile colic in the community. Arch. Dis. Child. 84, 398–403 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. van Tilburg, M. A. L. et al. Prevalence of functional gastrointestinal disorders in infants and toddlers. J. Pediatr. 166, 684–689 (2015).

    Article  PubMed  Google Scholar 

  31. Chogle, A. et al. A population-based study on the epidemiology of functional gastrointestinal disorders in young children. J. Pediatr. 179, 139–143.e1 (2016).

    Article  PubMed  Google Scholar 

  32. Clifford, T. J., Campbell, M. K., Speechley, K. N. & Gorodzinsky, F. Infant colic: empirical evidence of the absence of an association with source of early infant nutrition. Arch. Pediatr. Adolesc. Med. 156, 1123–1128 (2002).

    Article  PubMed  Google Scholar 

  33. Canivet, C., Hagander, B., Jakobsson, I. & Lanke, J. Infantile colic — less common than previously estimated? Acta Paediatr. 85, 454–458 (1996).

    Article  PubMed  CAS  Google Scholar 

  34. van Sleuwen, B. E. et al. Comparison of behavior modification with and without swaddling as interventions for excessive crying. J. Pediatr. 149, 512–517 (2006).

    Article  PubMed  Google Scholar 

  35. Zwart, P., Vellema-Goud, M. G. A. & Brand, P. L. P. Characteristics of infants admitted to hospital for persistent colic, and comparison with healthy infants. Acta Paediatr. 96, 401–405 (2007).

    Article  PubMed  Google Scholar 

  36. Lester, B. M., Boukydis, C. F. Z., Garcia-Coll, C. T. & Hole, W. T. Colic for developmentalists. Infant Ment. Health J. 11, 321–333 (1990).

    Google Scholar 

  37. Illingworth, R. S. Infantile colic revisited. Arch. Dis. Child. 60, 981–985 (1985).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. James-Roberts, I. S., Conroy, S. & Wilsher, K. Clinical, developmental and social aspects of infant crying and colic. Infant Child Dev. 4, 177–189 (1995).

    Google Scholar 

  39. Barr, R. G., Paterson, J. A., MacMartin, L. M., Lehtonen, L. & Young, S. N. Prolonged and unsoothable crying bouts in infants with and without colic. J. Dev. Behav. Pediatr. 26, 14–23 (2005).

    PubMed  Google Scholar 

  40. Lester, B. M., Zachariah Boukydis, C. F., Garcia-Coll, C. T., Hole, W. & Peucker, M. Infantile colic: acoustic cry characteristics, maternal perception of cry, and temperament. Infant Behav. Dev. 15, 15–26 (1992).

    Article  Google Scholar 

  41. Fuller, B. F., Keefe, M. R., Curtin, M. & Garvin, B. J. Acoustic analysis of cries from “normal” and “irritable” infants. West. J. Nurs. Res. 16, 243–253 (1994).

    Article  PubMed  CAS  Google Scholar 

  42. Zeskind, P. S. & Barr, R. G. Acoustic characteristics of naturally occurring cries of infants with “colic”. Child Dev. 68, 394–403 (1997).

    Article  PubMed  CAS  Google Scholar 

  43. St James-Roberts, I. What is distinct about infants’ “colic” cries? Arch. Dis. Child. 80, 56–61; discussion 62 (1999).

    Article  PubMed Central  Google Scholar 

  44. Carey, W. B. Colic - primary excessive crying as an infant-environment interaction. Pediatr. Clin. North Am. 31, 993–1005 (1984).

    Article  PubMed  CAS  Google Scholar 

  45. Illingworth, R. S. Three-months’ colic. Arch. Dis. Child. 29, 165–174 (1954).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Shamir, R. et al. Infant crying, colic, and gastrointestinal discomfort in early childhood; a review of the evidence and most plausible mechanisms. J. Pediatr. Gastroenterol. Nutr. 57, S1–S45 (2013).

    PubMed  Google Scholar 

  47. James-Roberts, I. S. & Alvarez, M. Emergence of a developmental explanation for prolonged crying in 1-to 4-month-old infants: review of the evidence. J. Pediatr. Gastroenterol. Nutr. 57, S30–S36 (2013).

    Article  Google Scholar 

  48. Barr, R. G., Konner, M., Bakeman, R. & Adamson, L. Crying in!Kung San infants: a test of the cultural specificity hypothesis. Dev. Med. Child Neurol. 33, 601–610 (1991).

    Article  PubMed  CAS  Google Scholar 

  49. Barr, R. G., Paterson, J. A., MacMartin, L. M., Calinoiu, N. & Young, S. N. ‘What is colic?’: a test of the early difficult temperament hypothesis. Pediatr. Res. 47, 23A (2000).

    Google Scholar 

  50. Barr, R. G. The early crying paradox: a modest proposal. Hum. Nat. 1, 355–389 (1990).

    Article  PubMed  CAS  Google Scholar 

  51. Barr, R. G. in New Evidence On Unexplained Early Crying: Its Origins, nature, and management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 87–104 (Johnson & Johnson Pediatric Institute, Skillman, New Jersey, 2001).

  52. St James-Roberts, I., Goodwin, J., Peter, B., Adams, D. & Hunt, S. Individual differences in responsivity to a neurobehavioural examination predict crying patterns of 1-week-old infants at home. Dev. Med. Child Neurol. 45, 400–407 (2003).

    Article  Google Scholar 

  53. Trevarthen, C. & Aitken, K. J. in Regression Periods in Human Infancy (ed. Heimann, M.) 107–184 (Lawrence Erlbaum Associates, Mahwah, New Jersey, 2003).

  54. Barr, R. G., Young, S. N., Wright, J. H., Gravel, R. & Alkawaf, R. Differential calming responses to sucrose taste in crying infants with and without colic. Pediatrics 103, e68 (1999).

    Article  PubMed  CAS  Google Scholar 

  55. Marsh, D. F., Hatch, D. J. & Fitzgerald, M. Opioid systems and the newborn. Br. J. Anaesth. 79, 787–795 (1997).

    Article  PubMed  CAS  Google Scholar 

  56. Leuchter, R. H.-V., Darque, A. & Hüppi, P. S. Brain maturation, early sensory processing, and infant colic. J. Pediatr. Gastroenterol. Nutr. 57, S18–S25 (2013).

    Article  Google Scholar 

  57. de Weerth, C., Fuentes, S., Puylaert, P. & de Vos, W. M. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics 131, e550–e558 (2013).

    Article  PubMed  Google Scholar 

  58. Rhoads, J. M. et al. Altered fecal microflora and increased fecal calprotectin in infants with colic. J. Pediatr. 155, 823–828.e1 (2009).

    Article  PubMed  CAS  Google Scholar 

  59. Roos, S. et al. 454 Pyrosequencing analysis on faecal samples from a randomized DBPC trial of colicky infants treated with Lactobacillus reuteri DSM 17938. PLoS ONE 8, e56710 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Savino, F. et al. Comparison of formula-fed infants with and without colic revealed significant differences in total bacteria, Enterobacteriaceae and faecal ammonia. Acta Paediatr. 106, 573–578 (2017).

    Article  PubMed  CAS  Google Scholar 

  61. Dryl, R. & Szajewska, H. Probiotics for management of infantile colic: a systematic review of randomized controlled trials. Arch. Med. Sci. https://doi.org/10.5114/aoms.2017.66055 (2017).

  62. Clarke, G. et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 18, 666–673 (2013).

    Article  PubMed  CAS  Google Scholar 

  63. Mayer, E. A. et al. Gut/brain axis and the microbiota. J. Clin. Invest. 125, 926–938 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  64. de Weerth, C., Fuentes, S. & de Vos, W. M. Crying in infants: on the possible role of intestinal microbiota in the development of colic. Gut Microbes 4, 416–421 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Eutamène, H. et al. Luminal contents from the gut of colicky infants induce visceral hypersensitivity in mice. Neurogastroenterol. Motil. 29, e12994 (2017).

    Article  CAS  Google Scholar 

  66. Savino, F. et al. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr. 98, 1582–1588 (2009).

    Article  PubMed  CAS  Google Scholar 

  67. Pärtty, A., Kalliomäki, M., Salminen, S. & Isolauri, E. Infantile colic is associated with low-grade systemic inflammation. J. Pediatr. Gastroenterol. Nutr. 64, 691–695 (2017).

    Article  PubMed  Google Scholar 

  68. Savino, F. et al. Antagonistic effect of Lactobacillus strains against gas-producing coliforms isolated from colicky infants. BMC Microbiol. 11, 157 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Nanthakumar, N. N., Fusunyan, R. D., Sanderson, I. & Walker, W. A. Inflammation in the developing human intestine: a possible pathophysiologic contribution to necrotizing enterocolitis. Proc. Natl Acad. Sci. USA 97, 6043–6048 (2000).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. He, Y. et al. The human milk oligosaccharide 2′-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 65, 33–46 (2016).

    Article  PubMed  CAS  Google Scholar 

  72. Pärtty, A. et al. Compositional development of Bifidobacterium and Lactobacillus microbiota is linked with crying and fussing in early infancy. PLoS ONE 7, e32495 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Ewaschuk, J. B. et al. Secreted bioactive factors from Bifidobacterium infantis enhance epithelial cell barrier function. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1025–G1034 (2008).

    Article  PubMed  CAS  Google Scholar 

  74. Chichlowski, M., De Lartigue, G., German, J. B., Raybould, H. E. & Mills, D. A. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function. J. Pediatr. Gastroenterol. Nutr. 55, 321–327 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Liu, Y., Fatheree, N. Y., Mangalat, N. & Rhoads, J. M. Human-derived probiotic Lactobacillus reuteri strains differentially reduce intestinal inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G1087–G1096 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Smits, H. H. et al. Selective probiotic bacteria induce IL-10–producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell–specific intercellular adhesion molecule 3–grabbing nonintegrin. J. Allergy Clin. Immunol. 115, 1260–1267 (2005).

    Article  PubMed  CAS  Google Scholar 

  77. Ali, A. M. Helicobacter pylori and infantile colic. Arch. Pediatr. Adolesc. Med. 166, 648–650 (2012).

    Article  PubMed  Google Scholar 

  78. Ali, A. S. A. & Borei, M. B. M. Helicobacter pylori and Egyptian infantile colic. J. Egypt. Soc. Parasitol. 43, 327–332 (2013).

    Article  PubMed  Google Scholar 

  79. Carreira, H., Bastos, A., Peleteiro, B. & Lunet, N. Breast-feeding and Helicobacter pylori infection: systematic review and meta-analysis. Public Health Nutr. 18, 500–520 (2015).

    Article  PubMed  Google Scholar 

  80. Rautava, S., Collado, M. C., Salminen, S. & Isolauri, E. Probiotics modulate host-microbe interaction in the placenta and fetal gut: a randomized, double-blind, placebo-controlled trial. Neonatology 102, 178–184 (2012).

    Article  PubMed  Google Scholar 

  81. Rautava, S., Luoto, R., Salminen, S. & Isolauri, E. Microbial contact during pregnancy, intestinal colonization and human disease. Nat. Rev. Gastroenterol. Hepatol. 9, 565–576 (2012).

    Article  PubMed  CAS  Google Scholar 

  82. Zijlmans, M. A. C., Korpela, K., Riksen-Walraven, J. M., de Vos, W. M. & de Weerth, C. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology 53, 233–245 (2015).

    Article  PubMed  Google Scholar 

  83. Penders, J. et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118, 511–521 (2006).

    Article  PubMed  Google Scholar 

  84. Rutayisire, E., Huang, K., Liu, Y. & Tao, F. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants’ life: a systematic review. BMC Gastroenterol. 16, 86 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Aloisio, I. et al. Influence of intrapartum antibiotic prophylaxis against group B Streptococcus on the early newborn gut composition and evaluation of the anti-Streptococcus activity of Bifidobacterium strains. Appl. Microbiol. Biotechnol. 98, 6051–6060 (2014).

    PubMed  CAS  Google Scholar 

  86. Clifford, T. J., Campbell, M. K., Speechley, K. N. & Gorodzinsky, F. Sequelae of infant colic: evidence of transient infant distress and absence of lasting effects on maternal mental health. Arch. Pediatr. Adolesc. Med. 156, 1183–1188 (2002).

    Article  PubMed  Google Scholar 

  87. Corvaglia, L. et al. Influence of intrapartum antibiotic prophylaxis for group B Streptococcus on Gut microbiota in the first month of life. J. Pediatr. Gastroenterol. Nutr. 62, 304–308 (2016).

    Article  PubMed  CAS  Google Scholar 

  88. Mentula, S., Tuure, T., Koskenala, R., Korpela, R. & Könönen, E. Microbial composition and fecal fermentation end products from colicky infants – a probiotic supplementation pilot. Microb. Ecol. Health Dis. 20, 37–47 (2008).

    Article  CAS  Google Scholar 

  89. Savino, F. et al. Bacterial counts of intestinal Lactobacillus species in infants with colic. Pediatr. Allergy Immunol. 16, 72–75 (2005).

    Article  PubMed  CAS  Google Scholar 

  90. Savino, F. et al. Intestinal microflora in breastfed colicky and non-colicky infants. Acta Paediatr. 93, 825–829 (2004).

    Article  PubMed  CAS  Google Scholar 

  91. Adlerberth, I. Establishment of the gut microbiota in Western infants. Acta Pædiatr. 98, 229–238 (2009).

    Article  PubMed  CAS  Google Scholar 

  92. Pärtty, A., Lehtonen, L., Kalliomäki, M., Salminen, S. & Isolauri, E. Probiotic Lactobacillus rhamnosus GG therapy and microbiological programming in infantile colic: a randomized, controlled trial. Pediatr. Res. 78, 470–475 (2015).

    Article  PubMed  CAS  Google Scholar 

  93. Savino, F. et al. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics 126, e526–e533 (2010).

    Article  PubMed  Google Scholar 

  94. Camilleri, M., Park, S.-Y., Scarpato, E. & Staiano, A. Exploring hypotheses and rationale for causes of infantile colic. Neurogastroenterol. Motil. 29, e12943 (2017).

    Article  Google Scholar 

  95. Hofmann, A., F. in Enterohepatic Circulation of Bile Acids. Comprehensive Physiology 567–596 (John Wiley & Sons, USA, 2011).

    Google Scholar 

  96. Pavlidis, P. et al. Systematic review: bile acids and intestinal inflammation- luminal aggressors or regulators of mucosal defence? Aliment. Pharmacol. Ther. 42, 802–817 (2015).

    Article  PubMed  CAS  Google Scholar 

  97. Lester, R. Diarrhea and malabsorption in the newborn. N. Engl. J. Med. 297, 505–507 (1977).

    Article  PubMed  CAS  Google Scholar 

  98. Lester, R. et al. Fetal bile salt metabolism. The intestinal absorption of bile salt. J. Clin. Invest. 59, 1009–1016 (1977).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Bampton, P. A., Dinning, P. G., Kennedy, M. L., Lubowski, D. Z. & Cook, I. J. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G443–G449 (2002).

    Article  PubMed  CAS  Google Scholar 

  100. Spiller, R. C., Brown, M. L. & Phillips, S. F. Decreased fluid tolerance, accelerated transit, and abnormal motility of the human colon induced by oleic acid. Gastroenterology 91, 100–107 (1986).

    Article  PubMed  CAS  Google Scholar 

  101. Dawson, P. A., Lan, T. & Rao, A. Bile acid transporters. J. Lipid Res. 50, 2340–2357 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Ridlon, J. M., Kang, D.-J. & Hylemon, P. B. Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241–259 (2005).

    Article  PubMed  CAS  Google Scholar 

  103. Wood, J. D. Enteric nervous system: reflexes, pattern generators and motility. Curr. Opin. Gastroenterol. 24, 149–158 (2008).

    Article  PubMed  Google Scholar 

  104. Dinan, T. G. & Cryan, J. F. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology 37, 1369–1378 (2012).

    Article  PubMed  CAS  Google Scholar 

  105. Kenny, S. E. et al. Delayed maturation of the interstitial cells of Cajal: a new diagnosis for transient neonatal pseudoobstruction. Report of two cases. J. Pediatr. Surg. 33, 94–98 (1998).

    Article  PubMed  CAS  Google Scholar 

  106. Riezzo, G. et al. Gastric electrical activity and gastric emptying in term and preterm newborns. Neurogastroenterol. Motil. 12, 223–229 (2000).

    Article  PubMed  CAS  Google Scholar 

  107. Halpern, R. & Coelho, R. Excessive crying in infants. J. Pediatr. (Rio. J.). 92, S40–S45 (2016).

    Article  Google Scholar 

  108. Indrio, F. et al. The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J. Pediatr. 152, 801–806 (2008).

    Article  PubMed  Google Scholar 

  109. Indrio, F. et al. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. J. Physiol. Pharmacol. 60 (Suppl. 6), 27–31 (2009).

    PubMed  Google Scholar 

  110. Jakobsson, I. & Lindberg, T. Cow’s milk as a cause of infantile colic in breast-fed infants. Lancet 2, 437–439 (1978).

    Article  PubMed  CAS  Google Scholar 

  111. Lucassen, P. L., Assendelft, W. J., Gubbels, J. W., van Eijk, J. T. & Douwes, A. C. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics 106, 1349–1354 (2000).

    Article  PubMed  CAS  Google Scholar 

  112. Iacovou, M., Ralston, R. A., Muir, J., Walker, K. Z. & Truby, H. Dietary management of infantile colic: a systematic review. Matern. Child Health J. 16, 1319–1331 (2012).

    Article  PubMed  Google Scholar 

  113. Jones, P. M. & Gupta, S. K. in Pediatric Gastrointestinal and Liver Disease (eds Wyllie, R., Hyams, J. S. & Kay, M.) 115–123 (Elsevier Health Sciences, 2015).

  114. Moore, D. J., Robb, T. A. & Davidson, G. P. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J. Pediatr. 113, 979–984 (1988).

    Article  PubMed  CAS  Google Scholar 

  115. Thomas, D. W., McGilligan, K., Eisenberg, L. D., Lieberman, H. M. & Rissman, E. M. Infantile colic and type of milk feeding. Am. J. Dis. Child. 141, 451–453 (1987).

    PubMed  CAS  Google Scholar 

  116. Ståhlberg, M. R. Infantile colic: occurrence and risk factors. Eur. J. Pediatr. 143, 108–111 (1984).

    Article  PubMed  Google Scholar 

  117. Barr, R. G., Kramer, M. S., Pless, I. B., Boisjoly, C. & Leduc, D. Feeding and temperament as determinants of early infant crying/fussing behavior. Pediatrics 84, 514–521 (1989).

    PubMed  CAS  Google Scholar 

  118. Lucas, A. & St James-Roberts, I. Crying, fussing and colic behaviour in breast- and bottle-fed infants. Early Hum. Dev. 53, 9–18 (1998).

    Article  PubMed  CAS  Google Scholar 

  119. Evans, K., Evans, R. & Simmer, K. Effect of the method of breast feeding on breast engorgement, mastitis and infantile colic. Acta Paediatr. 84, 849–852 (1995).

    Article  PubMed  CAS  Google Scholar 

  120. Søndergaard, C. et al. Psychosocial distress during pregnancy and the risk of infantile colic: a follow-up study. Acta Paediatr. 92, 811–816 (2003).

    Article  PubMed  Google Scholar 

  121. van den Berg, M. P. et al. Paternal depressive symptoms during pregnancy are related to excessive infant crying. Pediatrics 124, e96–e103 (2009).

    Article  PubMed  Google Scholar 

  122. Petzoldt, J. et al. Maternal anxiety disorders predict excessive infant crying: a prospective longitudinal study. Arch. Dis. Child. 99, 800–806 (2014).

    Article  PubMed  Google Scholar 

  123. Canivet, C. A., Ostergren, P.-O., Rosén, A.-S., Jakobsson, I. L. & Hagander, B. M. Infantile colic and the role of trait anxiety during pregnancy in relation to psychosocial and socioeconomic factors. Scand. J. Public Health 33, 26–34 (2005).

    Article  PubMed  Google Scholar 

  124. Bolten, M. I., Fink, N. S. & Stadler, C. Maternal self-efficacy reduces the impact of prenatal stress on infant’s crying behavior. J. Pediatr. 161, 104–109 (2012).

    Article  PubMed  Google Scholar 

  125. Freedman, S. B., Al-Harthy, N. & Thull-Freedman, J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics 123, 841–848 (2009).

    Article  PubMed  Google Scholar 

  126. Reijneveld, S. A., Brugman, E. & Hirasing, R. A. Infantile colic: maternal smoking as potential risk factor. Arch. Dis. Child. 83, 302–303 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Søndergaard, C., Henriksen, T. B., Obel, C. & Wisborg, K. Smoking during pregnancy and infantile colic. Pediatrics 108, 342–346 (2001).

    Article  PubMed  Google Scholar 

  128. Canivet, C. A., Ostergren, P.-O., Jakobsson, I. L., Dejin-Karlsson, E. & Hagander, B. M. Infantile colic, maternal smoking and infant feeding at 5 weeks of age. Scand. J. Public Health 36, 284–291 (2008).

    Article  PubMed  Google Scholar 

  129. Milidou, I., Henriksen, T. B., Jensen, M. S., Olsen, J. & Sondergaard, C. Nicotine replacement therapy during pregnancy and infantile colic in the offspring. Pediatrics 129, e652–e658 (2012).

    Article  PubMed  Google Scholar 

  130. Milidou, I., Søndergaard, C., Jensen, M. S., Olsen, J. & Henriksen, T. B. Gestational age, small for gestational age, and infantile colic. Paediatr. Perinat. Epidemiol. 28, 138–145 (2014).

    Article  PubMed  Google Scholar 

  131. Douglas, P. & Hill, P. Managing infants who cry excessively in the first few months of life. BMJ 343, d7772 (2011).

    Article  PubMed  Google Scholar 

  132. Gormally, S. in New Evidence on Unexplained Early Crying: Its Origins, Nature, and Management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 133–148 (Skillman, New Jersey: Johnson & Johnson Pediatric Round Table Series, 2001).

  133. Vandenplas, Y. Algorithms for common gastrointestinal disorders. J. Pediatr. Gastroenterol. Nutr. 63 (Suppl. 1), S38–S40 (2016).

    PubMed  Google Scholar 

  134. Vandenplas, Y. et al. Functional gastro-intestinal disorder algorithms focus on early recognition, parental reassurance and nutritional strategies. Acta Paediatr. 105, 244–252 (2016).

    Article  PubMed  Google Scholar 

  135. Nurko, S. et al. in Rome IV Pediatric Functional Gastrointestinal Disorders (eds Di Lorenzo, C. et al.) 171–190 (The Rome Foundation, Raleigh, North Carolina, 2016).

  136. Roberts, D. M., Ostapchuk, M. & O’Brien, J. G. Infantile colic. Am. Fam. Physician 70, 735–740 (2004).

    PubMed  Google Scholar 

  137. Barr, R. G., Kramer, M. S., Boisjoly, C., McVey-White, L. & Pless, I. B. Parental diary of infant cry and fuss behaviour. Arch. Dis. Child. 63, 380–387 (1988).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Bellaïche, M., Levy, M. & Jung, C. Treatments for infant colic. J. Pediatr. Gastroenterol. Nutr. 57, S27–S30 (2013).

    Article  Google Scholar 

  139. Murray, L. & Cooper, P. in New Evidence on Unexplained Early Infant Crying: Its Origins, Nature and Management. (eds Barr, R. G, St James-Roberts, I. & Keefe, M. R.) 149–164 (Johnson & Johnson Pediatric Institute, Skillman, New Jersey, 2001).

  140. Christian, C. W. & Block, R. Abusive head trauma in infants and children. Pediatrics 123, 1409–1411 (2009).

    Article  PubMed  Google Scholar 

  141. Kurth, E., Kennedy, H. P., Spichiger, E., Hösli, I. & Stutz, E. Z. Crying babies, tired mothers: what do we know? A systematic review. Midwifery 27, 187–194 (2011).

    Article  PubMed  Google Scholar 

  142. Barr, R. G. et al. Effectiveness of educational materials designed to change knowledge and behaviors regarding crying and shaken-baby syndrome in mothers of newborns: a randomized, controlled trial. Pediatrics 123, 972–980 (2009).

    Article  PubMed  Google Scholar 

  143. Barr, R. G. et al. Do educational materials change knowledge and behaviour about crying and shaken baby syndrome? A randomized controlled trial. Can. Med. Assoc. J. 180, 727–733 (2009).

    Article  Google Scholar 

  144. Keefe, M. R. et al. Effectiveness of an intervention for colic. Clin. Pediatr. (Phila). 45, 123–133 (2006).

    Article  PubMed  Google Scholar 

  145. Taubman, B. Clinical trial of the treatment of colic by modification of parent-infant interaction. Pediatrics 74, 998–1003 (1984).

    PubMed  CAS  Google Scholar 

  146. Taubman, B. Parental counseling compared with elimination of cow’s milk or soy milk protein for the treatment of infant colic syndrome: a randomized trial. Pediatrics 81, 756–761 (1988).

    PubMed  CAS  Google Scholar 

  147. Salisbury, A. L. et al. A randomized control trial of integrated care for families managing infant colic. Infant Ment. Health J. 33, 110–122 (2012).

    Google Scholar 

  148. Juffer, F., Bakermans-Kranenburg, M. J. & van Ljzendoorn, M. H. Promoting Positive Parenting: an Attachment-Based Intervention. (Lawrence Erlbaum Associates, 2008).

  149. White-Traut, R. & Nelson, M. N. Maternally administered tactile, auditory, visual, and vestibular stimulation: relationship to later interactions between mothers and premature infants. Res. Nurs. Health 11, 31–39 (1988).

    Article  PubMed  CAS  Google Scholar 

  150. Brackbill, Y. Cumulative effects of continuous stimulation on arousal level in infants. Child Dev. 42, 17–26 (1971).

    Article  PubMed  CAS  Google Scholar 

  151. Brackbill, Y. Continuous stimulation reduces arousal level: stability of the effect over time. Child Dev. 44, 43–46 (1973).

    Article  PubMed  CAS  Google Scholar 

  152. van der Wal, M. F., van den Boom, D. C., Pauw-Plomp, H. & de Jonge, G. A. Mothers’ reports of infant crying and soothing in a multicultural population. Arch. Dis. Child. 79, 312–317 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Bennett, C., Underdown, A. & Barlow, J. Massage for promoting mental and physical health in typically developing infants under the age of six months. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858 (2013).

  154. Parkin, P. C., Schwartz, C. J. & Manuel, B. A. Randomized controlled trial of three interventions in the management of persistent crying of infancy. Pediatrics 92, 197–201 (1993).

    PubMed  CAS  Google Scholar 

  155. Barr, R. G. et al. Carrying as colic therapy: a randomized controlled trial. Pediatrics 87, 623–630 (1991).

    PubMed  CAS  Google Scholar 

  156. Heine, R. G. Cow’s-milk allergy and lactose malabsorption in infants with colic. J. Pediatr. Gastroenterol. Nutr. 57, S25–S27 (2013).

    Article  Google Scholar 

  157. Jakobsson, I. & Lindberg, T. Cow’s milk proteins cause infantile colic in breast-fed infants: a double-blind crossover study. Pediatrics 71, 268–271 (1983).

    PubMed  CAS  Google Scholar 

  158. Evans, R. W., Fergusson, D. M., Allardyce, R. A. & Taylor, B. Maternal diet and infantile colic in breast-fed infants. Lancet 1, 1340–1342 (1981).

    Article  PubMed  CAS  Google Scholar 

  159. Hill, D. J. et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics 116, e709–e715 (2005).

    Article  PubMed  Google Scholar 

  160. Lothe, L. & Lindberg, T. Cow’s milk whey protein elicits symptoms of infantile colic in colicky formula-fed infants: a double-blind crossover study. Pediatrics 83, 262–266 (1989).

    PubMed  CAS  Google Scholar 

  161. Jakobsson, I., Lothe, L., Ley, D. & Borschel, M. W. Effectiveness of casein hydrolysate feedings in infants with colic. Acta Paediatr. 89, 18–21 (2000).

    Article  PubMed  CAS  Google Scholar 

  162. Arikan, D., Alp, H., Gözüm, S., Orbak, Z. & Cifçi, E. K. Effectiveness of massage, sucrose solution, herbal tea or hydrolysed formula in the treatment of infantile colic. J. Clin. Nurs. 17, 1754–1761 (2008).

    Article  PubMed  Google Scholar 

  163. Forsyth, B. W. Colic and the effect of changing formulas: a double-blind, multiple-crossover study. J. Pediatr. 115, 521–526 (1989).

    Article  PubMed  CAS  Google Scholar 

  164. Vandenplas, Y. et al. Randomised controlled trial demonstrates that fermented infant formula with short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides reduces the incidence of infantile colic. Acta Paediatr. 106, 1150–1158 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Hall, B., Chesters, J. & Robinson, A. Infantile colic: a systematic review of medical and conventional therapies. J. Paediatr. Child Health 48, 128–137 (2012).

    Article  PubMed  Google Scholar 

  166. Lucassen, P. L. et al. Effectiveness of treatments for infantile colic: systematic review. BMJ 316, 1563–1569 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Lothe, L., Lindberg, T. & Jakobsson, I. Cow’s milk formula as a cause of infantile colic: a double-blind study. Pediatrics 70, 7–10 (1982).

    PubMed  CAS  Google Scholar 

  168. Campbell, J. P. Dietary treatment of infant colic: a double-blind study. J. R. Coll. Gen. Pract. 39, 11–14 (1989).

    PubMed  PubMed Central  CAS  Google Scholar 

  169. Oggero, R., Garbo, G., Savino, F. & Mostert, M. Dietary modifications versus dicyclomine hydrochloride in the treatment of severe infantile colics. Acta Paediatr. 83, 222–225 (1994).

    Article  PubMed  CAS  Google Scholar 

  170. Berseth, C. L., Johnston, W. H., Stolz, S. I., Harris, C. L. & Mitmesser, S. H. Clinical response to 2 commonly used switch formulas occurs within 1 day. Clin. Pediatr. (Phila). 48, 58–65 (2009).

    Article  PubMed  Google Scholar 

  171. Iacono, G. et al. Severe infantile colic and food intolerance: a long-term prospective study. J. Pediatr. Gastroenterol. Nutr. 12, 332–335 (1991).

    Article  PubMed  CAS  Google Scholar 

  172. Agostoni, C. et al. Soy protein infant formulae and follow-on formulae. J. Pediatr. Gastroenterol. Nutr. 42, 352–361 (2006).

    Article  PubMed  CAS  Google Scholar 

  173. Hill, C. et al. Expert consensus document: the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat. Rev. Gastroenterol. Hepatol. 11, 506–514 (2014).

    Article  PubMed  Google Scholar 

  174. Harb, T., Matsuyama, M., David, M. & Hill, R. J. Infant colic — what works. J. Pediatr. Gastroenterol. Nutr. 62, 668–686 (2016).

    Article  PubMed  Google Scholar 

  175. Chau, K. et al. Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938. J. Pediatr. 166, 74–78 (2015).

    Article  PubMed  CAS  Google Scholar 

  176. Mi, G.-L. et al. Effectiveness of Lactobacillus reuteri in infantile colic and colicky induced maternal depression: a prospective single blind randomized trial. Antonie Van Leeuwenhoek 107, 1547–1553 (2015).

    Article  PubMed  Google Scholar 

  177. Sung, V. et al. Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial. BMJ 348, g2107 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Szajewska, H., Gyrczuk, E. & Horvath, A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J. Pediatr. 162, 257–262 (2013).

    Article  PubMed  Google Scholar 

  179. Sung, V. et al. Lactobacillus reuteri to treat infant colic: a meta-analysis. Pediatrics 141, e20171811 (2018).

    Article  PubMed  Google Scholar 

  180. Rautava, S., Kainonen, E., Salminen, S. & Isolauri, E. Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant. J. Allergy Clin. Immunol. 130, 1355–1360 (2012).

    Article  PubMed  CAS  Google Scholar 

  181. Kianifar, H. et al. Synbiotic in the management of infantile colic: a randomised controlled trial. J. Paediatr. Child Health 50, 801–805 (2014).

    Article  PubMed  Google Scholar 

  182. Indrio, F. et al. Prophylactic use of a probiotic in the prevention of colic, regurgitation, and functional constipation: a randomized clinical trial. JAMA Pediatr. 168, 228–233 (2014).

    Article  PubMed  Google Scholar 

  183. Ganguli, K. et al. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune-mediated inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G132–G141 (2013).

    Article  PubMed  CAS  Google Scholar 

  184. Liu, Y., Fatheree, N. Y., Mangalat, N. & Rhoads, J. M. Lactobacillus reuteri strains reduce incidence and severity of experimental necrotizing enterocolitis via modulation of TLR4 and NF- B signaling in the intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G608–G617 (2012).

    Article  PubMed  CAS  Google Scholar 

  185. Livingston, M., Loach, D., Wilson, M., Tannock, G. W. & Baird, M. Gut commensal Lactobacillus reuteri 100–123 stimulates an immunoregulatory response. Immunol. Cell Biol. 88, 99–102 (2010).

    Article  PubMed  Google Scholar 

  186. Rodes, L. et al. Effect of probiotics Lactobacillus and Bifidobacterium on gut-derived lipopolysaccharides and inflammatory cytokines: an in vitro study using a human colonic microbiota model. J. Microbiol. Biotechnol. 23, 518–526 (2013).

    Article  PubMed  CAS  Google Scholar 

  187. Penna, F. J., Péret, L. A., Vieira, L. Q. & Nicoli, J. R. Probiotics and mucosal barrier in children. Curr. Opin. Clin. Nutr. Metab. Care 11, 640–4 (2008).

  188. Mattar, A. F., Drongowski, R. A., Coran, A. G. & Harmon, C. M. Effect of probiotics on enterocyte bacterial translocation in vitro. Pediatr. Surg. Int. 17, 265–268 (2001).

    Article  PubMed  CAS  Google Scholar 

  189. Sherman, M. P. New concepts of microbial translocation in the neonatal intestine: mechanisms and prevention. Clin. Perinatol. 27, 565–579 (2010).

    Article  Google Scholar 

  190. Kim, H. K. et al. Probiotic supplementation influences faecal short chain fatty acids in infants at high risk for eczema. Benef. Microbes 6, 783–90 (2015).

  191. Kamiya, T. et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut 55, 191–196 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Rousseaux, C. et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37 (2007).

    Article  PubMed  CAS  Google Scholar 

  193. Candela, M. et al. Interaction of probiotic Lactobacillus and Bifidobacterium strains with human intestinal epithelial cells: adhesion properties, competition against enteropathogens and modulation of IL-8 production. Int. J. Food Microbiol. 125, 286–292 (2008).

    Article  PubMed  CAS  Google Scholar 

  194. Collado, M. C., Meriluoto, J. & Salminen, S. Role of commercial probiotic strains against human pathogen adhesion to intestinal mucus. Lett. Appl. Microbiol. 45, 454–460 (2007).

    Article  PubMed  CAS  Google Scholar 

  195. Indrio, F. et al. Prebiotics improve gastric motility and gastric electrical activity in preterm newborns. J. Pediatr. Gastroenterol. Nutr. 49, 258–261 (2009).

    Article  PubMed  Google Scholar 

  196. Indrio, F. et al. Lactobacillus reuteri accelerates gastric emptying and improves regurgitation in infants. Eur. J. Clin. Invest. 41, 417–422 (2011).

    Article  PubMed  Google Scholar 

  197. Cleusix, V., Lacroix, C., Vollenweider, S., Duboux, M. & Le Blay, G. Inhibitory activity spectrum of reuterin produced by Lactobacillus reuteri against intestinal bacteria. BMC Microbiol. 7, 101 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Spinler, J. K. et al. Human-derived probiotic Lactobacillus reuteri demonstrate antimicrobial activities targeting diverse enteric bacterial pathogens. Anaerobe 14, 166–171 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Simone, M. et al. The probiotic Bifidobacterium breve B632 inhibited the growth of Enterobacteriaceae within colicky infant microbiota cultures. Biomed. Res. Int. 2014, 301053 (2014).

    PubMed  PubMed Central  Google Scholar 

  200. Biagioli, E., Tarasco, V., Lingua, C., Moja, L. & Savino, F. Pain-relieving agents for infantile colic. Cochrane Database Syst. Rev. 9, CD009999 (2016).

    PubMed  Google Scholar 

  201. Anheyer, D. et al. Herbal medicines for gastrointestinal disorders in children and adolescents: a systematic review. Pediatrics 139, e20170062 (2017).

    Article  PubMed  Google Scholar 

  202. Reinthal, M. et al. Effects of minimal acupuncture in children with infantile colic – a prospective, quasi-randomised single blind controlled trial. Acupunct. Med. 26, 171–182 (2008).

    Article  PubMed  Google Scholar 

  203. Landgren, K. & Hallström, I. Effect of minimal acupuncture for infantile colic: a multicentre, three-armed, single-blind, randomised controlled trial (ACU-COL). Acupunct. Med. 35, 171–179 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Dobson, D. et al. Manipulative therapies for infantile colic. Cochrane Database Syst. Rev. 12, CD004796 (2012).

    PubMed  Google Scholar 

  205. Bennedbaek, O. et al. [Infants with colic. A heterogenous group possible to cure? Treatment by pediatric consultation followed by a study of the effect of zone therapy on incurable colic]. Ugeskr. Laeger 163, 3773–3778 (2001).

    PubMed  CAS  Google Scholar 

  206. Vik, T. et al. Infantile colic, prolonged crying and maternal postnatal depression. Acta Paediatr. 98, 1344–1348 (2009).

    Article  PubMed  Google Scholar 

  207. Radesky, J. S. et al. Inconsolable infant crying and maternal postpartum depressive symptoms. Pediatrics 131, e1857–e1864 (2013).

    Article  PubMed  Google Scholar 

  208. Howell, E. A., Mora, P. & Leventhal, H. Correlates of early postpartum depressive symptoms. Matern. Child Health J. 10, 149–157 (2006).

    Article  PubMed  Google Scholar 

  209. Akman, I. et al. Mothers’ postpartum psychological adjustment and infantile colic. Arch. Dis. Child. 91, 417–419 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Howard, C. R., Lanphear, N., Lanphear, B. P., Eberly, S. & Lawrence, R. A. Parental responses to infant crying and colic: the effect on breastfeeding duration. Breastfeed. Med. 1, 146–155 (2006).

    Article  PubMed  Google Scholar 

  211. Reijneveld, S. A., van der Wal, M. F., Brugman, E., Sing, R. A. H. & Verloove-Vanhorick, S. P. Infant crying and abuse. Lancet 364, 1340–1342 (2004).

    Article  PubMed  Google Scholar 

  212. Levitzky, S. & Cooper, R. Infant colic syndrome —maternal fantasies of aggression and infanticide. Clin. Pediatr. (Phila.) 39, 395–400 (2000).

    Article  CAS  Google Scholar 

  213. Barr, R. G., Trent, R. B. & Cross, J. Age-related incidence curve of hospitalized shaken baby syndrome cases: convergent evidence for crying as a trigger to shaking. Child Abuse Negl. 30, 7–16 (2006).

    Article  PubMed  Google Scholar 

  214. Canivet, C., Jakobsson, I. & Hagander, B. Infantile colic. Follow-up at four years of age: still more “emotional”. Acta Paediatr. 89, 13–17 (2000).

    Article  PubMed  CAS  Google Scholar 

  215. Rautava, P., Lehtonen, L., Helenius, H. & Sillanpää, M. Infantile colic: child and family three years later. Pediatrics 96, 43–47 (1995).

    PubMed  CAS  Google Scholar 

  216. Smarius, L. J. C. A. et al. Excessive infant crying doubles the risk of mood and behavioral problems at age 5: evidence for mediation by maternal characteristics. Eur. Child Adolesc. Psychiatry 26, 293–302 (2017).

    Article  PubMed  Google Scholar 

  217. Savino, F. et al. A prospective 10-year study on children who had severe infantile colic. Acta Paediatr. Suppl. 94, 129–132 (2005).

    Article  PubMed  Google Scholar 

  218. Rao, M. R., Brenner, R. A., Schisterman, E. F., Vik, T. & Mills, J. L. Long term cognitive development in children with prolonged crying. Arch. Dis. Child. 89, 989–992 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Wolke, D., Rizzo, P. & Woods, S. Persistent infant crying and hyperactivity problems in middle childhood. Pediatrics 109, 1054–1060 (2002).

    Article  PubMed  Google Scholar 

  220. Hemmi, M. H., Wolke, D. & Schneider, S. Associations between problems with crying, sleeping and/or feeding in infancy and long-term behavioural outcomes in childhood: a meta-analysis. Arch. Dis. Child. 96, 622–629 (2011).

    Article  PubMed  Google Scholar 

  221. Partty, A., Kalliomaki, M., Salminen, S. & Isolauri, E. Infant distress and development of functional gastrointestinal disorders in childhood. JAMA Pediatr. 167, 977 (2013).

    Article  PubMed  Google Scholar 

  222. Romanello, S. et al. Association between childhood migraine and history of infantile colic. JAMA 309, 1607 (2013).

    Article  PubMed  CAS  Google Scholar 

  223. Gelfand, A. A., Goadsby, P. J. & Allen, I. E. The relationship between migraine and infant colic: a systematic review and meta-analysis. Cephalalgia 35, 63–72 (2015).

    Article  PubMed  Google Scholar 

  224. Sillanpää, M. & Saarinen, M. Infantile colic associated with childhood migraine: a prospective cohort study. Cephalalgia 35, 1246–1251 (2015).

    Article  PubMed  Google Scholar 

  225. Gelfand, A. A. Infant colic — a baby’s migraine? Cephalalgia 35, 1243–1245 (2015).

    Article  PubMed  Google Scholar 

  226. Kalliomäki, M., Laippala, P., Korvenranta, H., Kero, P. & Isolauri, E. Extent of fussing and colic type crying preceding atopic disease. Arch. Dis. Child. 84, 349–350 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Castro-Rodríguez, J. A. et al. Relation between infantile colic and asthma/atopy: a prospective study in an unselected population. Pediatrics 108, 878–882 (2001).

    Article  PubMed  Google Scholar 

  228. Miller, J. J., McVeagh, P., Fleet, G. H., Petocz, P. & Brand, J. C. Breath hydrogen excretion in infants with colic. Arch. Dis. Child. 64, 725–729 (1989).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Hyams, J. S., Geertsma, M. A., Etienne, N. L. & Treem, W. R. Colonic hydrogen production in infants with colic. J. Pediatr. 115, 592–594 (1989).

    Article  PubMed  CAS  Google Scholar 

  230. Barr, R. G., Hanley, J., Patterson, D. K. & Wooldridge, J. Breath hydrogen excretion in normal newborn infants in response to usual feeding patterns: evidence for “functional lactase insufficiency” beyond the first month of life. J. Pediatr. 104, 527–533 (1984).

    Article  PubMed  CAS  Google Scholar 

  231. Douwes, A. C., Oosterkamp, R. F., Fernandes, J., Los, T. & Jongbloed, A. A. Sugar malabsorption in healthy neonates estimated by breath hydrogen. Arch. Dis. Child. 55, 512–515 (1980).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  232. Kanabar, D., Randhawa, M. & Clayton, P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J. Hum. Nutr. Diet. 14, 359–363 (2001).

    Article  PubMed  CAS  Google Scholar 

  233. Miller, J. J., McVeagh, P., Fleet, G. H., Petocz, P. & Brand, J. C. Effect of yeast lactase enzyme on colic in infants fed human milk. J. Pediatr. 117, 261–263 (1990).

    Article  PubMed  CAS  Google Scholar 

  234. Ståhlberg, M. R. & Savilahti, E. Infantile colic and feeding. Arch. Dis. Child. 61, 1232–1233 (1986).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Vandenplas, Y. et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American society for pediatric gastroenterology, hepatology, and nutrition (naspghan) and the European society for pediatric gastroenterology, hepatology, and nutrition. J. Pediatr. Gastroenterol. Nutr. 49, 498–547 (2009).

    Article  PubMed  Google Scholar 

  236. Berkowitz, D. Naveh, Y. & Berant, M. “Infantile colic” as the sole manifestation of gastroesophageal reflux. J. Pediatr. Gastroenterol. Nutr. 24, 231–233 (1997).

    Article  PubMed  CAS  Google Scholar 

  237. Heine, R. G., Jaquiery, A., Lubitz, L., Cameron, D. J. & Catto-Smith, A. G. Role of gastro-oesophageal reflux in infant irritability. Arch. Dis. Child. 73, 121–125 (1995).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Jordan, B., Heine, R. G., Meehan, M., Catto-Smith, A. G. & Lubitz, L. Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial. J. Paediatr. Child Health 42, 49–58 (2006).

    Article  PubMed  Google Scholar 

  239. Moore, D. J. et al. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J. Pediatr. 143, 219–223 (2003).

    Article  PubMed  CAS  Google Scholar 

  240. Heine, R. G., Jordan, B., Lubitz, L., Meehan, M. & Catto-Smith, A. G. Clinical predictors of pathological gastro-oesophageal reflux in infants with persistent distress. J. Paediatr. Child Health 42, 134–139 (2006).

    Article  PubMed  Google Scholar 

  241. Sutphen, J. L. Is it colic or is it gastroesophageal reflux? J. Pediatr. Gastroenterol. Nutr. 33, 110–111 (2001).

    Article  PubMed  CAS  Google Scholar 

  242. Putnam, P. E. GERD and crying: cause and effect or unhappy coexistence? J. Pediatr. 140, 3–4 (2002).

    Article  PubMed  Google Scholar 

  243. Savino, F. et al. Ghrelin and motilin concentration in colicky infants. Acta Paediatr. 95, 738–741 (2006).

    Article  PubMed  Google Scholar 

  244. Miller, A. R. & Barr, R. G. Infantile colic. Is it a gut issue? Pediatr. Clin. North Am. 38, 1407–1423 (1991).

    Article  PubMed  CAS  Google Scholar 

  245. Kurtoglu, S., Uzüm, K., Hallac, I. K. & Coskum, A. 5-Hydroxy-3-indole acetic acid levels in infantile colic: is serotoninergic tonus responsible for this problem? Acta Paediatr. 86, 764–765 (1997).

    Article  PubMed  CAS  Google Scholar 

  246. Stevens, B., Yamada, J. & Ohlsson, A. Sucrose for analgesia in newborn infants undergoing painful procedures. Cochrane Database Syst. Rev. 20, CD001069 (2010).

    Google Scholar 

  247. Markestad, T. Use of sucrose as a treatment for infant colic. Arch. Dis. Child. 76, 356–357; discussion 357–358 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Leung, A. K. C. & Lemay, J. F. Infantile colic: a review. J. R. Soc. Promot. Health 124, 162–166 (2004).

    Article  PubMed  Google Scholar 

  249. Sethi, K. S. & Sethi, J. K. Simethicone in the management of infant colic. Practitioner 232, 508 (1988).

    PubMed  CAS  Google Scholar 

  250. Danielsson, B. & Hwang, C. P. Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr. Scand. 74, 446–450 (1985).

    Article  PubMed  CAS  Google Scholar 

  251. Metcalf, T. J., Irons, T. G., Sher, L. D. & Young, P. C. Simethicone in the treatment of infant colic: a randomized, placebo-controlled, multicenter trial. Pediatrics 94, 29–34 (1994).

    PubMed  CAS  Google Scholar 

  252. Savino, F., Cresi, F., Castagno, E., Silvestro, L. & Oggero, R. A randomized double-blind placebo-controlled trial of a standardized extract of Matricariae recutita, Foeniculum vulgare and Melissa officinalis (ColiMil) in the treatment of breastfed colicky infants. Phytother. Res. 19, 335–340 (2005).

    Article  PubMed  Google Scholar 

  253. Alexandrovich, I., Rakovitskaya, O., Kolmo, E., Sidorova, T. & Shushunov, S. The effect of fennel (Foeniculum Vulgare) seed oil emulsion in infantile colic: a randomized, placebo-controlled study. Altern. Ther. Health Med. 9, 58–61 (2003).

    PubMed  Google Scholar 

  254. Weizman, Z., Alkrinawi, S., Goldfarb, D. & Bitran, C. Efficacy of herbal tea preparation in infantile colic. J. Pediatr. 122, 650–652 (1993).

    Article  PubMed  CAS  Google Scholar 

  255. Newmaster, S. G., Grguric, M., Shanmughanandhan, D., Ramalingam, S. & Ragupathy, S. DNA barcoding detects contamination and substitution in North American herbal products. BMC Med. 11, 222 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  256. Rodriguez-Gonzalez, M. et al. Toxicity of remedies for infantile colic. Arch. Dis. Child. 99, 1147–1148 (2014).

    Article  PubMed  Google Scholar 

  257. Cui, K. M. et al. Electro-acupuncture relieves chronic visceral hyperalgesia in rats. Neurosci. Lett. 376, 20–23 (2005).

    Article  PubMed  CAS  Google Scholar 

  258. Liao, J. M. et al. Electroacupuncture at Hoku elicits dual effect on autonomic nervous system in anesthetized rats. Neurosci. Res. 42, 15–20 (2002).

    Article  PubMed  Google Scholar 

  259. Skjeie, H., Skonnord, T., Fetveit, A. & Brekke, M. Acupuncture for infantile colic: a blinding-validated, randomized controlled multicentre trial in general practice. Scand. J. Prim. Health Care 31, 190–196 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  260. Adams, D. et al. The safety of pediatric acupuncture: a systematic review. Pediatrics 128, e1575–e1587 (2011).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

J.Z., P.D.B., M.L.H., C.d.W. and M.A.B. researched data for this article and drafted the initial manuscript. All authors contributed equally to substantial discussions of content and reviewing and/or editing the manuscript before submission.

Corresponding author

Correspondence to Judith Zeevenhooven.

Ethics declarations

Competing interests

M.A.B. was a member of the Pediatric Working Committee of the Rome Foundation that developed the Rome IV criteria for infants and toddlers discussed in this Review. M.A.B. is a scientific consultant for Shire, Sucampo, AstraZeneca, Norgine, Zeria, Coloplast, Danone, Friesland Campina, Sensus and Novalac. P.D.B. is a scientific consultant for CR2O and participated as a speaker for Winclove Probiotics. J.Z., M.P.L. and C.d.W. declare no competing interests.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeevenhooven, J., Browne, P.D., L’Hoir, M.P. et al. Infant colic: mechanisms and management. Nat Rev Gastroenterol Hepatol 15, 479–496 (2018). https://doi.org/10.1038/s41575-018-0008-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41575-018-0008-7

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing