Heine, Ralf G.
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.
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