Guidelines may encourage overdiagnosis of cow’s milk allergy among infants

The international Milk Allergy in Primary Care guidelines may promote overdiagnosis by labeling normal infant symptoms as possible cow’s milk allergy, according to a study published in Clinical & Experimental Allergy.

“We looked at the frequency of symptoms associated in guidelines with non-IgE-mediated cow’s milk allergy in children,” author Rosie Vincent, MBChB, a dermatology clinical fellow at Bristol Royal Infirmary, told Healio.

“The study was prompted by increasing diagnoses of non-IgE-mediated cow’s milk allergy despite a true prevalence of around 1% and increasing prescriptions of specialist formula milks in infants,” said Vincent, who also is an honorary clinical research fellow at University of Bristol.

The researchers performed a secondary analysis of data from the Enquiring About Tolerance (EAT) study, which investigated whether early introduction of allergenic foods into an infant’s diet reduced the risk for development of an allergy to that food.

The 1,303 healthy infants in the cohort were exclusively breastfed until at least age 3 months. The researchers randomly assigned them to a standard introduction group (SIG) or to an early introduction group (EIG).

The infants in the EIG group were introduced to six allergenic foods including cow’s milk alongside breastfeeding. The infants in the SIG group were exclusively breastfed until approximately age 6 months.

Researchers saw the infants at clinic visits at age 3 and 12 months. Also, parents answered monthly questionnaires about their infant’s general health and consumption of allergenic foods until their infant was age 12 months.

The questionnaires asked parents if their infant had any adverse reactions to food since the 3-month assessment or since the previous questionnaire, such as eczema, breathing problems or gastrointestinal issues.

The international Milk Allergy in Primary Care (iMAP) guidelines identify colic, reflux, food refusal or aversion, diarrhea, constipation, pruritis, rashes and atopic dermatitis among their mild-to-moderate symptoms of non-IgE-mediated cow’s milk allergy. Diarrhea, vomiting, abdominal pain, blood or mucus in stools and severe atopic dermatitis are included in the symptoms of severe allergy.

“The main finding from the study is how common the symptoms mentioned in the iMAP guidance for non-IgE-mediated cow’s milk allergy are,” Vincent said.

Specifically, 25% of families reported two or more mild-to-moderate non-IgE cow’s milk allergy symptoms each month from ages 3 and 12 months, and 1.4% reported severe symptoms. The researchers noted these figures peaked at age 3 months (mild-moderate, 38%; severe, 4.2%), when the infants weren’t yet consuming cow’s milk.

By age 12 months, 73.6% of the infants had experienced multiple mild-to-moderate symptoms, with 9.3% experiencing multiple severe symptoms, at least 1 of the months.

The mean monthly reporting of milk-related symptoms was 2.2% between 3 and 12 months, with the mean for individual symptoms ranging from 0.2% for blood in stool to 45.8% for vomiting, which peaked at age 3 months among 78.1% of infants.

Colic, vomiting and abdominal discomfort were most frequent at age 3 months and diminished with age, whereas food reversal and aversion increased over the first 12 months. Diarrhea and constipation increased during infancy as well, whereas skin symptoms were more stable.

Fewer participants met the threshold for severe symptoms of cow’s milk allergy, with abdominal pain reaching the highest percentage at 13.1% at 3 months. Most severe symptoms had a monthly reported prevalence between 1% and 2%.

However, only 0.6% of the EAT participants (n = 7 of 1,166; 137 lost to follow-up) were ultimately diagnosed with an IgE-mediated cow’s milk allergy by age 3 years, including 0.7% (n = 4 of 597) of the SIG group and 0.5% (n = 3 of 569) of the EIG group.

“These findings suggest that the vast majority of children with these symptoms do not have cow’s milk allergy,” Vincent said.

At 6 months, researchers observed no difference in the proportion of children with two or more mild-to-moderate symptoms between those consuming and not consuming cow’s milk (29.5% vs. 35.3%) nor between those with or without eczema at baseline (15.8% vs. 16.7%). This lack of a difference persisted when researchers looked at infants with two or more severe symptoms (consumption vs. no consumption of cow’s milk, 2.2% vs. 1.1%; eczema, 1.1% vs. 1.3%).

The researchers caution that robust data should support guidelines to prevent the harms of overdiagnosis that exceed the damage of missed and delayed cow’s milk allergy diagnoses that they aim to prevent.

“Doctors should use this evidence as a reference. The frequency of these symptoms is in a representative group of normal, healthy infants. Doctors should also interpret such guidelines cautiously to avoid medicalizing normal infant symptoms, which in turn leads to unwarranted prescriptions of specialized formula milks, with cost to families ... and to adverse outcomes for breastfeeding rates,” Vincent said.

Also, the researchers said, mild, transient or isolated symptoms should not be overinterpreted and diagnosis should be considered where symptoms are multiple, significant, persistent and treatment-resistant. Parents, the researchers continued, should be encouraged to appreciate the normality of common infant symptoms.

“It is important not to plant the seed of suspicion of cow’s milk allergy unless there are sufficient grounds to do so. Doctors should take care to not use the guidelines for non-IgE-mediated cow’s milk allergy without taking into account whether the infant could just be experiencing normal infant symptoms,” Vincent said.

Research in this area should continue, Vincent added.

“In the absence of a simple diagnostic test for non-IgE cow’s milk allergy, further research is required to identify which combination of symptoms are both specific and sensitive for the condition,” she said.

For more information:

Rosie Vincent, MBChB, can be reached at rosievincent3@nhs.net or on Twitter @RosieVince.