Cow's-milk protein (CMP) allergy may affect as many as 3% of infants, whereas all food allergies have been estimated to occur in 7% to 8% of infants in the first year of life (1–3). CMP is one of the major antigens first introduced in an infant's diet whether its source is from breast milk (4) or infant formula. Young infants may be especially prone to cow's-milk protein–induced enterocolitis (CMPIE) because their immature digestive system is more permeable to food allergens that can then interact with the submucosal immune elements of the gastrointestinal (GI) tract (5). Treatment consists of indirectly removing the offending antigen from the infant's diet by eliminating CMP from the mother's diet in breast-feeding infants or directly removing the offending antigen by a change in infant formula for infants on a cow's-milk–based infant formula. The majority respond well to an extensively hydrolyzed formula (6).
Although CMP is the most common cause of protein-induced enterocolitis, a variety of additional foods have been implicated in infants. A search through Ovid Citations, MEDLINE, Scopus, CENTRAL and Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews failed to identify randomized controlled trials related to adverse GI events following introduction of complementary foods in infants diagnosed with CMPIE. However, there are documented case reports of adverse reactions to rice (7–13), oats, barley and other grains (14), poultry (14,15), lentils, peas (15), squash, and sweet potatoes (14).
Before this prospective trial, we retrospectively analyzed reported problems of first complementary food introduction in 32 infants diagnosed as having a CMPIE. Infants were reported to have blood in the stools, mucus in the stools, abdominal pain, and irritability. These sensitivities were related to infant cereal introduction in 63% of the infants and to vegetable introduction in 12% of the infants. The purpose of the present study was to determine whether differences in type of food introduction can be related to the development of adverse reactions in a prospective approach.
PATIENTS AND METHODS
The primary objective was to compare the incidence of new GI symptoms with the introduction of either milk-free infant rice cereal or carrots as the first complementary food introduced at 6 months old in infants previously diagnosed with CMPIE. The secondary objective of the present study was to compare the reported gastrointestinal (GI) signs and symptoms associated with the first food introduction and their frequency of occurrence.
Infants with a diagnosis of CMPIE were randomized to receive either commercial pureed carrots (group A) or commercial milk-free infant rice cereal (group B). GI signs and symptoms were recorded during a 2-week period following the first food introduction.
Infants diagnosed as having a CMPIE were referred to the clinical dietitian in the Division of Gastroenterology, Hepatology, and Nutrition at the Children's Hospital of Eastern Ontario (CHEO), Ottawa, Canada. The diagnosis of CMPIE was made by any of the 4 pediatric gastroenterologists at the CHEO based on clinical symptoms, negative search for other causes of the GI symptoms, and response to therapy.
Infants were excluded if they had other previous or current medical/surgical problems, if they were premature, if they were not fed orally, or if they were on a course of antibiotics, corticosteroids, salicylate-containing products, nonsteroidal anti-inflammatory drugs, or antireflux medication. They were also excluded if solid foods were introduced before enrollment in the study, if there was reintroduction of milk protein into the maternal diet or reintroduction of a cow's-milk–based infant formula in the infant's diet within 4 weeks before enrollment in the study.
The research design was a randomized controlled trial. The randomization took place when infants were 5½ months old (±1 week). Infants were randomly assigned to carrots or milk-free infant rice cereal using a blinded randomization protocol with the study allocation being drawn from a sealed opaque envelope. The envelopes were sequentially numbered to ensure allocation concealment. The research assistant and the statistician were blinded to the first food group introduced because they were collecting and analyzing the data. The dietitian was not blinded; she reviewed how to introduce the food for the 2-week period. The brand name for the milk-free infant rice cereal and pureed carrots was Beech Nut and they were supplied free of charge to parents/guardians for the duration of the solid-food trial.
A 2-week food/symptom diary before the first food introduced served as a baseline to measure GI symptoms (diary no. 1). A second 2-week food/symptom diary immediately followed diary no. 1, in which milk-free infant rice cereal or carrots were introduced to the infant and served to assess the primary and secondary objectives (diary no. 2). If there were no new GI symptoms after diary no. 2, then the baby was considered to be tolerant to the food and this was the end of the food/symptom diary. If new GI symptoms occurred during diary no. 2, then both the solid food and the diary were stopped. There was a 2-week wait for GI symptoms to completely disappear and a third food/symptom diary was initiated using the same solid food as diary no. 2 (diary no. 3).
Diary no. 3 served to confirm the reaction to the solid food that caused GI symptoms in diary no. 2. If there were no new GI symptoms after diary no. 3, then the baby was considered to be tolerant to the food. If new GI symptoms were again present in diary no. 3, then the baby was considered to be intolerant to the food. The food/symptom diaries were based on a validated dietary interview from the TRIGR study (nutritional prevention of type 1 diabetes) and were adapted to our study population (16). Approval of the present study was obtained from the CHEO research ethics board.
According to our retrospective analysis, 63% of infants were found to develop GI symptoms within 2 weeks after the initiation of milk-free infant cereal. This information was used as a basis for sample size calculation for the present study. Briefly assuming a 1:1 randomization ratio between intervention groups, an overall type I error rate of 5% (2-sided), and a type II error rate of 20% (implying 80% statistical power), the aim was to find an absolute minimal clinically important reduction in symptoms of 48% between infants randomized to either milk-free infant rice cereal or pureed carrots using Fisher exact test. Assuming a 15% loss to follow-up, our final sample size was set at 39.
Descriptive summaries of demographic and clinical characteristics of the infants at baseline were computed. Dichotomous variables were summarized using percentages, and normally distributed continuous variables were summarized using means together with standard deviations.
The incidence of any new GI symptoms (yes or no) measured at 2 weeks was calculated for each study group along with a 95% confidence interval using the Wilson score method (17). The incidence estimates were compared between study groups using the Fisher exact test. A logistic regression, with study group and breast-feeding both in the model, was used to assess the difference between the 2 groups and the effect of breast-feeding on the primary outcome.
The incidence of each individual new GI symptom was described and compared between groups using the Fisher exact test. The time to the onset of any new GI symptom was plotted using Kaplan-Meier curves and compared using the log-rank test. The change in the frequency of individual symptoms before and during the introduction of solid food was calculated for each group and compared using linear regression with adjustment for breast-feeding.
All of the statistical analyses were conducted using SPSS 17.0 (SPSS Inc, Chicago, IL) and R2.7.2 (17). A significance level of 0.05 was used for all of the analyses.
A total of 39 infants were enrolled in the study between January 2007 and August 2009. Their presenting symptoms included stools with blood (87%), gas and bloating (83%), loose stools (82%), and more than 5 bowel movements per day (75%) at a mean age of 2½ months of age. Other causes of enteritis were excluded and resolution of symptoms was noted in all of the infants following a dietary elimination of the CMP.
Of the 39 infants enrolled, 20 were randomized to pureed carrots (group A) and 19 were randomized to milk-free infant rice cereal (group B). One infant in group B was excluded from the analysis due to loss of data from the food/symptom diaries (Fig. 1). At the time of solid-food introduction, 20 infants were solely breast-fed, 11 were breast-fed with supplemental infant formula, and only 7 were on infant formula alone. As reported by parents, a total of 20 infants (53%) had a return of GI symptoms with soy, whether via breast milk (14 infants) or a soy infant formula (6 infants). Parents also reported on family history of food allergy, and there was no statistical difference between the 2 groups. Summarized in Table 1 are the baseline characteristics in both randomized groups.
When looking at the presence of any new GI symptom, 8 infants in group A and 10 infants in group B had new GI symptoms during the first food introduced. The incidence of a new GI symptom was 40% in group A (95% confidence interval [CI] 22–61) and 56% in group B (95% CI 34–75), which was not statistically different (P = 0.52). When adjusting for the type of feeding (breast milk vs no breast milk), the odds of developing new GI symptoms in group B was similar to group A (odds ratio 2.42, 95% CI 0.61–9.65, P = 0.21). However, with the 2 groups combined, there was a high overall incidence of new GI symptoms with solid-food introduction (47%, 95% CI 33–66). Diary no. 3 was not used in the analysis because it did not significantly change the results observed from diary no. 2 (only 3 infants had diary no. 3 filled out).
Listed in Table 2 are the observed GI signs and symptoms before solid-food introduction (diary no. 1) and during solid-food introduction (diary no. 2) in both groups of our study population. Overall, the most common symptoms associated with solid-food introduction were related to a change in stool characteristics (blood, mucus, consistency). The mean number of days for onset of new symptoms was 6.
We also compared the 2 groups in terms of the change in the frequency of GI symptoms as they relate to the first food introduced. For each symptom listed in Table 2, there was no statistical difference in the change of frequency of GI symptoms before versus during the first food introduced. This was true even after adjusting for the type of feeding (breast milk vs no breast milk) in a linear regression model (data not shown) except for the symptom of abdominal pain, which reached marginal significance (P = 0.051).
The mean number of days for the onset of a new GI symptom was 6 (95% CI 4–9 days) following complementary food introduction. The Kaplan-Meier curves revealed no discernable difference in the time to development of new GI symptoms between the 2 groups (Fig. 2, P = 0.45 from log-rank test). When compared by feeding type, the breast-feeding-only group showed a discernible shorter time to onset of new GI symptoms compared with the other subjects (Fig. 3). However, this difference did not reach statistical significance (P = 0.082 from log-rank test).
Following our retrospective analysis that suggested a differential development of GI symptoms when the first food was an infant cereal, this randomized trial was undertaken. However, no difference in the development of GI symptoms was determined between infants starting with either carrots or milk-free infant rice cereal. Furthermore, we were unable to observe a significant difference in the onset of new GI signs and symptoms, even after adjusting for breast-feeding.
The incidence of new GI signs and symptoms following first food introduction is high at 47%. It has been reported that the cumulative incidence of adverse reaction to food was 35% before age 2, with milk accounting for 12% (16). These results show there is a high likelihood of onset of new GI signs and symptoms with first complementary food regardless of type of food. The most common symptoms associated with solid-food introduction were related to stools (blood, mucus, consistency) and these symptoms reflect the original GI signs and symptoms that were most commonly seen upon diagnosis. Although the average time of onset of GI signs and symptoms was 6 days, this ranged up to a 10-day period following the introduction of either the carrots or infant rice cereal.
The CMPIE population studied had that were colonic symptoms involving changes in stool characteristics typical of non-IgE mediated allergy. The majority of infants were breast-fed, and successful treatment of their CMPIE was achieved with either cow's-milk protein avoidance by breast-feeding mothers or use of an extensively hydrolysed formula. Only 3 infants (16%) had to progress to an amino acid formula, which is similar to reports in the literature claiming that up to 20% of infants need an amino acid formula to settle symptoms (6). An average of 53% of infants in our study also reacted to soy, and this is in concordance with previous studies (17).
The limitations of the study relate to parental report of GI symptoms. Many other factors needed to be taken into consideration such as teething, ear infections, and viral infections that could have also been the cause of the GI symptoms. Symptoms may have been related to the mother's diet; she may have had some milk ingredients without knowing. Only 3 infants went on to diary no. 3, which shows that the clinical symptoms were not severe enough for the parents to stop the food, but this did not help in identifying whether the symptoms were a true adverse reaction to the food. However, there was strong compliance with the parental reporting of GI symptoms in the food diaries and with respect to the only first food that needed to be introduced.
We believe that the introduction of solid food has an effect on the sensitive GI tract of infants diagnosed as having CMPIE. No matter which food is introduced first, there is a great risk of the return of GI symptoms with solid-food introduction. This shows an ongoing sensitivity of the GI tract rather than an adverse reaction to food. There is no evidence from our study to deviate from the recommended solid-food introduction guidelines of Health Canada, the World Health Organization, and the Canadian Pediatric Society for infants with CMPIE. If there are no new GI symptoms from a particular food within 10 days of its introduction, we would recommend another new food be introduced.
The authors acknowledge the support of Janice Barkey, Carolina Jimenez, Cathy Walker, and Julie Larocque in the recruitment of babies diagnosed as having CMPIE.
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