Blood in the stool of a young infant usually stems from milk protein intolerance, a nonimmunoglobulin E (IgE)–mediated milk protein allergy (1). Intolerance affects 7% to 15% of full-term infants (2,3), but this range probably underestimates the true proportion because many children with undetected occult blood in the stool are never diagnosed.
Infants with cow's-milk protein intolerance are usually switched to a casein hydrolysate or amino acid–based formula (4,5). They typically continue to receive this formula until 1 year of age, when they are rechallenged with a cow's-milk or soy protein formula (6). This approach is based on anecdotal observations that most infants with cow's-milk protein intolerance become tolerant by 12 months of age and do not develop colitis in response to reexposure. The prognosis for IgE-mediated milk protein allergy is less certain (7).
Rechallenging babies at 12 months of age has become common practice, but it is possible that many infants become tolerant sooner. If so, families could realize substantial savings by reverting to a less expensive formula at an earlier age. To explore this possibility, we rechallenged a small series of infants before they had reached their first birthday. The purpose of the study was to gather preliminary data for establishing an empirical timetable for the resolution of milk protein intolerance.
Study Design and Patients
This prospective, longitudinal cohort study enrolled infants <4 months of age receiving either breast milk or a cow's-milk or casein hydrolysate formula who presented to our hospital's Division of Pediatric Gastroenterology, Hepatology, and Nutrition between July 1, 2011, and December 31, 2012, and had a positive stool guaiac test in our office. Infants were excluded if they were receiving iron supplements or had any of the following conditions: anal fissure; bacterial enterocolitis; previous history of necrotizing enterocolitis or hematemesis; previous intestinal surgery; severe bloody diarrhea, dehydration, and the need for hospitalization and intravenous fluids secondary to presumed cow's-milk– and/or soy protein–induced enterocolitis.
Parents of eligible patients were invited to participate in the study and asked to provide written informed consent. Parents who gave consent were free to withdraw their infant at any time while continuing to receive medical care from our service. Study subjects were followed until they had reached 15 months of age or their milk protein intolerance had resolved. The study was approved by the hospital's institutional review board.
Food Challenge and Data Collection Protocol
Upon patient enrollment, a complete blood cell count with differential was obtained to test for anemia, and radioallergosorbent IgE blood levels were measured to test for allergy to milk or soy protein. Infants who were receiving breast milk or a cow's-milk formula at the time of enrollment were switched to a casein hydrolysate formula. If blood in the stool did not resolve within 3 weeks, those infants were then switched to an amino acid–based formula. Infants who were receiving casein hydrolysate at the time of enrollment were immediately switched to an amino acid–based formula.
Parents were shown how to apply a stool sample to a guaiac card and instructed to gather a specimen once a week and mail the card to the study office. Cards were read by a research coordinator or nurse and the readings verified by a nurse clinician or physician within 24 hours of receipt. When the guaiac cards tested negative for blood for 2 consecutive weeks, the parent was instructed to reduce the frequency of specimen collection to once per month.
Infants who had guaiac-negative stools for at least 2 consecutive months were rechallenged with the formula that had necessitated the most recent switch. Then, if 2 consecutive guaiacs 1 week apart were negative, the infant continued receiving the rechallenge formula. Otherwise, the infant was returned to the prechallenge formula until another rechallenge was conducted 2 to 3 months later. If an infant receiving casein hydrolysate had negative stool guaiacs for at least 2 consecutive months, the parent could rechallenge with a cow's-milk–based formula.
Of the 1250 infants <4 months of age with a variety of gastrointestinal problems who were seen in the study practice between July 1, 2011, and December 31, 2012, 25 were enrolled in the study. Of these, 16 patients completed the food challenge and data collection protocol. Parents of the remaining 9 infants decided to continue an amino acid formula rather than rechallenge the infant in an effort to return to a casein hydrolysate or cow's-milk–based formula.
The 10 boys and 6 girls who completed the study ranged in age from 2 weeks to 3 months at enrollment, averaging 1.7 ± 0.8 months (mean ± standard deviation). All of the subjects had been full-term deliveries, and none presented with a rash. One infant had been receiving breast milk, 2 cow's-milk formula, and 13 casein hydrolysate formula (started by their pediatrician before referral to our practice) at the time of enrollment. After a trial of casein hydrolysate, all of the 3 infants who had been receiving breast or cow's milk had to be switched to amino acid because blood in the stool did not resolve. Therefore, all 16 infants were receiving amino acid by 4 months of age (Fig. 1).
Blood samples at enrollment were sufficient to measure IgE levels in 13 of the 16 study subjects: none had a detectable level of IgE to milk or soy. In the 12 subjects with sufficient blood samples for measuring hemoglobin and hematocrit, the respective levels were 11.7 ± 1.5 g/dL (range 9.0–14.0 g/dL) and 34.1% ± 4.6% (range 27.0%–42.0%). Only 1 infant was anemic and required iron therapy. All of the 13 patients who had a complete blood cell count with differential had a normal eosinophil count.
Negative stool guaiac tests following rechallenge with casein hydrolysate indicated resolution of milk protein intolerance by the time subjects reached a mean age of 6.7 ± 1.0 months (95% confidence interval 6.2–7.2 months, range 5.4–9.5 months). By the age of 7 months, milk protein intolerance was resolved in 12 of the 16 infants (75.0%), the remainder having resolved by 10 months (Fig. 2). Six patients were successfully switched from casein hydrolysate to a cow's-milk formula between 9 and 14 months of age (Fig. 1).
To estimate savings associated with rechallenging infants before the first birthday, assume that an infant is switched back to the original formula following a negative rechallenge at age 7 months, that is, 5 months earlier than usual. The price of cow's-milk formula is approximately $8/day, as compared with $11/day for casein hydrolysate formula or $15/day for amino acid–based formula. Switching to cow's-milk formula would therefore save $3 to 7/day, $90 to 210/month, or approximately $450 to 1050 in >5 months, depending on the formula.
This study suggests that unexplained occult blood in the stool of infants <4 months of age often resolves by 7 months. It follows that infants with apparent milk protein intolerance could reasonably be rechallenged at 6 months. Because early reactions such as urticaria, angioedema, anaphylaxis, vomiting, or an acute flare of atopic dermatitis can occur when a baby is rechallenged, infants with severe symptoms should be referred to an allergist who can safely rechallenge them in the proper setting (2,8,9).
Study patients were drawn from a pediatric gastroenterology practice, so they probably represent more persistent cases than would typically be encountered in a general pediatric or family practice. This may explain why all 16 infants had to be switched to amino acid formula after having failed to respond to casein hydrolysate. In infants who do respond favorably to casein hydrolysate, it would be reasonable to anticipate even more rapid—or at least no less rapid—resolution than suggested by the timetable in Figure 2. A separate study would be required to confirm this expectation.
Once they had been successfully switched to an amino acid–based formula, study subjects were rechallenged after they had remained guaiac negative for at least 2 months. Because they did not undergo serial exposures at closely spaced intervals during that period (eg, weekly), milk protein intolerance may actually have resolved somewhat sooner than indicated in Figures 1 and 2.
In this study, as in everyday practice, cow's-milk protein intolerance was operationally defined as the presence of blood in the stool after exclusion of other causes (anal fissure, infection, necrotizing enterocolitis, and so forth). We did not positively confirm this etiology by rechallenging the infant with cow's milk as soon as blood had resolved after the switch to a hypoallergenic formula. Also, study subjects did not undergo flexible sigmoidoscopy with biopsy, a procedure not typically performed in response to a positive stool guaiac test in an infant. Therefore, other gastrointestinal lesions could have been present, such as ulcers or hemangiomas, but they represent relatively rare causes of blood in young infants. Although we cannot rule out such an etiology, study subjects were evaluated as most physicians do in their daily practice by first pursuing other, more common causes of blood in the stool. In all 16 infants, the blood did resolve after eliminating cow's-milk and casein hydrolysate formulas.
A larger sample of infants would most likely have produced a narrower confidence interval for the mean time to resolution. Nevertheless, the upper limit of the 95% confidence interval derived from our study sample (N = 16) was 7.2 months, providing a credible rationale for rechallenging several months earlier than has been the customary practice. A larger sample would also have permitted exploration of the effects of historical factors such as prematurity and family history of allergy on time to resolution.
This study suggests that it may be reasonable to treat infants with milk protein intolerance for 2 to 3 months with a hypoallergenic formula, then rechallenge them at 6 months of age, usually without causing recurrence of the hematochezia indicative of milk protein induced colitis. Larger studies should be undertaken to confirm and elaborate on these preliminary findings. Although physicians typically recommend waiting until the age of 12 months before rechallenging, switching to a less expensive formula at an earlier age could yield substantial cost savings to parents and insurers.
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