Journal of Pediatric Gastroenterology & Nutrition:
Cow's-Milk Allergy and Lactose Malabsorption in Infants With Colic
Heine, Ralf G.
Department of Gastroenterology & Clinical Nutrition, Royal Children's Hospital, Melbourne, Australia.
Correspondence to Ralf G. Heine, MD, Department of Gastroenterology & Clinical Nutrition, Royal Children's Hospital Melbourne, Parkville 3052, Victoria, Australia (e-mail: email@example.com).
The author reports no conflicts of interest.
Infant colic presents with episodes of persistent and inconsolable crying in the first weeks of life, which may place significant stress on families. The young infant often appears to be in significant pain, and medical assistance is commonly sought (1). In the majority of infants with colic, no organic cause is found (2,3). Only a few randomised placebo-controlled studies on the treatment of colic are available. Most treatments initiated at the peak of crying, when the child is approximately 6 weeks of age, are no more effective than placebo, because spontaneous improvement of colic symptoms usually occurs at around 3 to 4 months of age (4). In recent years, elimination of cow's-milk protein from the maternal diet or the use of hypoallergenic formulae have become common strategies in the treatment of infant colic (5). Studies supporting this practice, however, have some methological limitations and are mostly not population based. Because of a lack of clear diagnostic markers for non-immunoglobulin E (IgE)–mediated cow's-milk allergy (CMA) in infancy, the clinical management of colic is often empirical rather than evidence based. Although CMA appears to be increased in infants with persistent crying, the majority of infants with colic do not appear to have underlying food allergies.
EARLY IMMUNE MATURATION AND TOLERANCE DEVELOPMENT
The onset of infant colic in the first weeks of life coincides with several significant changes in the gut ecology and early immune programming. As the sterile gut of the newborn is increasingly colonised, gut bacteria significantly modulate early immune responses and tolerance development. Food proteins and bacterial antigens in the gut lumen are monitored by intestinal epithelial dendritic cells and processed via adaptive and innate immune pathways (6). At birth, the immune profile is skewed towards a predominance of T-helper 2 (TH2) immune responses, which increase the potential for allergic sensitisation to food antigens (7). Tolerance development is associated with the expansion of regulatory T lymphocytes that express tolerogenic cytokines and chemokines, including transforming growth factor-β and interleukin 10 (8). Reduced numbers of regulatory T lymphocytes and higher levels of TH2 cytokines are associated with an allergic phenotype (9).
Breast milk contains a range of intact food proteins (eg, cow's milk, egg, peanut, wheat) that may elicit immune responses via the neonatal gut–associated lymphatic tissue (10–14). Food-allergic reactions from breast milk have been demonstrated after maternal cow's-milk challenge (15). Infants with multiple food protein allergy (MFPA), a rare form of non-IgE-mediated food allergy and impaired tolerance development, present with severe, persistent crying (16–19). These infants develop severe irritability after ingestion of breast milk or formula (ie, cow's milk, soy, or extensively hydrolysed formula). Associated clinical features of MFPA include regurgitation/vomiting, persistent diarrhoea, and poor weight gain. The absence of eczema in the majority of infants with persistent crying suggests non-IgE-mediated mechanisms. The association of MFPA with severe infant colic led to the hypothesis that persistent crying in early infancy may be a manifestation of non-IgE-mediated food allergy.
COW'S-MILK ALLERGY AND INFANT COLIC
Cow's milk is one of the first foods introduced into the diet of infants; therefore, CMA represents one of the first allergic manifestations in early infancy, which affects approximately 2% of infants. An early study demonstrated a high prevalence of colic in infants with CMA: In a sequential cohort of 100 patients with challenge-proven CMA, 44% of the infants studied displayed irritable and colicky behavior during a cow's-milk challenge (20). Several trials have since demonstrated a treatment benefit for soy and extensively hydrolysed formulae in infants with colic, even when no other symptoms of food protein allergy were evident (21–27).
Maternal elimination diets reduce the secretion of food proteins into breast milk and may provide a treatment for a proportion of breast-fed infants with colic. Jakobsson and Lindberg (28) noted that one-third of breast-fed infants with colic improved after maternal dietary cow's-milk elimination, and relapsed on reintroduction of cow's milk into the mother's diet. Evans et al (23), however, were unable to confirm these findings. A more recent clinical trial examined the role of a broad-based hypoallergenic maternal elimination diet in 91 exclusively breast-fed infants younger than 6 weeks old with colic (21). Mothers were randomly allocated to a low-allergen diet (avoiding cow's milk, soy, wheat, egg, peanut, nuts, fish, and shellfish) or an unrestricted control diet. Clinical response after 1 week was defined as a reduction in crying/fussing duration by at least 25%, as assessed by validated 48-hour cry charts. Significantly more infants responded to the maternal low-allergen diet compared with the control diet, although symptomatic improvement occurred in both treatment arms. After 1 week, the clinical response rate in the low-allergen group was 74%, compared with 37% in the control group—a risk reduction of 37% in favour of the maternal elimination diet. This corresponded with a reduction in crying duration by 274 minutes/48 hours in the low-allergen group versus 102 minutes/48 hours in the control group (P = 0.028). In spite of these reductions in crying, the maternal overall assessment of treatment response (“better,” “same,” or “worse”) did not differ significantly between the 2 interventions. The study suggested that maternally ingested food proteins are transferred to breast milk and may contribute to colic symptoms in breast-fed infants. The exact mechanisms remain to be defined, however. The relative contribution of a multiple-food elimination diet, as compared with cow's-milk elimination alone, could not be differentiated.
Several clinical trials have assessed the effects of formula on colic and demonstrated a significant treatment benefit of hypoallergenic formulae (22). In a study of 70 infants with severe colic, 50 (71%) improved after a change to soy formula and relapsed within 24 hours after cow's-milk challenge (29). Other studies have shown an improvement in colic symptoms in response to extensively hydrolysed formulae (30–32). A meta-analysis of these studies found a significant beneficial treatment effect for extensively hydrolysed formulae in infants with colic (22,33). Lack of response after treatment with hypoallergenic formulae may in some infants be caused by the residual allergenicity of extensively hydrolysed whey or casein formula (19,34). In infants who are intolerant to extensively hydrolysed formulae, amino acid–based formula (AAF) has been shown to be effective and safe (35,36). Several groups have assessed the effect of AAF on persistent crying (16,37–39). These uncontrolled studies provided preliminary evidence that AAF may be effective in reducing persistent crying; however, further prospective trials are required to assess the efficacy and cost-effectiveness of this approach in the community.
Infants with lactose malabsorption often experience abdominal pain and may present with unsettled behaviour or prolonged crying. Despite this, lactose malabsorption is generally not considered to be a significant factor in infants with persistent crying (33,40). Several studies have assessed the effect of lactose-free formula on persistent crying. Moore et al (41) examined the effects of lactose on breath hydrogen production in infants with and without colic. They found that breath hydrogen concentrations, after intake of human milk or lactose-containing formula, were higher in infants with colic, compared with controls. Two subsequent randomised controlled trials found no significant clinical benefit for lactose restriction in breast-fed or formula-fed infants with colic (42,43). A double-blind placebo-controlled study in 53 infants found a minor improvement in colic symptoms after preincubation of milk with lactase (44); however, the response appeared to be variable, and the trial was inconclusive. Low-lactose formula or pretreatment of breast milk with lactase are, therefore, not recommended in the treatment of infantile colic or persistent crying (22).
INVESTIGATION AND MANAGEMENT OF INFANTS WITH COLIC AND SUSPECTED FOOD ALLERGY
Infant colic is generally not associated with IgE-mediated CMA, and skin prick tests are usually negative (45). Conversely, a negative skin prick test does not rule out the non-IgE-mediated form of CMA. Skin prick testing or measurement of cow's-milk–specific serum IgE antibodies are therefore not clinically useful in infants with colic. The diagnosis of non-IgE-mediated CMA relies on the demonstration of a reduction in crying duration after cow's-milk elimination, and a relapse of symptoms after cow's-milk challenge. A positive challenge also may be associated with other symptoms, such as increased vomiting/regurgitation, diarrhoea, or eczema (46).
As infant colic generally improves towards 3 to 4 months of age, the persistence of symptoms beyond 4 months may indicate a higher risk of underlying pathologies, including CMA. In infants with severe or unremitting colic symptoms beyond 4 months and those with other clinical features of CMA (persistent diarrhoea, vomiting, or eczema), a limited trial of a cow's-milk protein–free diet should be considered (47). In younger infants with colic, the clinical response to a dairy-free diet is more variable. Formula-fed infants should be started on an extensively hydrolysed formula (22). Lactose-free formula is not recommended. In breast-fed infants, a maternal elimination diet may be effective (21).
In infants who improved within 2 to 4 weeks of commencing a cow's-milk–free diet, the diagnosis of CMA should be confirmed by subsequent cow's-milk challenge, either with cow's-milk–based formula or via the maternal diet. Because food elimination and challenge sequences are cumbersome, however, parents often are not motivated to perform formal food challenges after clinical remission has been achieved. This may lead to unnecessary elimination diets and may predispose to poor nutritional outcomes. A paediatric dietitian should supervise the nutritional adequacy of the elimination diet, including maternal calcium and micronutrient requirements. Many infants with colic and CMA will tolerate cow's-milk protein from 9 to 12 months of age, and some infants will remain allergic to cow's milk until 2 to 3 years of age (47). It is therefore important for infants to be reviewed at regular intervals until tolerance to cow's-milk protein has been demonstrated.
1. Goldfeld SR, Wright M, Oberklaid F. Parents, infants and health care: utilization of health services in the first 12 months of life. J Paediatr Child Health
2. Barr RG. Colic and crying syndromes in infants. Pediatrics
1998; 102 (5 Suppl E):1282–1286.
3. Freedman SB, Al-Harthy N, Thull-Freedman J. The crying infant: diagnostic testing and frequency of serious underlying disease. Pediatrics
4. Hall B, Chesters J, Robinson A. Infantile colic: a systematic review of medical and conventional therapies. J Paediatr Child Health
5. Iacovou M, Ralston RA, Muir J, et al. Dietary management of infantile colic: a systematic review. Matern Child Health J
6. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science
7. Prescott SL, Macaubas C, Smallacombe T, et al. Development of allergen-specific T-cell memory in atopic and normal children. Lancet
8. Chehade M, Mayer L. Oral tolerance and its relation to food hypersensitivities. J Allergy Clin Immunol
9. Hinz D, Simon JC, Maier-Simon C, et al. Reduced maternal regulatory T cell numbers and increased T helper type 2 cytokine production are associated with elevated levels of immunoglobulin E in cord blood. Clin Exp Allergy
10. Brandtzaeg P. The gut as communicator between environment and host: immunological consequences. Eur J Pharmacol
2011; 668 (Suppl 1):S16–S32.
11. Sorva R, Makinen-Kiljunen S, Juntunen-Backman K. Beta-lactoglobulin secretion in human milk varies widely after cow's milk ingestion in mothers of infants with cow's milk allergy. J Allergy Clin Immunol
12. Palmer DJ, Gold MS, Makrides M. Effect of maternal egg consumption on breast milk ovalbumin concentration. Clin Exp Allergy
13. Vadas P, Wai Y, Burks W, et al. Detection of peanut allergens in breast milk of lactating women. JAMA
14. Chirdo FG, Rumbo M, Anon MC, et al. Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Scand J Gastroenterol
15. Jarvinen KM, Makinen-Kiljunen S, Suomalainen H. Cow's milk challenge through human milk evokes immune responses in infants with cow's milk allergy. J Pediatr
16. Hill DJ, Cameron DJ, Francis DE, et al. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol
17. Hill DJ, Heine RG, Cameron DJ, et al. The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance. J Pediatr
18. De Boissieu D, Matarazzo P, Rocchiccioli F, et al. Multiple food allergy: a possible diagnosis in breastfed infants. Acta Paediatr
19. De Boissieu D, Dupont C. Allergy to extensively hydrolyzed cow's milk proteins in infants: safety and duration of amino acid-based formula. J Pediatr
20. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr
21. Hill DJ, Roy N, Heine RG, et al. Effect of a low-allergen maternal diet on colic among breastfed infants: a randomized, controlled trial. Pediatrics
22. Lucassen PL, Assendelft WJ, Gubbels JW, et al. Effectiveness of treatments for infantile colic: systematic review. BMJ
23. Evans RW, Fergusson DM, Allardyce RA, et al. Maternal diet and infantile colic in breast-fed infants. Lancet
24. Campbell JP. Dietary treatment of infant colic: a double-blind study. J R Coll Gen Pract
25. Lothe L, Lindberg T, Jakobsson I. Cow's milk formula as a cause of infantile colic: a double-blind study. Pediatrics
26. Hill DJ, Hudson IL, Sheffield LJ, et al. A low allergen diet is a significant intervention in infantile colic: results of a community-based study. J Allergy Clin Immunol
1995; 96 (6 Pt 1):886–892.
27. Forsyth BW. Colic and the effect of changing formulas: a double-blind, multiple-crossover study. J Pediatr
28. Jakobsson I, Lindberg T. Cow's milk proteins cause infantile colic in breast-fed infants: a double-blind crossover study. Pediatrics
29. Iacono G, Carroccio A, Montalto G, et al. Severe infantile colic and food intolerance: a long-term prospective study. J Pediatr Gastroenterol Nutr
30. Lucassen PL, Assendelft WJ, Gubbels JW, et al. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomized, placebo-controlled trial. Pediatrics
31. 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
32. Jakobsson I, Lothe L, Ley D, et al. Effectiveness of casein hydrolysate feedings in infants with colic. Acta Paediatr
33. Lucassen PL, Assendelft WJ. Systematic review of treatments for infant colic. Pediatrics
34. Vanderhoof JA, Murray ND, Kaufman SS, et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. J Pediatr
35. Isolauri E, Sutas Y, Makinen-Kiljunen S, et al. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr
36. Niggemann B, Binder C, Dupont C, et al. Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis. Pediatr Allergy Immunol
37. Hill DJ, Heine RG, Cameron DJ, et al. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr
38. Estep DC, Kulczycki A Jr. Colic in breast-milk-fed infants: treatment by temporary substitution of neocate infant formula. Acta Paediatr
39. Estep DC, Kulczycki A Jr. Treatment of infant colic with amino acid-based infant formula: a preliminary study. Acta Paediatr
40. Garrison MM, Christakis DA. A systematic review of treatments for infant colic. Pediatrics
2000; 106 (1 Pt 2):184–190.
41. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr
42. Stahlberg MR, Savilahti E. Infantile colic and feeding. Arch Dis Child
43. Miller JJ, McVeagh P, Fleet GH, et al. Effect of yeast lactase enzyme on “colic” in infants fed human milk. J Pediatr
1990; 117 (2 Pt 1):261–263.
44. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet
45. Moravej H, Imanieh MH, Kashef S, et al. Predictive value of the cow's milk skin prick test in infantile colic. Ann Saudi Med
46. Heine RG, Elsayed S, Hosking CS, et al. Cow's milk allergy in infancy. Curr Opin Allergy Clin Immunol
47. Allen KJ, Davidson GP, Day AS, et al. Management of cow's milk protein allergy in infants and young children: an expert panel perspective. J Paediatr Child Health
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