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Introducing formula to infants at risk for allergic disease

Introducing formula to infants at risk for allergic disease
Literature review current through: Jan 2024.
This topic last updated: Jul 24, 2023.

INTRODUCTION — The term "allergy" refers to a hypersensitivity reaction initiated by immunologic mechanisms. Three factors are needed to develop allergic disease: the appropriate genetic background, contact with the allergen(s), and environmental factors, such as timing, amount, and frequency of exposure.

The most prevalent allergic or atopic disorders include atopic dermatitis (AD), asthma, allergic rhinitis (AR), and food allergies. These conditions afflict 20 percent of the population of the United States, and their prevalence appears to be increasing in developed nations. The increase in atopic diseases has been recognized as a pandemic, thus emphasizing the need for effective allergy prevention [1].

Convincing studies support the existence of a critical time early in infancy during which the genetically predisposed atopic infant is at higher risk for becoming sensitized [2]. Thus, dietary interventions in the first year of life have been analyzed for their effects on the prevalence of allergic disease [3].

Studies examining the associations between the use of various infant formulas and the development of allergic diseases in infants at high risk for atopic conditions are discussed in this topic review. Associations between early or delayed introduction of complementary foods and the development of atopy are reviewed separately, as are other aspects of the primary prevention of allergic disease. (See "Primary prevention of allergic disease: Maternal diet in pregnancy and lactation" and "The impact of breastfeeding on the development of allergic disease" and "Introducing highly allergenic foods to infants and children".)

OVERVIEW — The definition of an infant at high risk for developing allergic disease is reviewed here, as are the different formulas available for infants.

Infants at high risk for developing allergy — An infant is defined as "high risk" for developing allergic disease if there is at least one first-degree relative (parent or sibling) with a documented allergic condition: atopic dermatitis (AD), asthma, allergic rhinitis (AR), or food allergy [4]. This definition is based upon a consensus among several committees representing the American Academy of Pediatrics (AAP), the joint guidelines of the European Society for Pediatric Allergology and Clinical Immunology (ESPACI), and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) [5,6].

Infants who have already developed atopic diseases such as AD and/or hen's egg allergy are also at increased risk of developing additional allergic disease such as asthma or other food allergies [7].

Types of formulas — The types of formula available include the following:

Conventional cow's milk (CM) formulas

Partial whey hydrolysate formulas (pHF-W)

Partial casein/whey hydrolysate formulas

Extensive casein or whey hydrolysate formulas (eHF-C or eHF-W)

Soy protein-based formulas

Amino acid-based formulas

Other mammalian milks, such as goat's milk, are allergenically very similar to CM, and other plant-based milks such as almond milk or rice milk are very low in protein and fat compared with CM. Thus, these are not suitable alternatives to CM-based formulas for infants not exclusively breastfed for the first four to six months of life. (See "Food allergens: Clinical aspects of cross-reactivity", section on 'Cow's milk' and "Management of food allergy: Nutritional issues", section on 'Cow's milk allergy'.)

Protein hydrolysates are termed "partial" or "extensive," depending on the degree of hydrolysis and ultrafiltration. Allergenicity decreases as the extent of hydrolysis and filtration increases. In the United States and Canada, formulas are considered hypoallergenic if they have demonstrated with 95 percent confidence that at least 90 percent of infants with documented cow's milk allergy (CMA) will not react with defined symptoms to the formula under double-blind, placebo-controlled conditions [8].

The partially hydrolyzed formulas (pHFs) available in the US, Good Start (pHF-W), Good Start Gentlease (partial casein/whey hydrolysate), and Total Comfort (partial casein/whey hydrolysate), are not considered hypoallergenic, as they contain significantly large peptides that can induce an allergic response in patients with CMA. In one study, pHF (pHF-W) caused allergic reactions in approximately 50 percent of CMA infants [2].

Three casein-based extensively hydrolyzed formulas (eHFs) are available in the US, Alimentum, Nutramigen, and Pregestimil, and they are considered hypoallergenic because they contain peptides that are sufficiently small that at least 90 percent of children with CMA will tolerate them [9].

Amino acid-based formulas, such as Neocate, EleCare, and Puramino (formerly called NutramigenAA), are the formulas considered closest to being nonallergenic. They have been approved for use in children who still react to eHFs and are an excellent source of nutrition for highly allergic children. Their disadvantages are high cost and low palatability.

FORMULA SELECTION FOR THE HIGH-RISK INFANT — Human milk is the optimal source of nutrition for term infants during the first four to six months of life [6]. There is no evidence to support administration of hydrolyzed formula, soy formula, or one particular formula over another in preference to exclusive breastfeeding to prevent atopic disease in high-risk infants [10], although observational data show an inverse association between early exposure to conventional cow's milk (CM) formula (exclusive or as a daily supplement to breastfeeding) and development of cow's milk allergy (CMA) [11-13]. The quality of data are low and inconsistent with regard to the use of hypoallergenic formula for the prevention of allergic disease in high-risk infants. Some individual studies have suggested that using a hydrolyzed formula rather than a conventional CM formula for high-risk infants who cannot be exclusively breastfed for the first four to six months of life has a protective effect for prevention of eczema. However, a 2016 meta-analysis that examined use of conventional and hydrolyzed CM formulas in high-risk infants found limited efficacy with regard to prevention of atopic disease for most measures [14], while a 2017 meta-analysis examining only the effect of a specific partial whey hydrolysate formula (pHF-W) formula compared with CM formula found a decreased risk of eczema in high-risk infants at certain ages [15]. Amino acid-based formulas have not yet been studied in the primary prevention of allergy.

In 2019, the American Academy of Pediatrics (AAP) updated their clinical report on nutritional interventions and the development of atopic disease in infants and children to state that there is a lack of evidence that a pHF or an extensively hydrolyzed formula (eHF) prevents atopic disease in infants and children, even in those at high risk for allergic disease [6]. The European Academy of Allergy and Clinical Immunology (EAACI) food allergy prevention guidelines were updated in 2020 and state that there is no consistent evidence that hydrolyzed formulas reduce the risk of food allergy [16]. A 2021 joint consensus report that included the American Academy of Allergy, Asthma, and Immunology (AAAAI); the American College of Allergy, Asthma, and Immunology (ACAAI); and the Canadian Society for Allergy and Clinical Immunology (CSACI) also concluded that there is no protective benefit for preventing food allergy or food sensitization by using a hydrolyzed formula [17]. The Australasia Society of Clinical Immunology and Allergy (ASCIA) no longer recommends a pHF or eHF over a conventional CM formula for the prevention of atopic disease [18].

This section reviews the data on the role of various infant formulas in the prevention of allergic diseases in high-risk infants [4,10]. For infants who are not at increased risk for atopy, there is no conclusive evidence that one formula provides any advantage over another. Formula selection for infants with CMA is discussed separately. (See "Milk allergy: Management" and "Management of food allergy: Nutritional issues".)

Breastfeeding versus hydrolyzed formulas — Human milk is the optimal source of nutrition for term infants during the first four to six months of life [19]. However, parents may occasionally inquire about the use of a hydrolyzed formula in preference to breast milk for the prevention of allergic disease. A 2018 systematic review determined that there were no eligible long-term studies comparing prolonged use of hydrolyzed formulas with breastfeeding [20]. Therefore, there are no data directly addressing this issue.

The only studies comparing hydrolyzed formulas with breast milk examined early- and short-term exposure to hydrolyzed formula, which did not appear to have any impact on the development of allergic disease [20]. Two studies compared feeding with hydrolyzed formula or human milk during the first three days of life or while in the hospital. One followed 129 infants for signs of any allergic disease up to age 24 months [21], and the other followed 3559 infants for the development of CMA up to a mean age of 27 months [22]. Neither reported a significant difference in the rates of allergic disease.

Studies examining the effects of breastfeeding on allergic disease are reviewed separately. (See "The impact of breastfeeding on the development of allergic disease" and "Infant benefits of breastfeeding".)

Studies comparing different formulas — Studies have examined the potential of various infant formulas to reduce the risk of atopic disease when used as a supplement or substitute for breast milk. There are a number of limitations with the available data, including a wide variation in study design and criteria for diagnosis of atopic diseases, as well as publication and methodologic biases [23].

Cow's milk formula versus partially hydrolyzed formula — Most individual studies comparing the effects of pHF-W and CM formulas on the prevention of allergy have suggested a preventive effect of pHFs, primarily on eczema development [24-28]. However, several later studies did not find a protective effect [29,30], and three meta-analyses from 2016 to 2018 are conflicting, with two showing no benefit and one showing benefit of a particular pHF-W over CM formula [14,15,20]. Confounding these multiple analyses are the changes in formula preparation and addition of supplements over the last several decades, as well as study limitations such as reverse causality. Thus, the available evidence does not support choosing a pHF over a CM formula for prevention of atopic disease in high-risk infants who are not able to exclusively breastfeed for the first four to six months of life.

A 2010 meta-analysis of formula consumption and risk of atopic dermatitis (AD) found that infants who were fed pHF had a lower risk of AD than those fed CM formula (summary relative risk estimate [SRRE] 0.45, 95% CI 0.4-0.7) [24]. An overall reduced risk in any atopic manifestation, which included AD, was also seen in infants fed pHF versus CM formula (SRRE 0.56, 95% CI 0.3-0.7). This meta-analysis did not include several trials with negative findings [29,30], however.

A 2016 meta-analysis of studies comparing pHFs with CM formula found no difference between the two formula groups with regard to the risk of eczema, recurrent wheeze, or food allergy up to 14 years of age and allergic rhinitis (AR) from 5 to 14 years of age [14]. They did find a significantly reduced risk of AR at zero to four years of age in the group fed pHFs, but there were methodologic concerns with the study that dominated this part of the meta-analysis.

A 2017 meta-analysis of the use of one specific type of pHF-W as an alternative to CM formula in high-risk infants found a reduced risk of allergy, particularly eczema, in certain age groups (zero to three years [three randomized, controlled trials (RCTs), n = 1000, relative risk (RR) 0.82, 95% CI 0.68-1.00] and zero to five to six years [two RCTs, n = 938, RR 0.83, 95% CI 0.69-0.99]). Using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis, the overall quality of the data was moderate to very low [15].

A 2018 meta-analysis of 12 studies that compared prolonged infant feeding with a hydrolyzed formula or a CM formula found no difference in all allergic diseases (asthma, eczema, rhinitis, food allergy) in infants (RR 0.88, 95% CI 0.76-1.01) and children (RR 0.85, 95% CI 0.69-1.05) or any specific allergic disease, including infant asthma (RR 0.57, 95% CI 0.31-1.04), eczema (RR 0.93, 95% CI 0.79-1.09), rhinitis (RR 0.52, 95% CI 0.14-1.85), food allergy (RR 1.42, 95% CI 0.87-2.33), and CMA (RR 2.31, 95% CI 0.24-21.97) [20].

Cow's milk formula versus extensively hydrolyzed formula — A 2016 meta-analysis comparing eHFs with conventional CM formula found no difference between the formula groups with regard to the risk of food allergy, AR, or recurrent wheezing [14]. A decreased risk of eczema was seen at 5 to 14 years of age, but not 0 to 4 years of age, in children fed a casein-based eHF during infancy, and no difference was seen in either age group on a whey-based eHF during infancy.

Partially hydrolyzed formula versus extensively hydrolyzed formula — Prolonged feeding of high-risk infants with a pHF or an extensively hydrolyzed casein formula (eHF-C)/extensively hydrolyzed whey formula (eHF-W) has been compared [31-33]. Pooled analysis of two of these studies, with a total of 352 infants, found no significant difference in the incidence of infant allergy, asthma, or food allergy [31,32]. Other studies have identified differences between feeding with pHFs and eHFs, including the German Infant Nutritional Intervention Study (GINI study), particular for eczema/AD [28,34-36]. A 2016 meta-analysis comparing pHF and eHF found no difference in the risk of eczema, recurrent wheeze, AR, or food allergy (specifically hen's egg) at 0 to 4 and 5 to 14 years of age.

The GINI study followed 945 high-risk newborn infants in a randomized trial investigating the effects of breastfeeding supplemented with different formulas (conventional CM formula, pHF-W, eHF-W, or eHF-C) in the first four months of life [34,37]. Mothers were encouraged to breastfeed exclusively for four months, although approximately two-thirds in each formula group introduced study formula during the first 30 days of life. This study found that hydrolyzed formulas (especially eHF-C), compared with conventional CM formulas, have the potential to reduce the risk of atopic disease when used as a supplement or substitute to breast milk during the first four months of life. A significant criticism of the GINI study, however, is that the significant findings above for three and six years of age were only seen in the per-protocol analysis, whereby infants were excluded if they had not received the assigned formula within the first four months of life, and not the intention to treat (ITT) analysis. Results from the 10-year and 11 to 15 years of age time points were from ITT analyses.

The following findings were reported [28,34-36]:

Clinician diagnosis of any allergic disease (food allergy, allergic urticaria, asthma, and AR) was significantly lower in the eHF-C and pHF-W groups at 3, 6, and 10 years of age (eHF-C: odds ratio [OR] 0.76, 95% CI 0.63-0.93; OR 0.80, 95% CI 0.69-0.93; and OR 0.83, 95% CI 0.72-0.95, respectively; pHF-W: OR 0.78, 95% CI 0.64-0.95; OR 0.82, 95% CI 0.70-0.96; and OR 0.87, 95% CI 0.77-0.99, respectively). However, rates of allergic manifestations other than AD were not affected at these ages.

Compared with conventional CM formula, rates of AD were lower for eHF-C at 3, 6, and 10 years of age (OR 0.69, 95% CI 0.54-0.88; OR 0.71, 95% CI 0.58-0.88; and OR 0.72, 95% CI 0.58-0.88, respectively) and between 11 to 15 years of age (OR 0.42, 95% CI 0.23–0.79). Similar findings were seen with pHF-W at three and six years of age only (OR 0.77, 95% CI 0.61-0.98 and OR 0.79, 95% CI 0.64-0.97, respectively) but not with eHF-W.

Asthma prevalence was lower in the eHF-C group between 11 and 15 years of age (OR 0.49, 95% CI 0.26-0.89), and AR prevalence was also lower in this age group for both pHF-W and eHF-C (OR 0.67, 95% CI 0.47-0.95 and OR 0.59, 95% CI 0.41-0.84, respectively). This difference was not seen at the other time points measured.

Compliance with eHF-C formula was the lowest of all the groups (18 percent stopped using eHF-C compared with 10 to 12 percent in the other groups).

Soy formula versus others — Soy formulas are widely used for feeding infants allergic to CM. However, feeding with a soy formula does not appear to have any greater benefit than other formulas in preventing atopy in high-risk infants.

A meta-analysis in high-risk infants without clinical evidence of allergy was performed to determine whether the use of a soy formula, compared with breast milk, a CM formula, or a hydrolyzed formula, in the first six months was effective in preventing allergy [38]. Five randomized or quasi-randomized eligible studies met set criteria. All studies compared the use of soy formula with a CM formula, and two studies also included a group fed a hydrolyzed formula, but no studies enrolled breastfed infants. Only one study with approximately 20 percent losses to follow-up reported a reduction in cumulative incidence of childhood allergy, asthma, and AR with the use of a soy formula compared with a CM formula. Analysis showed no significant difference in cumulative incidence of infant allergy (one study) or childhood allergy (three studies).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)

SUMMARY AND RECOMMENDATIONS

Human milk is the optimal source of nutrition for all term infants during the first four to six months of life, regardless of their risk for allergic disease. (See "Infant benefits of breastfeeding".)

In most research protocols, an infant is defined as "high risk" for developing allergic disease if there is at least one first-degree relative (parent or sibling) with a documented allergic condition (atopic dermatitis [AD], asthma, allergic rhinitis [AR], or food allergy). (See 'Infants at high risk for developing allergy' above.)

The available evidence is inconsistent and does not support choosing any one particular type of formula (cow's milk [CM], soy, partially hydrolyzed, or extensively hydrolyzed) over another for prevention of atopic disease in high-risk infants who are not able to exclusively breastfeed for the first four to six months of life. (See 'Formula selection for the high-risk infant' above.)

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