Tolerance and Safety of an Anti-Regurgitation Formula Containing Locust Bean Gum, Pre-, and Postbiotics: A Multi-Country Multi-Center Prospective Randomized Controlled Study in Infants with Regurgitation.

This multi-center prospective randomized controlled trial was a tolerance and safety study investigating the thickener locust bean gum (LBG) in infants with regurgitation, to support the re-evaluation of the safety of LBG in infant formula. The primary objective was to demonstrate that after an 8-week intervention, stool consistency was not inferior (i.e., was not looser or more watery) in infants fed an anti-regurgitation (AR) formula containing LBG vs. the stool consistency of infants fed with an unthickened control formula. A total of 103 full-term infants with regurgitation were randomized to the test or control formula. The test formula contained LBG (0.4 g/100 mL), short-chain galacto-oligosaccharides, and long-chain fructo-oligosaccharides (scGOS/lcFOS; 9:1; 0.4 g/100 mL) and postbiotics and the control formula contained scGOS/lcFOS (0.8 g/100 mL), the same amount of postbiotics, and did not contain LBG. The average stool consistency score at the 8th intervention week was the primary outcome parameter. Secondary outcome parameters were stool consistency at other timepoints, stool frequency, Infant Gastrointestinal Symptom Questionnaire (IGSQ) score, growth, (serious) adverse events ([S]AEs), regurgitation severity, and infant well-being. Overall, the infants were 36.9 ± 12.9 [mean ± SD] days old, 62.7% girls in the test, and 50.0% girls in the control group. The primary analysis showed that the test group did not have looser or more watery stools than the control group. IGSQ sum scores decreased comparably in both groups. The frequency of regurgitation was significantly lower in the test group compared to the control group (mixed model repeated measurement, p ≤ 0.028) and parent-reported well-being scores were favorable. Adequate growth was observed in both groups. Both products were well-tolerated and safe and the AR formula with LBG was efficacious in reducing regurgitation frequency. This study provides further evidence for the dietary management of regurgitation by LBG-containing formulae in infants who are not exclusively breastfed, and the reassurance it can bring to parents.

Potential risk of dental fluorosis associated with different baby formulas and water brands marketed in Spain.

Despite efforts to promote breastfeeding, many babies aged <6 months receive only baby formula reconstituted with bottled water. The intake of high levels of fluoride during amelogenesis has been associated with hypomineralization of the tooth enamel, with aesthetic and mechanical repercussions. The objective of this study was to determine the potential risk of dental fluorosis associated with baby formulas marketed in Spain. We measured 26 baby formulas frequently consumed in Spain; 17 brands for babies aged <6 months, 5 for those aged >6 months, and 4 ready-to-use brands. They were prepared with 4 types of water: distilled water and three brands of bottled water with different levels of fluoride. The fluoride concentration (mg/L or ppm F) was measured with an ion-specific electrode coupled to an ion analyzer. Each sample was prepared according to the manufacturer's instructions and analyzed in triplicate. A descriptive analysis was carried out. The minimum fluoride level found was 0.04 mg/L and the maximum was 1.02 mg/L. Considering the daily intake of these formulas, none exceeded the clinically-acceptable daily dose limit risk for fluorosis (0.07 mg F/day/kg body weight) when mixed with bottled water with a low level of fluoride (0.1 mg/L). However, when the same brands of formula were reconstituted with bottled water with a higher fluoride content (0.99 mg/L), they all exceeded the daily dose limit for the risk of fluorosis. As the potential risk of dental fluorosis associated with the formulas tested depends exclusively on the fluoride concentration of the waters used for reconstitution, formula packaging should contain a warning.

Infant Feeding Pattern Clusters Are Associated with Childhood Health Outcomes.

(1) Background: Feeding behavior habits have a pattern with a certain tendency during infancy. We aimed to identify the associations between feeding patterns in infancy and the subsequent 10-year childhood disease burden. (2) Methods: Data from 236,372 infants were obtained from the national health insurance and screening program records in South Korea. Parent-administered questionnaires during infancy provided details on the feeding type and types/frequency of complementary food for analyzing feeding patterns. The outcomes were all-cause hospitalization and the development of 15 representative childhood diseases until the age of 10 years. Anthropometric measurements obtained at 6 years of age were analyzed. To estimate outcome risks while considering multiple risk factors, we employed a Cox proportional hazard and modified Poisson regression. (3) Results: Three clusters were identified: high prevalence of breastfeeding with regular exposure to a variety of solid foods (n = 116,372, cluster 1), similar prevalence of breastfeeding and formula feeding with less exposure to solid foods (n = 108,189, cluster 2), and similar prevalence of breastfeeding and formula feeding with the least exposure to solid foods in infancy (n = 11,811, cluster 3). Compared with cluster 1, children in clusters 2 and 3 had increased risks of all-cause hospitalization (hazard ratio (HR), (95% confidence interval (CI)), 1.04 (1.03-1.06) and 1.08 (1.05-1.11), respectively). Children in clusters 2 and 3 had an increased risk of upper respiratory infection, pneumonia, and gastroenteritis, as well as neurobehavioral diseases. Overweight/obesity at the age of 6 years was associated with clusters 2 and 3. (4) Conclusions: Feeding patterns in infancy were associated with an increased risk of childhood disease burden.

Low-Protein Infant Formula and Obesity Risk.

Infant formulas have been designed to mimic human milk for infants who cannot be breastfed. The overall goal is to establish similar functional outcomes to assure optimal growth, development, maturation of the immune system, and programming of the metabolic system. However, after decades of improving infant formula, growth patterns and body composition development are still different in formula-fed infants compared to breastfed infants, which could contribute to an increased risk of obesity among formula-fed infants. It has been hypothesized that the lower protein concentration of breast milk compared to infant formula influences infants' growth and body composition. Thus, several trials in formula-fed infants with different protein intake levels have been performed to test this hypothesis. In this review, we discuss the current evidence on low-protein infant formula and obesity risk, including future perspectives and implications.

Síndrome de enterocolitis inducida por proteínas alimentarias que debuta con hiperamoniemia / Hyperammonaemia as onset of food protein-induced enterocolitis syndrome

Dentro de las alergias no mediadas por IgE, la enterocolitis inducida por proteínas alimentarias (FPIES) es el cuadro de mayor gravedad, pudiendo cursar con una clínica muy variada. El FPIES crónico se suele manifestar con letargia, palidez cutánea, desnutrición, vómitos intermitentes y/o diarrea crónica, asociados a múltiples alteraciones analíticas (leucocitosis con desviación a la izquierda, eosinofilia, anemia, trombocitosis, hipoproteinemia, hipoalbuminemia, metahemoglobinemia y acidosis metabólica). La resolución ocurre entre los 3 a 10 días tras la exclusión del alérgeno causante; vuelven a tolerarlo aproximadamente a los 3-5 años de edad. Se presenta el caso clínico de un lactante de 47 días alimentado con fórmula de inicio, que debuta con un cuadro de vómitos y diarreas con deshidratación grave, acidosis metabólica, metahemoglobinemia, hipoproteinemia, hipoalbuminemia e hiperamoniemia, siendo esta última una característica solo referenciada en un caso hasta la actualidad (AU)

Food protein-induced enterocolitis syndrome (FPIES) is the most severe non-IgE-mediated allergies, and has a broad clinical spectrum. Chronic FPIES usually manifests with lethargy, pallor, undernutrition, intermittent vomiting and/or chronic diarrhoea associated with multiple laboratory abnormalities (leucocytosis with left shift, eosinophilia, anaemia, thrombocytosis, hypoproteinaemia, hypoalbuminaemia, methemoglobinemia and metabolic acidosis). It resolves 3 to 10 days after exclusion of the causative allergen, and most patients develop tolerance to the protein again at approximately 3 to 5 years of age. We present the case of a 47-day-old infant who presented with vomiting and diarrhoea with severe dehydration, metabolic acidosis, methaemoglobinaemia, hypoproteinaemia, hypoalbuminaemia and hyperammonaemia, the latter being a feature that has only been described in one other case before. (AU)

Analysis of Serum Th2 Cytokines in Infants with Non-IgE Mediated Food Allergy Compared to Healthy Infants.

Background: The aim of this study is to assess the serum values of IL-4, IL-5, IL-10, and IL-13 in a group of infants with non-IgE mediated food allergies treated with a hydrolyzed formula and compare them with a group of healthy peers. Methods: A total of 53 infants aged 1 to 4 months, of which 34 with non-IgE mediated food allergies and 19 healthy infants were enrolled in this study. Infants were eligible if they had gastrointestinal symptoms of food allergy and needed to switch from their initial formula to hydrolyzed formulas with an improvement of symptoms. Controls were fed with either breastmilk or standard formula. Blood samples were taken within one week of a special diet for cases. Interleukinsin in peripheral blood was detected and analyzed using the real-time PCR MAMA method. Fecal calprotectin was evaluated using a quantitative assay. Results: Values of IL-4 and IL-13 were significantly higher in the non-IgE food allergy group compared to the control group (p < 0.05), while IL-5 and IL-10 were significantly lower than the control group (p < 0.05). Fecal calprotectin in the non-IgE food allergy group was significantly higher compared to the control group (p < 0.05). Conclusion: This study provides a theoretical basis that Th2 cytokine expression in infants with a non-IgE mediated food allergy is significantly different than in healthy infants; this finding supports the use of early dietetic treatment with hydrolyzed formulas.

Food Protein-Induced Enterocolitis Syndrome in Children with Down Syndrome: A Pilot Case-Control Study.

Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobin E-mediated food hypersensitivity disorder. However, little is known about the clinical features of FPIES in patients with Down syndrome (DS). Medical records of children with DS diagnosed at our hospital between 2000 and 2019 were retrospectively reviewed. Among the 43 children with DS, five (11.6%) were diagnosed with FPIES; all cases were severe. In the FPIES group, the median age at onset and tolerance was 84 days and 37.5 months, respectively. Causative foods were cow's milk formula and wheat. The surgical history of colostomy was significantly higher in the FPIES group than in the non-FPIES group. A colostomy was performed in two children in the FPIES group, both of whom had the most severe symptoms of FPIES, including severe dehydration and metabolic acidosis. The surgical history of colostomy and postoperative nutrition of formula milk feeding may have led to the onset of FPIES. Therefore, an amino acid-based formula should be considered for children who undergo gastrointestinal surgeries, especially colostomy in neonates or early infants. When an acute gastrointestinal disease is suspected in children with DS, FPIES should be considered. This may prevent unnecessary tests and invasive treatments.

Tolerance development in cow's milk-allergic infants receiving amino acid-based formula: A randomized controlled trial.

BACKGROUND: Tolerance development is an important clinical outcome for infants with cow's milk allergy. OBJECTIVE: This multicenter, prospective, randomized, double-blind, controlled clinical study (NTR3725) evaluated tolerance development to cow's milk (CM) and safety of an amino acid-based formula (AAF) including synbiotics (AAF-S) comprising prebiotic oligosaccharides (oligofructose, inulin) and probiotic Bifidobacterium breve M-16V in infants with confirmed IgE-mediated CM allergy. METHODS: Subjects aged ≤13 months with IgE-mediated CM allergy were randomized to receive AAF-S (n = 80) or AAF (n = 89) for 12 months. Stratification was based on CM skin prick test wheal size and study site. After 12 and 24 months, CM tolerance was evaluated by double-blind, placebo-controlled food challenge. A logistic regression model used the all-subjects randomized data set. RESULTS: At baseline, mean ± SD age was 9.36 ± 2.53 months. At 12 and 24 months, respectively, 49% and 62% of subjects were CM tolerant (AAF-S 45% and 64%; AAF 52% and 59%), and not differ significantly between groups. During the 12-month intervention, the number of subjects reporting at least 1 adverse event did not significantly differ between groups; however, fewer subjects required hospitalization due to serious adverse events categorized as infections in the AAF-S versus AAF group (9% vs 20%; P = .036). CONCLUSIONS: After 12 and 24 months, CM tolerance was not different between groups and was in line with natural outgrowth. Results suggest that during the intervention, fewer subjects receiving AAF-S required hospitalization due to infections.

Enrichment of infant formula with long-chain polyunsaturated fatty acids and risk of infection and allergy in the nationwide ELFE birth cohort.

BACKGROUND: The new European regulations require the enrichment of formulas with docosahexaenoic acid (DHA) because of the positive effects of long-chain polyunsaturated fatty acids (LCPUFAs) on neurodevelopment and visual acuity. In this observational study, we aimed to evaluate whether the consumption of LCPUFA-enriched formula was associated with the risk of infection and allergy in early childhood. METHODS: Analyses involved data from 8389 formula-fed infants from the ELFE birth cohort. Formula enrichment was identified from the list of ingredients of the formula consumed at 2 months. Infections (gastrointestinal, lower respiratory tract [LRTI], upper respiratory tract) and allergies (wheezing, itchy rash, asthma medication, food allergy) from age 2 months to 5.5 years were reported by parents during follow-up surveys. Multivariable logistic regression models were used to assess associations between the consumption of LCPUFA-enriched formula and the risk of infection and allergy. RESULTS: Among formula-fed infants at 2 months, 36% consumed formula enriched with DHA and arachidonic acid (ARA), and 11% consumed formula additionally enriched with eicosapentaenoic acid (EPA). Enriched formula consumption was not associated with infection or allergy, except for an association between consumption of DHA/ARA/EPA-enriched formula and lower use of asthma medications. Furthermore, as compared with non-DHA/ARA/EPA-enriched formula, consumption of formula with high EPA content (≥3.2 mg/100 kcal) was related to lower risk of LRTI and lower use of asthma medications. CONCLUSION: This study suggests that consumption of DHA/ARA/EPA-enriched formula (especially those with high EPA content) is associated with a lower risk of LRTI and lower use of asthma medications.

Consumption of differently processed milk products and the risk of asthma in children.

BACKGROUND: Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort. METHODS: We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)-based classifications for milk products. The data were analyzed using a joint model for longitudinal and time-to-event data. RESULTS: At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat-treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat-treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction. CONCLUSIONS: High consumption of infant formula and other strongly heat-treated milk products may be associated with the development of asthma.

Como o marketing de fórmulas lácteas influencia nossas decisões sobre alimentação infantil / How the marketing of formula milk influences our decisions on infant feeding

O marketing faz parte do cotidiano, vivenciado por praticamente todos. No entanto, o marketing de fórmulas lácteas é diferente do marketing de itens de uso diário, como xampu, sapatos ou geladeiras. As práticas alimentares das crianças nos primeiros 3 anos de vida afetam profundamente a sua sobrevivência, saúde e desenvolvimento ao longo da vida. A decisão de como alimentamos nossos bebês e crianças deve, portanto, ser baseada nas melhores informações e evidências verdadeiras, influenciadas apenas pelo que é melhor para a criança e os pais e livre de interesses comerciais. Em 1981, a 34ª Assembleia Mundial da Saúde adotou o Código Internacional de Comercialização de Substitutos do Leite Materno (o Código) para regular a comercialização de substitutos do leite materno. Quarenta anos depois, o marketing de fórmula láctea ainda representa um dos riscos mais subestimados para a saúde de bebês e crianças. Aumentar o aleitamento materno poderia prevenir cerca de 800.000 mortes de crianças menores de 5 anos e 20.000 mortes por câncer de mama entre as mães a cada ano. Apesar do Código e das subsequentes resoluções relevantes da Assembleia Mundial da Saúde, as empresas de fórmula láctea continuam a colocar as vendas e os interesses dos acionistas antes da saúde infantil e da população. Este relatório extrai informações de um grande estudo, encomendado pela Organização Mundial da Saúde e pelo Fundo das Nações Unidas para a Infância, realizado ao longo de dois anos. O estudo buscou ouvir diretamente as mulheres e aqueles que as influenciam ­ profissionais de saúde, parceiros, familiares membros e amigos ­ sobre sua exposição e experiência no marketing de fórmula láctea. Oito países foram incluídos ­ Bangladesh, China, México, Marrocos, Nigéria, África do Sul, Reino Unido da Grã-Bretanha e Irlanda do Norte, e Vietnã ­ representativos de países em suas regiões, mas diversos em seus níveis de renda, taxas de aleitamento materno exclusivo e implementação do Código. O estudo foi realizado em populações urbanas onde as tendências e valores sobre as práticas de alimentação infantil são estabelecidas e disseminadas para outras comunidades. O que emerge desta pesquisa é o quadro mais completo até o momento das experiências de mães e profissionais de saúde no marketing fórmula láctea ­ e é profundamente preocupante.

Effects of Early Weight Gain Velocity, Diet Quality, and Snack Food Access on Toddler Weight Status at 1.5 Years: Follow-Up of a Randomized Controlled Infant Formula Trial.

This study followed children who participated in a feeding trial in which the type of randomized infant formula fed from 2 weeks significantly affected weight gain velocity during the first 4 months and weight-for-length Z (WLZ) scores up to 11.5 months. We focused on measures of anthropometry, dietary intakes, and parenting related to the provision of snack foods that were collected at the end of the trial (1 year) and the 1.5 years follow-up visit. We not only describe what toddlers are eating, but we also determined the independent and/or interactive effects of randomized formula group, early weight gain velocity, the nutrient content of the post-formula diet, and maternal snack food practices, on toddlers' weight status. Diet quality underwent drastic changes during this 6-month period. As infant formula disappeared from the diet, fruit and 100% fruit juice intake increased slightly, while intake of "What We Eat in America" food categories sweetened beverages and snacks and sweets more than doubled. Added sugars accounted for 5% of energy needs at 1 year and 9% at 1.5 years. Generalized linear mixed models revealed that, independent of the randomized formula group, greater velocities of weight gain during early infancy and lower access to snacks as toddlers predicted higher WLZ and a greater proportion of toddlers with overweight at 1.5 years. Energy and added sugar intake had no significant effects. These findings add to the growing body of evidence that unhealthy dietary habits are formed even before formula weaning and that, along with improving early diet, transient rapid weight gain and parental feeding practices are modifiable determinants that may reduce risks for obesity.

Dietary Determinants of Anemia in Children Aged 6-36 Months: A Cross-Sectional Study in Indonesia.

Anemia has been acknowledged as worldwide problem, including in Indonesia. This cross-sectional study aims to explore dietary determinants as risk factors for anemia in children aged 6-36 months living in a poor urban area of Jakarta. The study was done in Kampung Melayu sub-district in Jakarta, Indonesia. Data was collected within two weeks in September-October 2020. A structured questionnaire for a 24-h recall and a semi-quantitative Food Frequency Questionnaire (FFQ) were used to collect the dietary intake data, and venous blood was withdrawn to determine the hemoglobin levels. Bivariate chi-square and multiple logistic regression tests were executed to explore the dietary determinant factors for anemia. We recruited 180 subjects. The average hemoglobin concentration was 11.4 ± 1.7 mg/dL; the anemia prevalence was 29.4%. The following variables were significantly associated with higher risk of anemia: no cow's milk formula consumption, inadequate intake of fats, protein, calcium, vitamin D, iron, zinc, vitamin A, vitamin C, vitamin B6, and vitamin B12. Only cow's milk formula consumption and zinc intake were revealed as the determinant factors of anemia. In conclusion, the prevalence of anemia was 29.4% among children aged 6-36 months old. Anemia was significantly associated with two dietary determinants as risk factors that are cow's milk formula consumption and zinc intake.

Clinical Evaluation of 16-Week Supplementation with 5HMO-Mix in Healthy-Term Human Infants to Determine Tolerability, Safety, and Effect on Growth.

Human milk oligosaccharides (HMOs) are complex sugars that occur naturally in human breast milk and provide many beneficial functions. Most formula products lack HMOs or contain only the most abundant HMO, 2'-fucosyllactose; however, benefits of HMOs come from multiple sugars. We therefore developed a mixture of five HMOs (5HMO-Mix) mimicking the natural concentrations of the top five HMOs (5.75 g/L total, comprising 52% 2'-fucosyllactose, 13% 3-fucosyllactose, 26% lacto-N-tetraose, 4% 3'-sialyllactose, and 5% 6'-sialyllactose) representing the groups of neutral, neutral-fucosylated, and sialylated HMOs. We conducted the first multicenter, randomized, controlled, parallel-group clinical study assessing the safety, tolerability, and effect on growth of formula containing the 5HMO-Mix in healthy infants. We enrolled 341 subjects aged ≤14 days; 225 were randomized into groups fed either with infant formula containing 5HMO-Mix (5HMO-Mix) or infant formula without HMOs (IF) for 4 months, with the others exclusively breastfed. There were no differences in weight, length, or head circumference gain between the two formula groups. The 5HMO-Mix was well tolerated, with 5HMO-Mix and breastfed infants producing softer stools at a higher stool frequency than the control formula group. Adverse events were equivalent in all groups. We conclude that the 5HMO-Mix at 5.75 g/L in infant formula is safe and well tolerated by healthy term infants during the first months of life.

Inappropriate diet and fatal malnutrition in a 10-year-old child fed only infant formula throughout life: Novel pathological diagnostic criterion for starvation via lipophagy.

Fatal starvation is rarely seen in developed countries; when it occurs, it may be associated with medicolegal problems. Forensic pathologists are required to determine leading causes of death and provide opinions on the influence of starvation, especially in cases of suspected child abuse. Recently, starvation-induced steatosis was suggested to be regulated by lipophagy. Here, we report an extremely rare case of death by malnutrition of a 10-year-old boy, who was fed only infant formula throughout his life. The deceased presented with severe hepatic steatosis, probably related to prolonged malnutrition. Fatty liver changes, with deposition of small lipid droplets deposited in the peripheral lobules. High levels of P62 protein (overexpression of which indicates an autophagy impairment) were seen around the central vein region, whereas light-chain-3 (LC3) protein (an indicator of lipophagy activation) was unremarkable. Thus, in our case, impaired lipophagy influenced starvation-induced steatosis. To our knowledge, this article is the first to evaluate the application of lipophagy in forensic investigations as an objective diagnostic criterion.

Long-Term Safety and Efficacy of Prebiotic Enriched Infant Formula-A Randomized Controlled Trial.

The present study aims to evaluate the effects of an infant formula supplemented with a mixture of prebiotic short and long chain inulin-type oligosaccharides on health outcomes, safety and tolerance, as well as on fecal microbiota composition during the first year of life. In a prospective, multicenter, randomized, double-blind study, n = 160 healthy term infants under 4 months of age were randomized to receive either an infant formula enriched with 0.8 g/dL of Orafti®Synergy1 or an unsupplemented control formula until the age of 12 months. Growth, fever (>38 °C) and infections were regularly followed up by a pediatrician. Digestive symptoms, stool consistency as well as crying and sleeping patterns were recorded during one week each study month. Fecal microbiota and immunological biomarkers were determined from a subgroup of infants after 2, 6 and 12 months of life. The intention to treat (ITT) population consisted of n = 149 infants. Both formulae were well tolerated. Mean duration of infections was significantly lower in the prebiotic fed infants (p < 0.05). The prebiotic group showed higher Bifidobacterium counts at month 6 (p = 0.006), and higher proportions of Bifidobacterium in relation to total bacteria at month 2 and 6 (p = 0.042 and p = 0.013, respectively). Stools of infants receiving the prebiotic formula were softer (p < 0.05). Orafti®Synergy1 tended to beneficially impact total daily amount of crying (p = 0.0594). Supplementation with inulin-type prebiotic oligosaccharides during the first year of life beneficially modulates the infant gut microbiota towards higher Bifidobacterium levels at the first 6 months of life, and is associated with reduced duration of infections.

The Impact of Formula Choice for the Management of Pediatric Cow's Milk Allergy on the Occurrence of Other Allergic Manifestations: The Atopic March Cohort Study.

OBJECTIVES: To compare the impact of different formulas on the occurrence of other atopic manifestations and the time of immune tolerance acquisition. STUDY DESIGN: In a 36-month prospective cohort study, the occurrence of other atopic manifestations (eczema, urticaria, asthma, and rhinoconjunctivitis) and the time of immune tolerance acquisition were comparatively evaluated in immunoglobulin E-mediated children with cow's milk allergy (CMA) treated with extensively hydrolyzed casein formula containing the probiotic L. rhamnosus GG (EHCF + LGG), rice hydrolyzed formula, soy formula, extensively hydrolyzed whey formula (EHWF), or amino acid-based formula. RESULTS: In total, 365 subjects were enrolled into the study, 73 per formula cohort. The incidence of atopic manifestations was 0.22 (Bonferroni-corrected 95% CI 0.09-0.34) in the EHCF + LGG cohort; 0.52 (0.37-0.67) in the rice hydrolyzed formula cohort; 0.58 (0.43-0.72) in the soy formula cohort; 0.51 (0.36-0.66) in the EHWF cohort; and 0.77 (0.64-0.89) in the amino acid-based formula cohort. The incidence of atopic manifestations in the rice hydrolyzed formula, soy formula, EHWF, and amino acid-based formula cohorts vs the EHCF + LGG cohort was always greater than the prespecified absolute difference of 0.25 at an alpha-level of 0.0125, with corresponding risk ratios of 2.37 (1.46-3.86, P < .001) for rice hydrolyzed formula vs EHCF + LGG; 2.62 (1.63-4.22, P < .001) for soy formula vs EHCF + LGG; 2.31 (1.42-3.77, P < .001) for EHWF vs EHCF + LGG; and 3.50 (2.23-5.49, P < .001) for amino acid-based formula vs EHCF + LGG. The 36-month immune tolerance acquisition rate was greater in the EHCF + LGG cohort. CONCLUSIONS: The use of EHCF + LGG for CMA treatment is associated with lower incidence of atopic manifestations and greater rate of immune tolerance acquisition.