Cow's milk allergy (CMA) is a common food allergy in infants and young children that can have a significant impact on the individual and their family due to dietary restrictions, risk of nutritional deficiencies, social limitations, and decreased quality of life. It also represents a financial burden for families and healthcare resources. There is an ongoing debate about the significance of early exposure to cow's milk proteins within hours or days after birth and its relationship to the risk of developing CMA later in life. Current recommendations for early introduction of cow's milk proteins in infants who cannot be breastfed vary and are inconsistent due to a lack of clear evidence. This knowledge gap underscores the need for further research to provide a definitive understanding of the relationship between early exposure to cow's milk proteins and the development of CMA, which will ultimately inform evidence-based prevention strategies to improve the health and well-being of affected individuals and their families. This trial aims to investigate whether early supplementation with various nutritional interventions (cow's milk formula \[CMF\], amino acids formula \[AAF\], donor human milk \[DHM\], or high-pressure processed "pascalized" donor human milk \[DHM-P\]) could serve as an effective strategy for the primary prevention of CMA in breastfed neonates. This study is an open-label randomized, controlled, head-to-head trial with four parallel arms and allocation 1:1:1:1.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
1,000
At least 10 ml daily of cow's milk formula (Bebiko 1 NUTRIFlor Expert®, Nutricia; formula with galactooligosaccharides and without probiotics); and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
At least 10 ml daily of amino-acid formula (Nutramigen Pureamino®, Reckitt Benckiser Group PLC); and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
At least 10 ml daily of donor human milk; and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
At least 10 ml daily of high-pressure processed "pascalized" donor human milk; and if additional supplementation will be needed (i.e., insufficient, partial, or discontinuation of breastfeeding), the randomly assigned nutritional intervention until the end of 4 months of age will be provided.
Medical University of Warsaw
Warsaw, Masovian Voivodeship, Poland
A cumulative incidence of cow's milk allergy confirmed by open oral food challenge
Time frame: At 4-6 and 12 months of age
A cumulative incidence of sensitization to cow's milk protein (cut-off levels for specific IgE level ≥0.35 allergen units [UA/mL] and ≥3 mm of wheal size in the skin prick test against cow's milk
Time frame: at 6 and 12 months of age
A point prevalence of cow's milk allergy confirmed by open oral food challenge
Time frame: at 4-6, and 12 months of age
An incidence of sensitization to cow's milk protein (cut-off levels for specific IgE level ≥0.35 allergen units [UA/mL] against cow's milk)
Time frame: at 4-6, and 12 months of age
In a subgroup of children with confirmed cow's milk allergy, the percentage of children with tolerance acquisition to cow's milk
Tolerance acquisition to cow's milk will be assessed by subsequent OFC with baked milk (in the form of biscuit or muffin); if baked milk is tolerated, the assessment of tolerance acquisition will be continued with the use of milk ladder.
Time frame: at 9 and/or 12 months
Percentage of children who received a full 3-day nutritional supplementation (3x10 ml according to the randomization) and then were exclusively or predominantly breastfed until 4 months of age
Time frame: Up to 4 month of age
A total score in the Cow's Milk-related Symptom Score (CoMiSS)
The total CoMiSS score ranges from 0 to 33, a score of ≥10 indicates CMA.
Time frame: at 4-6 and 12 months of age
Percentage of children exclusively breastfed
Time frame: at 4 and 6 months of age
Percentage of children with mixed feeding
Time frame: at 4 and 6 months of age
Change in Body Mass Index (BMI)-for-age z-score
weight and length will be checked each month in a telephone interview or parental report, or during follow-up visit assessed by study physician; change in mean value will be assessed between baseline and each time point
Time frame: at 4, 6 and 12 months of age
Change in length-for-age z-score
length will be checked each month in a telephone interview or parental report, or during follow-up visit assessed by study physician; change in mean value will be assessed between baseline and each time point
Time frame: at 4, 6 and 12 months of age
Adverse events related to the nutritional intervention (according to the randomization)
defined as any harmful events that may occur during the trial; the process of decision whether an adverse event is related to the intervention (attribution) will be made by the non-blinded principal investigator
Time frame: up to 12 months of age
A cumulative incidence of atopic dermatitis (defined as meeting the UK Working Party diagnostic Criteria)
Time frame: at 6 and 12 months of age
A cumulative incidence of allergic rhinitis (confirmed by study physician)
Time frame: at 6 and 12 months of age
A cumulative incidence of feeding difficulties who will be screened with The Montreal Children's Hospital Feeding Scale (MCH-FS scale)
Total score range from 14 to 98, score of 46 or higher indicates feeding difficulties.
Time frame: at 6 and 12 months of age
Human milk energy value (kcal/100 mL)
Time frame: at 4-14 days postpartum and 6 months of age
Total and true protein concentrations in human milk samples (g/100 mL)
Time frame: at 4-14 days postpartum and 6 months of age
Fat concentration in human milk samples (g/100 mL)
Time frame: at 4-14 days postpartum and 6 months of age
Lactose concentration in human milk samples (g/100 mL)
Time frame: at 4-14 days postpartum and 6 months of age
Dry mass content g/100 mL
Time frame: at 4-14 days postpartum and 6 months of age
IgA-anty CMA concentration in human milk samples (pg/mL)
Time frame: at 4-14 days postpartum
IL-1B, IL-6, IL-10, and TGF-beta concentrations in human milk samples (pg/mL)
Time frame: at 4-14 days postpartum
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