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Infant colic: Focusing on management of transient lactose intolerance

Introduction

Infantile colic is referred to a behavior repertoire of early childhood, often linked with irritability and crying.1Critch J. Infantile colic: Is there a role for dietary interventions? Paediatrics & Child Health. 2011;16(1):47-49.    During the crying episodes, infant is generally inconsolable, which can be severely distressing for the parents.2Roberts DM, Ostapchuk M, O’Brien JG. Infantile colic. Am Fam Physician. 2004 Aug 15;70(4):735-40.    Out of inherent parental concern, excessive crying has become a frequent reason for seeking medical consultation in the first months of life.3Marcon, Ana Carolina C., Vieira, Mario Cesar, & Morais, Mauro Batista de. (2014). Pediatrician›s knowledge on the management of the infant who cries excessively in the first months of life. Revista Paulista de Pediatria, 32(2), 187-192.    True colic in a well-fed and otherwise healthy infant was first defined in 1954 by “rule of three”:

  1. Crying with limb flexure > 3 hours per day (often in the evening)
  2. Lasting > 3 days per week
  3. Duration > 3 weeks (starting in the first weeks of life and ceasing between 3-6 months of age).2Roberts DM, Ostapchuk M, O’Brien JG. Infantile colic. Am Fam Physician. 2004 Aug 15;70(4):735-40.    4Waddell LJ. Management infantile colic: an update. The journal of family health care. 2013;23(3):17-22.   

A whole slew of studies have shown the prevalence of colic or crying/fussing problems in the range of 2% and 73% in infants younger than 12 months of age.5Vandenplas Y, Abkari A, Bellaiche M, et al. Prevalence and Health Outcomes of Functional Gastrointestinal Symptoms in Infants From Birth to 12 Months of Age. Journal of Pediatric Gastroenterology and Nutrition. 2015;61(5):531-537.    Similarly, a systematic review of 15 community-based surveys carried out to determine the occurrence of infantile colic in the first 3 months of life indicated a wide variation in the size of the population affected- ranging from 3% to 28% in prospective studies and from 8% to 40% in retrospective studies.5Vandenplas Y, Abkari A, Bellaiche M, et al. Prevalence and Health Outcomes of Functional Gastrointestinal Symptoms in Infants From Birth to 12 Months of Age. Journal of Pediatric Gastroenterology and Nutrition. 2015;61(5):531-537.

Infantile colic and problems

Infantile colic is generally not perceived to be a serious problem, yet is associated with adverse outcomes, which include:

Even though the term “colic” implies an underlying abdominal etiology, direct evidence for this localization is limited.8Gelfand AA. Infant Colic. Seminars in pediatric neurology. 2016;23(1):79-82. doi:10.1016/j.spen.2015.08.003.    Poor correlation has been observed between the condition and feeding method, gender, socioeconomic status, or family history of food allergy or atopy.4Waddell LJ. Management infantile colic: an update. The journal of family health care. 2013;23(3):17-22.    Ruling out the cause of infant colic therefore remains a critical part of the clinician’s evaluation.8Gelfand AA. Infant Colic. Seminars in pediatric neurology. 2016;23(1):79-82. doi:10.1016/j.spen.2015.08.003.

Causes of infantile colic

The etiology of infantile colic is not completely understood; however, it is undoubtedly multifactorial in origin (Box 1).4Waddell LJ. Management infantile colic: an update. The journal of family health care. 2013;23(3):17-22.    Various investigators have posited the role of nutrition in infantile colic.1Critch J. Infantile colic: Is there a role for dietary interventions? Paediatrics & Child Health. 2011;16(1):47-49.    In fact, infant colic has also been attributed to transient lactose intolerance.7Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet. 2001 Oct;14(5):359-63.    Cow’s milk given as a formula or used by the lactating mother has been found to result in excessive and unexplained crying by healthy infants, commonly in the evenings.9Stahlberg MR, Savilahti E. Infantile colic and feeding. Archives of Disease in Childhood. 1986;61(12):1232-1233.    In a review by Kanabar D et al, colic afflicts about 10% to 30% infants between 3 and 13 weeks old, whether breast- or formula-fed.7Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet. 2001 Oct;14(5):359-63.    This can be corroborated by a study conducted by Ståhlberg and colleagues on 10 children with infantile colic fed with breast milk and cow’s milk formula. It was found that colic was prevalent on 89% of the days on cow’s milk feeding and on 71% of the days on breast milk feeding. Healthy infants may thus have lactase deficiency of physiologic nature.9Stahlberg MR, Savilahti E. Infantile colic and feeding. Archives of Disease in Childhood. 1986;61(12):1232-1233.

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Infant colic: The problem of transient lactose intolerance and excessive gas production

Lactose is a disaccharide sugar and is abundant in mammalian milk. It is naturally metabolized by the enzyme lactase in the mucosal brush border of the intestine into absorbable sugars, namely glucose and galactose.10Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ : British Medical Journal. 2007;334(7608):1331-1332.    –11Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.    Intestinal lactase activity is known to be at peak during the perinatal period in most of the infants. However, by 2–12 years of age, individuals can be grouped under “lactase non-persistence” group- those with poor lactase activity (hypolactasia) and “lactase-persistence” group- those with preserved neonatal lactase activity.-11Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.    Reduced expression or impaired activity of lactase leads to compromised digestion of lactose, resulting in its malabsorption, which is occasionally asymptomatic.12Misselwitz B, Pohl D, Fruhauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    12Misselwitz B, Pohl D, Fruhauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    It is important to note here that lactose malabsorption does not necessarily cause lactose intolerance.10 In fact, only about one-third to half of lactose maldigesters are also intolerants.13Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.    Presence of symptoms indicates toward diagnosis of lactose intolerance, which largely depend on the rate and quantity of lactose reaching the colon and the type of colonic flora.10Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ : British Medical Journal. 2007;334(7608):1331-1332.    11Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.    When lactose is left unabsorbed, it undergoes digestion through a salvage pathway by gut bacteria. The lactose is cleaved into short-chain fatty acids and gas, mainly hydrogen (H2), carbon dioxide (CO2), and methane (CH4). The gas distends the intestines and likely explains the clinical syndrome that manifests with abdominal cramps, bloating, and flatulence.10Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ : British Medical Journal. 2007;334(7608):1331-1332.    12Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    Moreover, non-digested lactose creates an osmotic load that draws fluid and electrolytes into the intestinal lumen, resulting in loose stools or osmotic diarrhoea (Figure 1).14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.    In addition, fluid load imposed by the osmotic action of unabsorbed lactose in the small intestine acts as a hyper-peristaltic stimulus.15Infante D, Segarra O, Luyer BL. Dietary treatment of colic caused by excess gas in infants: Biochemical evidence. World Journal of Gastroenterology : WJG. 2011;17(16):2104-2108.

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Infant colic due to lactose intolerance- Breath hydrogen response to milk containing lactose in colicky and noncolicky infants

Colicky infants with lactose intolerance tend to produce H2 in their breath (in the fasting state) in response to lactosecontaining feedings, which is more than that produced by noncolicky infants. This has been substantiated by a study, conducted by Moore et al16Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr. 1988 Dec;113(6):979-84.    stating relationship between breath H2 and lactose-containing feedings (such as human milk or commercial formula) in 122 colicky and noncolicky healthy newborn infants. Nearly 83 infants (68%) developed colic (mild, moderate, or severe) by the age of 2.6 ± 1.8 weeks. Breath H2 values at both 6 weeks and 3 months were remarkably greater in colicky infants (40.6 ± 41.4 ppm and 27.7 ± 38.1 ppm, respectively) than noncolicky infants (14.8 ± 32.9 ppm and 8.5 ± 18.2 ppm, respectively). Additionally, more number of colicky infants had positive breath H2 tests in comparison to noncolicky infants at 6 weeks (78% vs. 36%) and 3 months (89% vs. 45%) (Figure 2). Failure to produce H2 throughout the breath H2 test was more common in noncolicky infants at both 6 weeks and 3 months. These findings suggest that colicky infants may manifest increased lactose malabsorption, indicative of differences in colonic bacterial fermentation conditions.16Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr. 1988 Dec;113(6):979-84.

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Transient or developmental lactase deficiency: Studies have postulated that transient lactase deficiency (TLD) could explain the symptoms of infantile colic in a significant number of cases. This type of lactase deficiency is commonly seen in infants born prematurely.17Silanikove N, Leitner G, Merin U. The Interrelationships between Lactose Intolerance and the Modern Dairy Industry: Global Perspectives in Evolutional and Historical Backgrounds. Nutrients. 2015;7(9):7312-7331.    The immature gastrointestinal tract, until at least 34 weeks’ gestation, is deficient of lactase and other disaccharidases. In neonates and young infants, up to 20% of the dietary lactose is estimated to reach the colon, where its bacterial break down decreases the fecal pH (5.0–5.5 is normal). This environment confers a beneficial effect by promoting growth of certain organisms (Bifidobacterium and Lactobacillus species) in lieu of potential pathogens (Proteus species, Escherichia coli, and Klebsiella species).14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.    The infants suffer from this problem only for a short time after they are born (about 3-4 months) as there is natural increase in the production of lactase enzyme with maturity, which eventually make them grow out of lactose intolerance symptoms (and its colic).18Data on file. Walter Bushnell.

Secondary lactase deficiency: This form of lactase deficiency is generally secondary to infection, diseases, or other problems that may incur small intestinal injury (Figure 3).17Silanikove N, Leitner G, Merin U. The Interrelationships between Lactose Intolerance and the Modern Dairy Industry: Global Perspectives in Evolutional and Historical Backgrounds. Nutrients. 2015;7(9):7312-7331.    Etiologies include celiac disease, gastroenteritis, Crohn’s disease, and acute infection (such as rotavirus) (Box 2). These conditions deplete the lactase-containing epithelial cells from the tips of the villi.13Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.    14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.     18Data on file. Walter Bushnell.    The epithelial cells that replace these areas are immature and lack lactase, leading to secondary lactase deficiency and lactose malabsorption. Moreover, young malnourished infants are highly susceptible to small intestinal atrophy that also results in deficiency of lactase.14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.    The abdominal symptoms are similar in presentation as the primary lactose malabsorption.13Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.

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Lactase deficiency secondary to diarrhea

Young children suffering from acute diarrhoea, typically infectious in origin, may temporarily have diminished levels of lactase. This means that the lactose may remain undigested, which inturn may worsen or prolong the diarrheal illness.19MacGillivray S1, Fahey T, McGuire W. Lactose avoidance for young children with acute diarrhoea. Cochrane Database Syst Rev. 2013 Oct 31;(10):CD005433. doi: 10.1002/14651858.CD005433.pub2.    A combination of infectious disease and mucosal injury in malnourished infants has been posited to further limit the capacity of lactase enzyme production. As a consequence, there is abnormal proliferation of bacteria in the gut, thereby predisposing to impaired immunity (Figure 4).20Nyeko R, Kalyesubula I, Mworozi E, Bachou H. Lactose intolerance among severely malnourished children with diarrhoea admitted to the nutrition unit, Mulago hospital, Uganda. BMC Pediatrics. 2010;10:31.    In a study including 332 infants, lactose intolerance was found to have a positive correlation with malnutrition. Around 77% of them were detected with reduced capacity to tolerate lactose. About 75 of 77 lactose-tolerant patients recovered within 3 weeks of administration of a milk formula. On the other hand, 111 of 195 with mild intolerance and 13 of 60 with severe lactose intolerance gradually recovered while receiving the milk formula.2121. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G, Cornado-Cornet MC. Carbohydrate intolerance in infants with diarrhea. J Pediatr. 1971 Nov;79(5):760-7.

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Congenital lactase deficiency: The congenital hypolactasia is a lifelong disorder; it manifests with infantile diarrhea from the first exposure to breast milk due to poorest lactase activity. It is a single autosomal recessive disorder and is extremely rare.13Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.    The premature stop codons induce an early truncation of the protein or missense mutations in the coding region of lactase-phlorizin hydrolase (LPH). As a result, levels of LPH are extremely low, yet the biopsy specimens of small intestine demonstrate normal shape of the microvilli. Typical symptoms include liquid and acidic diarrhea, meteorism, and severe malnutrition. Removal of lactose from the diet has been considered the primary treatment strategy. Since there is a risk of life-threatening dehydration and electrolyte loss in the newborns, early therapeutic intervention is warranted.14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.    22Diekmann L, Pfeiffer K, Naim HY. Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. BMC Gastroenterology. 2015;15:36.

Management of lactose intolerance

Treatment is individualized depending upon the type of hypolactasia identified. In primary lactase deficiency, the development of symptoms is correlated with the amount of lactose that needs to be ingested before the available lactase is saturated. In secondary lactase deficiency, treatment is etiology-based.10Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ : British Medical Journal. 2007;334(7608):1331-1332.    In cases with lactase non-persistence, therapy is considered only if intolerance symptoms are present. Elimination of milk and dairy products from the diet is common therapeutic strategy. However, this approach may impose serious nutritional imbalance, chiefly ascribed to lower intake of substances such as calcium, phosphorus, and vitamins, that may even be conducive to reduced bone mineral density. To overcome these limits, several studies have been carried out to find alternative approaches, such as exogenous β-galactosidase, yogurt and probiotics (for their bacterial lactase activity), pharmacological and nonpharmacological therapies. These interventions act by increasing the contact time between enzyme and substrate, thereby delaying the gastrointestinal transit time and chronic lactose ingestion, in turn enhancing colonic adaptation.23Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World Journal of Gastroenterology : WJG. 2006;12(2):187-191.    The current treatment options for management of infantile colic (along with clinical remarks) are listed in Table 1.24Kanabar D. Current treatment options in the management of infantile colic. 2008;19(7):24–8.    25Biagioli E, Tarasco V, Lingua C, Moja L, Savino F. Pain-relieving agents for infantile colic. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD009999.    26Anabrees J, Indrio F, Paes B, AlFaleh K. Probiotics for infantile colic: a systematic review. BMC Pediatrics. 2013;13:186.    27Kopel HM. Hydroxyzine as a pre-operative sedative: a double blind study with apprehensive children. Anesthesia Progress. 1971;18(6):127-133.

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Evidence on lactase in infantile colic

Lactase enzyme replacement is another option, which implies that symptoms could be relieved by externally introducing lactase in the infant feed.14Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.    This can be validated by a double-blind placebo-controlled crossover study7 that enrolled 53 infants with colic. They were either treated with placebo or pre-incubated lactase feed. It was observed that total crying time and breath hydrogen levels were significantly lower in the active group (about 45% lower) than in the placebo group.7Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet. 2001 Oct;14(5):359-63.    In yet another study,28 the investigators randomized the infants to receive either lactase or placebo drops to their formula feeds for 1 week, followed by 2 days “wash out”. In the second week, the addition was changed to make the subjects their own control. The formulas were refrigerated for 24 hours prior to ingestion. The parents were asked to maintain a diary of their crying time. The authors noted significant improvement in symptoms; the lactasetreated formula decreased crying time by 1.14 hours/day.27Trial 1 – A Trial of Lactase in the Management of Infant Colic. Available at: http:// colief-cy.com/trial1/. Accessed on: 31-05-17.   Infants can be administered lactase till 4 to 6 months of age, subsequent to which they start producing sufficient amount of lactase. Treatment recommendations are listed in Box 3.18

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Conclusion

Infantile colic is known to affect around 30% of infants on breast feed. It is a severely distressing condition for parents and one of the common reasons for seeking medical advice. Studies in infants have shown that majority of them develop colic due to lactose intolerance. Transient lactase deficiency is a common problem; wherein lactase levels in the intestine may not be enough to digest lactose in milk, which can be due to several causes, such as maturing GI tracts, overfeeding, damaged villi, or congenital. Some infants start producing sufficient lactase by 5 to 6 months. Therefore, in order to reduce the incidence of colic, lactase can be given along with feeds to effectively digest the lactose in milk. Administration of external lactase enzyme is well tolerated and is categorized under food supplements. Studies have demonstrated that lactase when given with feeds has reduced crying time by 45%. Lactase supplementation may be continued till 4 to 6 months during infancy, subsequent to which the babies may start producing sufficient amount of lactase. It is recommended to perform a trial of lactase for a week period in parents having difficulty in coping up.

References

  1. Critch J. Infantile colic: Is there a role for dietary interventions? Paediatrics & Child Health. 2011;16(1):47-49.
  2. Roberts DM, Ostapchuk M, O’Brien JG. Infantile colic. Am Fam Physician. 2004 Aug 15;70(4):735-40.
  3. Marcon, Ana Carolina C., Vieira, Mário César, & Morais, Mauro Batista de. (2014). Pediatrician›s knowledge on the management of the infant who cries excessively in the first months of life. Revista Paulista de Pediatria, 32(2), 187-192.
  4. Waddell LJ. Management infantile colic: an update. The journal of family health care. 2013;23(3):17-22.
  5. Vandenplas Y, Abkari A, Bellaiche M, et al. Prevalence and Health Outcomes of Functional Gastrointestinal Symptoms in Infants From Birth to 12 Months of Age. Journal of Pediatric Gastroenterology and Nutrition. 2015;61(5):531-537.
  6. Lucassen PL, Assendelft WJ, van Eijk JT, et al. Systematic review of the occurrence of infantile colic in the community. Arch Dis Child. 2001 May;84(5):398-403.
  7. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet. 2001 Oct;14(5):359-63.
  8. Gelfand AA. Infant Colic. Seminars in pediatric neurology. 2016;23(1):79-82. doi:10.1016/j.spen.2015.08.003.
  9. Ståhlberg MR, Savilahti E. Infantile colic and feeding. Archives of Disease in Childhood. 1986;61(12):1232-1233.
  10. Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ : British Medical Journal. 2007;334(7608):1331-1332.
  11. Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.
  12. Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.
  13. Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.
  14. Heyman MB; Committee on Nutrition. Lactose intolerance in infants, children, and adolescents. Pediatrics. 2006 Sep;118(3):1279-86.
  15. Infante D, Segarra O, Luyer BL. Dietary treatment of colic caused by excess gas in infants: Biochemical evidence. World Journal of Gastroenterology : WJG. 2011;17(16):2104-2108.
  16. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr. 1988 Dec;113(6):979-84.
  17. Silanikove N, Leitner G, Merin U. The Interrelationships between Lactose Intolerance and the Modern Dairy Industry: Global Perspectives in Evolutional and Historical Backgrounds. Nutrients. 2015;7(9):7312-7331.
  18. Data on file. Walter Bushnell.
  19. MacGillivray S1, Fahey T, McGuire W. Lactose avoidance for young children with acute diarrhoea. Cochrane Database Syst Rev. 2013 Oct 31;(10):CD005433. doi: 10.1002/14651858.CD005433.pub2.
  20. Nyeko R, Kalyesubula I, Mworozi E, Bachou H. Lactose intolerance among severely malnourished children with diarrhoea admitted to the nutrition unit, Mulago hospital, Uganda. BMC Pediatrics. 2010;10:31.
  21. 21. Lifshitz F, Coello-Ramirez P, Gutierrez-Topete G, Cornado-Cornet MC. Carbohydrate intolerance in infants with diarrhea. J Pediatr. 1971 Nov;79(5):760-7.
  22. Diekmann L, Pfeiffer K, Naim HY. Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene. BMC Gastroenterology. 2015;15:36.
  23. Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World Journal of Gastroenterology : WJG. 2006;12(2):187-191.
  24. Kanabar D. Current treatment options in the management of infantile colic. 2008;19(7):24–8.
  25. Biagioli E, Tarasco V, Lingua C, Moja L, Savino F. Pain-relieving agents for infantile colic. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD009999.
  26. Anabrees J, Indrio F, Paes B, AlFaleh K. Probiotics for infantile colic: a systematic review. BMC Pediatrics. 2013;13:186.
  27. Kopel HM. Hydroxyzine as a pre-operative sedative: a double blind study with apprehensive children. Anesthesia Progress. 1971;18(6):127-133.
  28. Trial 1 – A Trial of Lactase in the Management of Infant Colic. Available at: http:// colief-cy.com/trial1/. Accessed on: 31-05-17.
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