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Text of review

Synopsis

Infant formulas have been designed to try to lower the chances of developing allergy or food intolerance. These include hydrolysed cow's and soy milk formulas. Hydrolysed formulas break down the milk proteins into smaller, potentially less allergy producing proteins. The review of trials found that there is no evidence to support feeding with a hydrolysed formula to prevent allergy in preference to exclusive breastfeeding. In infants at high risk for allergy who are unable to be completely breastfed, there is limited evidence that feeding with a hydrolysed formula compared to a cow's milk formula reduces allergies in babies and children, including cow's milk allergy. Concerns regarding quality of the evidence and consistency of the results indicates further studies are needed.
 

Abstract

Background

Objectives

Search strategy

Selection criteria

Data collection & analysis

Main results

Ten eligible studies compared prolonged feeding with hydrolysed formula versus cow's milk formula in high risk infants. Meta-analysis found a significant reduction in infant allergy (seven studies, 2514 infants; typical RR 0.79, 95% CI 0.66, 0.94), but not in the incidence of childhood allergy (two studies, 950 infants; typical RR 0.85, 95% CI 0.69, 1.05). There was no significant difference in infant eczema (eight studies, 2558 infants, typical RR 0.84, 95% CI 0.68, 1.04), childhood eczema incidence (two studies, 950 infants, typical RR 0.83, 95% CI 0.63, 1.10), childhood eczema prevalence (one study, 872 infants; RR 0.66, 95% CI 0.43, 1.02), or infant or childhood asthma, rhinitis and food allergy. One study reported a significant reduction in infants with CMA with confirmed atopy (RR 0.36, 95% CI 0.15, 0.89). Subgroup analysis of trials blinded to formula found no significant difference in infant allergy (four studies, 2156 infants; typical RR 0.87, 95% CI 0.69, 1.08) or childhood allergy incidence (one study, 872 infants; RR 0.91, 95% CI 0.73, 1.14). No eligible trial examined the effect of prolonged hydrolysed formula feeding on allergy beyond early childhood. There is evidence that preterm or low birthweight infants fed a hydrolysed preterm formula have significantly reduced weight gain, but not in other growth parameters (head circumference or length). Studies in term infants report no adverse effects on growth.

Subgroup analysis of trials of partially hydrolysed versus cow's milk formula found a significant reduction in infant allergy (six studies, 1391 infants; typical RR 0.79, 95% CI 0.65, 0.97) but not childhood allergy, or infant or childhood asthma, eczema or rhinitis. Methodological concerns were the same as for the overall analysis. Analysis of trials of extensively hydrolysed formula versus cow's milk formula found no significant differences in allergy or food intolerance. Infants fed extensively hydrolysed formula compared with partially hydrolysed formula had a significant reduction in food allergy (two studies, 341 infants; typical RR 0.43, 95% CI 0.19, 0.99), but there was no significant difference in all allergy or any other specific allergy incidence. Comparing extensively hydrolysed casein containing formula with cow's milk formula, one study (431 infants) reported a significant reduction in childhood allergy incidence (RR 0.72, 95% CI 0.53, 0.97). Meta-analysis found a significant reduction in infant eczema (three studies, 1237 infants; typical RR 0.71, 95% CI 0.51, 0.97). One study reported a significant reduction in childhood eczema incidence (RR 0.66, 95% CI 0.44, 0.98) and prevalence (RR 0.50, 95% CI 0.27, 0.92).
 

Reviewers' conclusions

Background

Many infants with atopy do not have a family history of atopy (Bergmann 1994; Sears 1996; Tariq 1998). However, the risk of atopy is increased to about one in three if one first-degree relative (parent or sibling) is atopic, and 70% if both parents are atopic (Bergmann 1994; Bergmann 1998; Ronmark 2001; Sears 1996; Tariq 1998). The predictive value of family history is increased with the addition of cord blood IgE antibody testing, although its accuracy may not be adequate for population screening (Bergmann 1997; Bergmann 1998; Tariq 1998). An increased duration of exclusive breast feeding has been associated with a reduced incidence of childhood allergy (Gruskay 1982; Oddy 1999; Saarinen 1995; Saarinen 2000), although not all studies support this association particularly with adult allergy (Sears 2002; Wright 2001). However, many infants are not exclusively breast fed (UNICEF). As a result, infants may receive either short or long term supplementary or sole feeding with an infant formula (usually adapted cow's milk or soy milk), or be weaned from the breast to formula.

The term 'food intolerance' does not imply a specific mechanism but is defined as a reproducible adverse reaction to a specific food or food ingredient. Mechanisms for food intolerance may comprise enzyme defects, pharmacological effects, irritant effects, and toxic reactions (David 2000; Host 1994; Host 1995). Food intolerance is diagnosed by resolution of typical symptoms with elimination from the diet, with confirmation by blinded challenge. Around 2 - 3% of babies develop an intolerance to a particular food. The principle symptoms in infants with proven cow's milk protein intolerance (CMPI) are gastrointestinal (~ 50%), dermatological (~ 31%) and respiratory (~ 19%) (Host 1994; Host 1995; Schrander 1993). Two in every three infants with CMPI have a family history of atopy (Schrander 1993). CMPI is strongly associated with feeding an adapted cow's milk formula to infants in the first month of life (Host 1991). Many infants with CMPI become tolerant over time with approximately 30% at one year, 50% at two years and 70% at three years tolerant to cow's milk challenge. The risk of persisting intolerance is increased with evidence of atopy (Host 1995; Carroccio 2000b).

A diagnosis of allergy may be made either by questionnaire, clinician assessment and confirmed by specific skin or serological testing, or by allergen challenge. The diagnostic criteria for different atopic conditions are not uniform and the mode of ascertainment of atopy is variable. Although tests of bronchial hyperresponsiveness, challenge tests and classical tests of IgE mediated hypersensitivity have an imperfect correlation with allergy symptoms and clinical signs (Darsow 2000; Peat 2000), they are associated with an increased likelihood of allergy and significant disease (Ronmark 2001; Sears 1998; Sly 1999; Strachan 1996). In addition, there is some evidence that questionnaires, although compromised by selection and recall bias (Peat 2001), are suitable for allergy screening (Kilpelainen 2001; Ravault 2001). This review includes trials that diagnose allergy either by questionnaire or clinician assessment, with or without confirmation by laboratory testing.

Measures to prevent allergy and food intolerance have included maternal allergen avoidance during pregnancy (Custovic 2000; Kramer 2001; Zeiger 1989) and/or lactation (Custovic 2000; Zeiger 1989), periods of exclusive breast feeding (Custovic 2000; Gruskay 1982; Oddy 1999; Saarinen 1995; Saarinen 2000), and avoidance of potential allergens including food and environment antigens in the first year of life and beyond (Custovic 2000). Formulas prescribed to infants with the intention of preventing allergy and food intolerance include hydrolysed cow's milk, elemental formulas, and adapted soy or hydrolysed soy formulas. Hydrolysed formulas are designed to change the allergenic milk protein with the aim of preventing sensitisation or intolerance. They may be produced from cow's milk or soy milk, be derived from predominately whey or casein proteins and be partially or extensively hydrolysed. The aim of this review is to determine the evidence for the use of hydrolysed infant formulas for prevention of allergy and food intolerance. This review does not include treatment of infants with clinically recognised allergy or food intolerance.
 

Objectives

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

• Hydrolysed cow's milk and soy formulas
• Extensively and partially hydrolysed formulas

Hydrolysed formulas may be used for either:

• Early, short term supplementary or sole formula feeding in infants unable to be exclusively breast fed in the first days of life
• Prolonged supplementation of breast fed infants or sole formula feeding in infants in the first months of life
• Weaning from the breast using infant formula

The control group may include infants who receive:

• Exclusive human milk (either breast fed or expressed)
• An adapted cow's milk formula

The following comparisons were prespecified:
1. Early short term hydrolysed formula versus human milk.
2. Prolonged use of a hydrolysed formula versus human milk.
3. Early short term hydrolysed formula versus cow's milk formula.
4. Prolonged use of a hydrolysed formula versus cow's milk formula.

Subgroup analyses included (see methods for definitions):
1. According to infant risk of allergy or food intolerance:

• Low risk infants (no family history allergy or food intolerance in 1^st degree relatives);
• High risk infants (family history allergy or food intolerance in 1^st degree relatives or high cord IgE level).

2. According to extent of protein hydrolysis:

• Extensively hydrolysed formula versus cow's milk formula;
• Partially hydrolysed formula versus cow's milk formula;
• Extensively hydrolysed formula versus partially hydrolysed formula.

3. According to indication for use:

• Prolonged sole formula feeding,
• Supplemental feeding or for weaning from the breast using infant formula.

4. According to method of ascertainment of allergy:

• Allergy / food intolerance confirmed by test.
• Blinded measurement for allergy or food intolerance.

5. According to type of protein hydrolysate used:

• Partially hydrolysed whey formula versus cow's milk formula.
• Partially hydrolysed casein formula versus cow's milk formula.
• Extensively hydrolysed whey formula versus cow's milk formula.
• Extensively hydrolysed casein formula versus cow's milk formula.
• Hydrolysed soy formula versus cow's milk formula.

Studies that included other allergy prevention interventions (e.g. maternal dietary avoidance measures, environmental allergy reduction measures) in the treatment and not the control group were excluded. Studies that had other allergy prevention interventions in both treatment and control groups were eligible.
 

Types of outcome measures

• All allergy including asthma, atopic dermatitis, allergic rhinitis or food allergy
• Food intolerance

Secondary outcomes:

• Asthma
• Atopic dermatitis / eczema
• Allergic rhinitis
• Cow's milk or soy protein intolerance
• Cow's milk or soy protein allergy
• Food allergy
• Food intolerance
• Urticaria
• Anaphylaxis

Potential harms:

• Growth parameters including head circumference and weight gain
• Cost
• Infant feed refusal

A specific allergy or food intolerance may be diagnosed on the basis of:

• History of recurrent and persistent symptoms typical of the allergy or food intolerance
• Clinician diagnosis of allergy or food intolerance
• Clinical allergy and food intolerance confirmed by testing includes detection of allergen sensitisation by either skin testing or serological testing for specific IgE (e.g. RAST or EAST), asthma confirmed by respiratory function testing for presence of bronchial hyperresponsiveness and food intolerance confirmed by elimination/challenge.

The following definitions of age of allergy were used:

• Infant allergy incidence: allergy occurring up to two years of age.
• Childhood allergy incidence: allergy occurring up to 10 years of age (or up to age of latest report between two and 10 years).
• Childhood allergy prevalence: allergy reported that was present between two and 10 years of age.
• Adolescent allergy: allergy present from 10 to 18 years age.
• Adult allergy: allergy present after 18 years age.

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003), MEDLINE (1966 - January 2003), EMBASE (1980 - January 2003) and CINAHL (1982 - January 2003) and previous reviews including cross references (all articles referenced), previous reviews including cross references, abstracts, conferences (Pediatric Academic Societies 1998-2002 and Perinatal Society of Australia and New Zealand 1998-2003), and journal hand searching mainly in the English language.

The search was updated March 2006 with additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006), MEDLINE (1966 - March 2006), EMBASE (1980 - March 2006) and CINAHL (1982 - March 2006) and previous reviews including cross references (all articles referenced), previous reviews including cross references, abstracts, conferences (Pediatric Academic Societies 2003 - 2005 and Perinatal Society of Australia and New Zealand 2004 - 2005).

The search strategy included the following keywords, using the search fields of abstract, MeSH subject headings, exploded subject heading, publication type, subject heading word, text word, and title: A search on all fields for [infant* OR newborn* OR neonat* OR pediatric* OR paediatric*] AND [feed* OR food OR formula* OR hydrolysed* OR allergies OR diet* OR protein OR milk*] was conducted. The search was limited to: [random* OR trial* OR comparative study OR controlled study].
 

Methods of the review

Eligibility of studies for inclusion were assessed independently by each review author. Only studies with > = 80% reporting of randomised infants were included. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the trials included was evaluated regarding adequacy of randomisation and allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals. A data collection form was used to aid extraction of relevant information and data from each included study. Each review author extracted the data separately. Data were compared and differences resolved by consensus. The standard methods of the Neonatal Review Group were used to synthesise the data. Effects are expressed as relative risk (RR), risk difference (RD) and 95% confidence intervals (CI) for categorical data, and weighted mean difference (WMD) and 95% CI for continuous data. Data were examined for heterogeneity using the chi-square test for heterogeneity. Heterogeneity was quantified using the I² statistic. The fixed effect model was used for meta-analysis where enrolled infants and interventions were similar and no significant heterogeneity was found. Sources of heterogeneity were explored in subgroup analysis.

Where the term 'hydrolysed formula' is used without a reference to type, this refers to both extensively and partially hydrolysed formulas. Studies that used hydrolysed formula for early (first few days of life) supplemental or sole infant feeding were not pooled with studies that used hydrolysed formula for prolonged feeding. All comparisons were performed including only studies with no different co-interventions prescribed for the prevention of allergy in either study arm (e.g. in treatment and not control group). Allergy preventing co-interventions included modifications to mothers diet when pregnant or breast feeding, or environmental modifications such as avoidance of pet hair and host dust mite reduction measures. Restricting analyses to studies with no differential co-interventions was not originally prespecified in the protocol.

Subgroup analyses were performed according to:
1. Infant risk of allergy or food intolerance: low risk infants (no family history allergy or food intolerance in 1st degree relatives); high risk infants (family history allergy or food intolerance in 1st degree relatives or high cord blood IgE level).

2. Extent of protein hydrolysis: extensively hydrolysed formula versus cow's milk formula; partially hydrolysed formula versus cow's milk formula; extensively hydrolysed formula versus partially hydrolysed formula. An extensively hydrolysed formula should meet the definition provided by the AAP Committee on Nutrition (AAP 2000) - the extensively hydrolysed proteins derived from cow's milk in which most of the nitrogen is in the form of free amino acids and peptides ≤ 1500 kDaltons, and should, at a minimum, ensure with 95% confidence that 90% of infants with documented CMA will not react with defined symptoms to the formula under double-blind, placebo-controlled conditions.

3. Indication for use: prolonged sole formula feeding; supplemental formula feeding or weaning from the breast using infant formula.

4. Method of ascertainment of allergy or food intolerance: Clinical allergy confirmed by challenge testing or testing for atopy (e.g. skin testing or serological testing for specific IgE, asthma confirmed by testing for presence of bronchial hyperresponsiveness and food intolerance confirmed by elimination/challenge). Included in this definition is clinical allergy in a patient where atopy has been confirmed by testing (e.g. asthma where atopy has been confirmed by skin prick testing or RAST for specific IgE); blinded measurement for allergy or food intolerance - where measurement of outcome blinded to treatment allocation (this analysis was not prespecified).

5. Type of protein hydrolysate used: partially hydrolysed whey formula versus cow's milk formula; partially hydrolysed casein formula versus cow's milk formula; extensively hydrolysed whey formula versus cow's milk formula; extensively hydrolysed casein formula versus cow's milk formula; hydrolysed soy formula versus cow's milk formula.

Sensitivity analysis was performed for studies of adequate methodology defined as adequate randomisation and allocation concealment, and < 10% losses to follow up.
 

Description of studies

Types of infants enrolled:

• High risk: most studies (Chirico 1997; de Seta 1994; Halken 2000; Lam 1992; Mallet 1992; Marini 1996; Nentwich 2001; Oldaeus 1997; Tsai 1991; Vandenplas 1992; von Berg 2003; Willems 1993) enrolled infants at high risk of allergy on the basis of either a history of allergy in a first degree relative and/or a high cord IgE level. Lam 1992 did not report 'high risk' criteria.
• Risk not specified: studies that did not enrol infants on basis of perceived risk of allergy included: Juvonen 1996 enrolled healthy term infants although 62% had a family history of allergy; Maggio 2005 enrolled preterm infants &le; 1750g and &le; 34 weeks; Picaud 2001 enrolled infants < 1500g, &le; 15 days; Saarinen 1999 enrolled healthy term infants requiring supplemental feeding in hospital; Szajewska 2001 enrolled low birthweight infants (< 2000g) with tolerance of full enteral feeds.
• Low risk: Vandenplas 1993 enrolled healthy term infants and excluded infants with a family history of allergy.

Types of interventions:
See 'Table of Included Studies' for types of formula used in each study.

1. EARLY SHORT TERM FEEDING OF HYDROLYSED FORMULA VERSUS HUMAN MILK FEEDING
Two studies (Juvonen 1996; Saarinen 1999) compared a hydrolysed formula with pasteurised donor human milk used for early infant feeding. Juvonen 1996 gave sole bottle feeds for three days then all infants were exclusively breast fed. Saarinen 1999 gave supplemental feeds when required while infants were in hospital (average four days). Mothers were then encouraged to breast feed.

2. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS HUMAN MILK FEEDING
No study was found that compared prolonged hydrolysed formula feeding with human milk feeding (either breast or expressed).

3. EARLY SHORT TERM FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Two studies (Juvonen 1996; Saarinen 1999) compared a hydrolysed formula with an adapted cow's milk formula. Juvonen 1996 gave sole bottle feeds for three days then all infants were exclusively breast fed. Saarinen 1999 gave supplemental feeds when required while infants were in hospital (average four days). Mothers were then encouraged to breast feed.

4 PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Prolonged supplemental or sole feeding with a hydrolysed formula versus an adapted cow's milk formula without differential co-interventions was reported by 14 studies (Chirico 1997; de Seta 1994; Lam 1992; Maggio 2005; Mallet 1992; Marini 1996; Oldaeus 1997; Picaud 2001; Szajewska 2001; Tsai 1991; Vandenplas 1992; Vandenplas 1993; von Berg 2003; Willems 1993). Three studies (Chirico 1997; Marini 1996; Oldaeus 1997) reported additional allergy avoidance measures in both the hydrolysed formula and adapted cow's milk formula groups.

5. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - LOW RISK INFANTS
One study (Vandenplas 1993) compared prolonged feeding with a hydrolysed formula with cow's milk formula in low risk infants but only reported infant growth.

6. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - HIGH RISK INFANTS
Ten studies (Chirico 1997; de Seta 1994; Lam 1992; Mallet 1992; Marini 1996; Oldaeus 1997; Tsai 1991; Vandenplas 1992; von Berg 2003; Willems 1993) compared prolonged feeding with a hydrolysed formula and a cow's milk formula in high risk infants.

7. PROLONGED FEEDING OF EXTENSIVELY HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Three studies ( Mallet 1992; Oldaeus 1997; Szajewska 2001) compared prolonged feeding with an extensively hydrolysed formula with an adapted cow's milk formula.

8. PROLONGED FEEDING OF PARTIALLY HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Twelve studies (Chirico 1997; de Seta 1994; Lam 1992; Marini 1996; Oldaeus 1997; Picaud 2001; Szajewska 2001; Tsai 1991; Vandenplas 1992; Vandenplas 1993; von Berg 2003; Willems 1993) compared prolonged feeding with a partially hydrolysed formula with an adapted cow's milk formula.

9. PROLONGED FEEDING OF EXTENSIVELY HYDROLYSED FORMULA VERSUS PARTIALLY HYDROLYSED FORMULA
Four studies (Halken 2000; Nentwich 2001; Oldaeus 1997; Szajewska 2001) compared prolonged feeding with extensively hydrolysed formula with a partially hydrolysed formula.

10. PROLONGED SOLE FORMULA FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Prolonged sole formula feeding was reported by 10 studies (Chirico 1997; de Seta 1994; Lam 1992; Maggio 2005; Marini 1996; Picaud 2001; Szajewska 2001; Vandenplas 1992; Vandenplas 1993; Willems 1993) with six studies reporting allergy (Chirico 1997; de Seta 1994; Lam 1992; Marini 1996; Vandenplas 1993; Willems 1993).

11. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - ALLERGY / FOOD INTOLERANCE CONFIRMED BY TEST
Three studies confirmed atopy or food intolerance in patients with clinical allergy by testing (Chirico 1997; Oldaeus 1997; Vandenplas 1992).

12. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - BLINDED MEASUREMENT
Assessment for allergy without knowledge of patient allocation was reported by 11 studies (Halken 2000; Nentwich 2001; Oldaeus 1997; Saarinen 1999; Vandenplas 1992; Vandenplas 1993; von Berg 2003; Willems 1993).

13. PROLONGED FEEDING OF HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - STUDIES OF ADEQUATE METHODOLOGY
Maggio 2005; Oldaeus 1997; Szajewska 2001 and Tsai 1991 studied prolonged feeding of a hydrolysed formula compared to an adapted cow's milk formula with no co-interventions and are included in the sensitivity analysis of studies of adequate methodology (adequate randomisation and allocation concealment and < 10% losses to follow up).

14. PROLONGED FEEDING OF PARTIALLY HYDROLYSED WHEY FORMULA VERSUS COW'S MILK FORMULA
Ten studies (Chirico 1997; de Seta 1994; Lam 1992; Maggio 2005; Marini 1996; Picaud 2001; Tsai 1991; Vandenplas 1992; Vandenplas 1993; von Berg 2003) compared a partially hydrolysed whey formula to an adapted cow's milk formula.

15. PROLONGED FEEDING OF PARTIALLY HYDROLYSED CASEIN FORMULA CONTAINING FORMULA VERSUS COW'S MILK FORMULA
Two studies (Oldaeus 1997; Szajewska 2001) compared a partially hydrolysed formula containing casein to an adapted cow's milk formula.

16. PROLONGED FEEDING OF EXTENSIVELY HYDROLYSED WHEY FORMULA VERSUS COW'S MILK FORMULA
One study (von Berg 2003) compared an extensively hydrolysed whey formula to an adapted cow's milk formula.

17. PROLONGED FEEDING OF EXTENSIVELY HYDROLYSED CASEIN FORMULA CONTAINING FORMULA VERSUS COW'S MILK FORMULA
Four studies (Mallet 1992; Oldaeus 1997; Szajewska 2001; von Berg 2003) compared a extensively hydrolysed formula containing casein to an adapted cow's milk formula.

No study compared a hydrolysed soy formula to an adapted cow's milk formula.

No study compared a hydrolysed soy formula to a hydrolysed cow's milk formula.

Types of outcomes:
Most studies reported clinical allergy, atopy (specific IgE or skin prick tests) and challenge test results separately (i.e. atopy and challenge test results were not reported in infants with allergic symptoms as prespecified by this review). Therefore, the majority of outcomes reported in this review are for clinical allergy that was ascertained by questionnaire and / or physician assessment. Blinded (to study formula) clinician assessment for allergy was reported by Chirico 1997 at 6 months; Halken 2000 at six, 12 and 18 months; Nentwich 2001 at six and 12 months; Oldaeus 1997 at nine, 12 and 18 months; Saarinen 1999 to mean age 27 months; Vandenplas 1992 at 12 months; and von Berg 2003 at one and three years.

Studies that performed confirmatory testing for atopy included Chirico 1997 (RAST 6 months), Halken 2000 (unblinded food elimination / challenge ), Juvonen 1996 (skin prick tests one and two years, total IgE), Mallet 1992 (RAST four and 12 months), Marini 1996 (RAST in first year and skin prick tests in second and third years), Nentwich 2001(specific IgE six and 12 months), Oldaeus 1997 (DBPCFC, skin prick tests, specific IgE at 18 months), Saarinen 1999 (unblinded cow's milk elimination / challenge), Tsai 1991 (specific IgE at two, six and 12 months, skin prick tests for infants with suspected CMA), Vandenplas 1992 (specific IgE, skin prick tests, unblinded food elimination / challenge to 12 months). In only three studies were allergy test results reported according to the presence of clinical symptoms of allergy or food intolerance (Chirico 1997; Oldaeus 1997; Vandenplas 1992). Definitions for allergy varied between studies but usually required persistent or recurring symptoms and signs in the absence of another obvious clinical explanation. For definitions of 'any allergy' and individual allergies for each study, see 'Characteristics of included studies'. Several studies did not report allergy but are included as they reported measures of growth in low allergy risk low birthweight infants (Maggio 2005; Picaud 2001; Szajewska 2001) and healthy low risk term infants (Vandenplas 1993) on a hydrolysed formula.
 

Methodological quality of included studies

Allocation concealment was probable for 10 studies (Chirico 1997; Maggio 2005; Marini 1996; Oldaeus 1997; Picaud 2001; Szajewska 2001; Tsai 1991; Vandenplas 1992; Vandenplas 1993; von Berg 2003). Allocation concealment was unclear for four studies including de Seta 1994 (method of allocation not reported), Halken 2000 (used quasi-random allocation method but blinded intervention), Mallet 1992 (method of allocation not reported) and Saarinen 1999 (quasi-random allocation method but blinded intervention). Studies with inadequate allocation concealment included Juvonen 1996 (quasi-random allocation, unblinded study), Lam 1992 (method not reported), Nentwich 2001 (quasi-random allocation, unblinded prescribing) and Willems 1993 (quasi-random allocation and unblinded study).

Blinding of treatment was reported by Chirico 1997; Halken 2000; Oldaeus 1997; Picaud 2001; Saarinen 1999; Szajewska 2001; Vandenplas 1992; Vandenplas 1993; von Berg 2003.

Blinding of measurement: physician assessment without knowledge of patient allocation was reported by eight studies (Halken 2000; Nentwich 2001; Oldaeus 1997; Saarinen 1999; Szajewska 2001; Vandenplas 1992; Vandenplas 1993; von Berg 2003). Blinding of measurement of allergy was reported by six studies (Halken 2000; Nentwich 2001; Oldaeus 1997; Saarinen 1999; Vandenplas 1992; von Berg 2003). Blinding of measurement of clinical allergy was not reported by eight studies (Chirico 1997; de Seta 1994; Juvonen 1996; Lam 1992; Maggio 2005; Picaud 2001; Tsai 1991; Willems 1993). Unblinded measurements were performed by Mallet 1992 and Marini 1996.

Losses to follow up: only studies with < 20% losses to follow up are included in this review. Studies with < 10% losses to follow up included de Seta 1994 (none reported), Lam 1992 (8%), Maggio 2005 (none), Mallet 1992 (7% at four months), Oldaeus 1997 (9%), Szajewska 2001 (none) and Vandenplas 1993 (9% but all in hydrolysed group). Saarinen 1999 followed up infants by mother self reporting and well baby clinic reporting. Infants with CMA maintained on a national register. Compliance rates are not reported.

Studies of adequate methodology as prespecified (adequate randomisation and allocation concealment and < 10% losses to follow up) included Maggio 2005, Oldaeus 1997, Szajewska 2001, Tsai 1991 and Vandenplas 1993 .
 

Results

The following subgroup analyses were considered, but as no significant benefits were reported, the results are not duplicated:
1. Both studies enrolled infants irrespective of family history allergy or food intolerance in 1st degree relatives.
2. Extent of protein hydrolysis: Juvonen 1996 and Saarinen 1999 compared an extensively hydrolysed formula versus pasteurised donor human milk.
3. Indication for use: both studies used formula for early short term infant formula feeding.
4. Method of ascertainment of allergy: Saarinen 1999 reported outcomes of an unblinded elimination / challenge for CMA. Juvonen 1996 did not report criteria for diagnosis of allergy.
5. Type of protein hydrolysate used: Juvonen 1996 compared an extensively hydrolysed casein formula versus pasteurised donor human milk. Saarinen 1999 compared an extensively hydrolysed whey formula versus pasteurised donor human milk.

Sensitivity analysis: neither study was considered to be of adequate methodology.

COMPARISON 02: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS HUMAN MILK FEEDING
No studies were eligible that compared these interventions.

COMPARISON 03: EARLY SHORT TERM FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Two studies (Juvonen 1996; Saarinen 1999) compared a short period of early supplemental or sole feeding with a hydrolysed formula with an adapted cow's milk formula. All mothers were subsequently encouraged to breast feed in both trials. Juvonen 1996 (77 infants) reported no significant difference in childhood allergy incidence (RR 1.37, 95% CI 0.33, 5.71), childhood asthma incidence (RR 3.08, 95% CI 0.13, 73.26), childhood eczema incidence (RR 0.34, 95% CI 0.04, 3.15), childhood food allergy (RR 1.37, 95% CI 0.33, 5.71) and childhood CMA (5.13, 95% CI 0.25, 103.43). Saarinen 1999 (3478 infants) reported a reduction in infant CMA of borderline significance (RR 0.62, 95% CI 0.38, 1.00; RD -0.01, 95% CI -0.02, 0.00).

The following subgroup analyses were considered, but as no significant benefits were reported, the results are not duplicated:
1. Both studies enrolled infants irrespective of family history allergy or food intolerance in 1st degree relatives.
2. Extent of protein hydrolysis: Juvonen 1996 and Saarinen 1999 compared an extensively hydrolysed formula versus cow's milk formula.
3. Indication for use: both studies used formula for early short term infant formula feeding.
4. Method of ascertainment of allergy: Saarinen 1999 reported outcomes of an unblinded elimination / challenge for CMA. Juvonen 1996 did not report criteria for diagnosis of allergy.
5. Type of protein hydrolysate used: Juvonen 1996 compared an extensively hydrolysed casein formula versus cow's milk formula. Saarinen 1999 compared an extensively hydrolysed whey formula versus cow's milk formula.

Sensitivity analysis: neither study was considered to be of adequate methodology.

COMPARISON 04: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Ten studies compared prolonged hydrolysed formula to adapted cow's milk formula feeding without any other differential (in one group only) allergy preventative co-interventions. Seven studies reported all allergy, with two studies (Lam 1992; Vandenplas 1993) reporting a significant reduction in infant allergy and one (Marini 1996) reporting a significant reduction in childhood allergy incidence. Meta-analysis (seven studies, 2514 infants) found a significant reduction in infant allergy (typical RR 0.79, 95% CI 0.66, 0.94; RD -0.04, 95% CI -0.08, -0.01), and meta-analysis (two studies, 950 infants) found no significant difference in childhood allergy incidence (typical RR 0.85, 95% CI 0.69, 1.05).

Five studies reported asthma, with meta-analysis (four studies, 318 infants) finding no significant difference in infant asthma (typical RR 0.57, 95% CI 0.31, 1.04). Marini 1996 (78 infants) reported no significant difference in childhood asthma incidence (RR 0.38, 95% CI 0.08, 1.84). von Berg 2003 (872 infants) reported no significant difference in childhood asthma prevalence (RR 1.06, 95% CI 0.70, 1.61).

Eight studies reported eczema with no individual study reporting a significant reduction in eczema at any time. Meta-analysis (eight studies, 2558 infants) found no significant difference in infant eczema infancy (typical RR 0.84, 95% CI 0.68, 1.04). Meta-analysis (two studies, 950 infants) found no significant difference in childhood eczema incidence (typical RR 0.83, 95% CI 0.63, 1.10). von Berg 2003 (872 infants) reported no significant difference in childhood eczema prevalence (RR 0.66, 95% CI 0.43, 1.02).

Two studies reported rhinitis, with meta-analysis (256 infants) finding no significant difference in infant rhinitis (RR 0.52, 95% CI 0.14, 1.85). Marini 1996 (78 infants) reported no significant difference in childhood rhinitis incidence (RR 0.48, 95% CI 0.04, 5.03).

Oldaeus 1997 (141 infants) reported no significant difference in infant food allergy (RR 1.82, 95% CI 0.64, 5.16). Vandenplas 1992 (67 infants) reported a significant reduction in infant CMA (RR 0.36, 95% CI 0.15, 0.89).

The following subgroup analyses were performed:

COMPARISON 05: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - LOW RISK INFANTS
No eligible study reported allergy outcomes in infants at low risk of allergy. Outcomes for growth in preterm or low birthweight infants fed a preterm hydrolysed or preterm cow's milk formula are as for Comparison 04. All subsequent analyses for allergy outcomes are in high risk infants.

COMPARISON 06: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - HIGH RISK INFANTS
All seven studies comparing prolonged hydrolysed formula feeding to adapted cow's milk formula feeding without any other allergy preventative co-interventions enrolled infants at high risk of allergy. See Comparison 05 for outcomes.

COMPARISON 07: PROLONGED FEEDING: EXTENSIVELY HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Four studies (Mallet 1992; Oldaeus 1997; Szajewska 2001; von Berg 2003) compared an extensively hydrolysed formula with a cow's milk formula. No individual study reported a significant reduction in all allergy or any specific allergy or food intolerance. Meta-analysis (two studies, 1561 infants) found no significant difference in infant allergy (typical RR 0.87, 95% CI 0.68, 1.13). von Berg 2003 (651 infants) reported no significant difference in childhood allergy incidence (RR 0.89, 95% CI 0.71, 1.13). Oldaeus 1997 (96 infants) reported no significant difference in infant asthma (RR 0.61, 95% CI 0.18, 2.04). von Berg 2003 (661 infants) reported no significant difference in childhood asthma prevalence (RR 1.02, 95% CI 0.65, 1.59). Meta-analysis (three studies, 1726 infants) found no significant difference in infant eczema (typical RR 0.83, 95% CI 0.63, 1.08). von Berg 2003 (661 infants) reported no significant difference in childhood eczema incidence (RR 0.86, 95% CI 0.63, 1.17) or prevalence (RR 0.64, 95% CI 0.40, 1.02). Oldaeus 1997 (96 infants) reported no significant difference in infant rhinitis incidence (RR 2.76, 95% CI 0.12, 66.22) and food allergy (RR 1.15, 95% CI 0.33, 4.02). Szajewska 2001, in 30 low birth weight infants at low risk of allergy, reported no significant difference in weight gain over the first 12 weeks (MD weight gain -2.02 g/day, 95% CI -5.76, 1.72).

COMPARISON 08: PROLONGED FEEDING: PARTIALLY HYDROLYSED VERSUS COW'S MILK FORMULA
Two studies (Lam 1992; Vandenplas 1992) independently reported a significant reduction in any infant allergy. Meta-analysis (seven studies, 1482 infants) found a significant reduction in any infant allergy (typical RR 0.79, 95% CI 0.65, 0.97). Meta-analysis of two studies (Marini 1996; von Berg 2003) found no significant difference in childhood allergy incidence (typical RR 0.86, 95% CI 0.67, 1.10). There was significant (p = 0.04) and substantial (I² = 75.2%) heterogeneity between studies, with Marini 1996 reporting a significant reduction (RR 0.42, 95% CI 0.19, 0.90) and von Berg 2003 no significant difference (RR 0.95, 95% CI 0.73, 1.25).

Meta-analysis (four studies, 268 infants) found no significant difference in infant asthma (typical RR 0.54, 95% CI 0.28, 1.04). Marini 1996 (78 infants) reported no significant difference in childhood asthma incidence (RR 0.38, 95% CI 0.08, 1.84) and von Berg 2003 (432 infants) reported no significant difference in childhood asthma prevalence (RR 1.15, 95% CI 0.70, 1.88). Meta-analysis (seven studies, 1361 infants) found no significant difference in infant eczema (typical RR 0.89, 95% CI 0.69, 1.13). Meta-analysis (two studies, 500 infants) found no significant difference in childhood eczema incidence (typical RR 0.85, 95% CI 0.61, 1.19) and von Berg 2003 reported no significant difference in childhood eczema prevalence (RR 0.71, 95% CI 0.41, 1.22). Meta-analysis (three studies, 206 infants) found no significant difference in infant rhinitis (typical RR 0.40, 95% CI 0.09, 1.70). Marini 1996 (78 infants) reported no significant difference in childhood rhinitis incidence (RR 0.48, 95% CI 0.04, 5.03). Oldaeus 1997 (91 infants) reported no significant difference in infant food allergy (RR 2.56, 95% CI 0.86, 7.56). Vandenplas 1992 reported a significant reduction in CMA in infancy (RR 0.36, 95% CI 0.15, 0.89).

Meta-analysis (two studies, 46 infants) in low birth weight or preterm infants fed a partially hydrolysed preterm infant formula versus a preterm infant cow's milk formula found no significant difference in weight gain (WMD -1.15 g/kg/day, 95% CI -2.90, 0.60).

COMPARISON 09: PROLONGED FEEDING: EXTENSIVELY HYDROLYSED FORMULA VERSUS PARTIALLY HYDROLYSED FORMULA
Four studies (Halken 2000; Nentwich 2001; Oldaeus 1997; von Berg 2003) compared prolonged feeding with an extensively hydrolysed formula to a partially hydrolysed formula in infants at high risk of allergy. No individual study reported any significant differences in allergy or food intolerance incidence. Meta-analysis (three studies, 1806 infants) found no significant difference in infant allergy (typical RR 0.93, 95% CI 0.75, 1.16). von Berg 2003 (661 infants) reported no significant difference in childhood allergy incidence (RR 0.93, 95% CI 0.74, 1.18).

Meta-analysis (two studies, 341 infants) found no significant difference in infant asthma incidence (typical RR 1.72, 95% CI 0.74, 3.96). von Berg 2003 (661 infants) reported no significant difference in childhood asthma prevalence (RR 0.89, 95% CI 0.58, 1.35). Meta-analysis (four studies, 1865 infants) found no significant difference in infant eczema (typical RR 0.89, 95% CI 0.73, 1.10). von Berg 2003 (661 infants) reported no significant difference in childhood eczema incidence (RR 0.92, 95% CI 0.69, 1.26) and prevalence (RR 0.90, 95% CI 0.54, 1.52). Meta-analysis of (two studies, 341 infants) found no significant difference in infant rhinitis (typical RR 1.25, 95% CI 0.36, 4.29). Meta-analysis of the same two studies (Halken 2000; Oldaeus 1997) found a significant reduction in infant food allergy (typical RR 0.43, 95% CI 0.19, 0.99). Halken 2000 (246 infants) reported no significant difference in infant CMA (RR 0.13, 95% CI 0.01, 1.16).

One study compared use of an extensively hydrolysed preterm formula with a partially hydrolysed preterm formula (Szajewska 2001) in 30 low birth weight infants at low risk of allergy, and reported no significant difference in weight gain over the first 12 weeks (MD weight gain -0.70 g/day, 95% CI -4.57, 3.17).

COMPARISON 10: PROLONGED SOLE FORMULA FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA
Six studies enrolled infants on sole formula feeds. Vandenplas 1992 reported a significant reduction in any infant allergy (RR 0.45, 95% CI 0.22 0.94). Meta-analysis (five studies, 425 infants) found a significant reduction in infant allergy (typical RR 0.61, 95% CI 0.46, 0.80). Marini 1996 reported a significant reduction in childhood allergy incidence (RR 0.42, 95% CI 0.19, 0.90).

Meta-analysis (two studies, 144 infants) found no significant difference in infant asthma (typical RR 0.57, 95% CI 0.25, 1.31). Marini 1996 reported no significant difference in childhood asthma incidence (RR 0.38, 95% CI 0.08, 1.84).

Meta-analysis (four studies, 271 infants) found no significant difference in infant eczema (typical RR 0.74, 95% CI 0.45, 1.21). Marini 1996 (78 infants) reported no significant difference in childhood asthma incidence (RR 0.42, 95% CI 0.14, 1,26) and childhood rhinitis incidence (RR 0.48, 95% CI 0.04, 5.03). Vandenplas 1992 reported a significant reduction in infant CMA (RR 0.36, 95% CI 0.15, 0.89).

COMPARISON 11: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - ALLERGY / FOOD INTOLERANCE CONFIRMED BY TEST
Most studies documented clinical allergy and results of confirmatory testing for allergy or atopy separately. Of studies that confirmed atopy in patients with clinical allergy, Vandenplas 1992 reported a significant reduction in infant atopy confirmed by specific IgE (RR 0.45, 95% CI 0.22, 0.94). There were no infants with atopic rhinitis in one study (Oldaeus 1997) or atopic eczema in another (Chirico 1997). Oldaeus 1997 (141 infants) reported no significant difference in infant food allergy confirmed by specific IgE (RR 1.82, 95% CI 0.64, 5.16). Vandenplas 1992 reported a significant reduction in infant CMA confirmed by specific IgE (RR 0.36, 95% CI 0.15, 0.89). Oldaeus 1997 reported no significant difference in infant food intolerance confirmed by DBPCFC (RR 0.48, 95% CI 0.07, 3.33).

COMPARISON 12: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - BLINDED MEASUREMENT
Assessment for allergy without knowledge of patient allocation was reported by 5 studies (Halken 2000; Nentwich 2001; Oldaeus 1997; Vandenplas 1992; von Berg 2003). Meta-analysis (three studies, 2156 infants) found no significant difference in infant allergy (typical RR 0.87, 95% CI 0.69, 1.08). von Berg 2003 (872 infants) reported no significant difference in childhood allergy incidence (RR 0.91, 95% CI 0.73, 1.14). Oldaeus 1997 (141 infants) reported no significant difference in infant asthma (RR 0.48, 95% CI 0.17, 1.42) and von Berg 2003 (872 infants) reported no significant difference in childhood asthma prevalence (RR 1.06, 95% CI 0.70, 1.61). Meta-analysis of three studies (2124 infants) found no significant difference in infant eczema (typical RR 0.88, 95% CI 0.69, 1.14). von Berg 2003 (872 infants) reported no significant difference in childhood eczema incidence (RR 0.88, 95% CI 0.66, 1.18) or prevalence (RR 0.66, 95% CI 0.43, 1.02). Oldaeus 1997 (141 infants) reported no significant difference in infant rhinitis (RR 1.47, 95% CI 0.06, 35.37) or infant food allergy (RR 1.82, 95% CI 0.64, 5.16). Vandenplas 1992 (67 infants) reported a significant reduction in infant CMA (RR 0.36, 95% CI 0.15, 0.89).

COMPARISON 13: PROLONGED FEEDING: HYDROLYSED FORMULA VERSUS COW'S MILK FORMULA - STUDIES OF ADEQUATE METHODOLOGY
Maggio 2005; Oldaeus 1997; Szajewska 2001 and Tsai 1991 studied prolonged feeding of a hydrolysed formula compared to an adapted cow's milk formula with no co-interventions and are included in the sensitivity analysis of studies of adequate methodology (adequate randomisation and allocation concealment and < 10% losses to follow up). Oldaeus 1997 (141 infants) reported no significant difference in infant allergy (RR 1.13, 95% CI 0.69, 1.85). Meta-analysis of two studies (Oldaeus 1997; Tsai 1991) with 174 infants found no significant difference in infant asthma (typical RR 0.56, 95% CI 0.23, 1,38), infant eczema (typical RR 1.06, 95% CI 0.68, 1.65) or infant rhinitis (typical RR 0.40, 95% CI 0.09, 1.70). Oldaeus 1997 reported no significant difference in infant food allergy (RR 1.82, 95% CI 0.64, 5.16).

Meta-analysis of two studies (Maggio 2005; Szajewska 2001) comparing preterm infant formulas found a significant reduction in weight gain (WMD weight gain -2.43 g/kg/day, 95% CI -4.53, -0.34) for infants on hydrolysed preterm infant formula.

COMPARISON 14: PROLONGED FEEDING: PARTIALLY HYDROLYSED WHEY FORMULA VERSUS COW'S MILK FORMULA
Meta-analysis (six studies, 1391 infants) found a significant reduction in infant allergy (typical RR 0.73, 95% CI 0.59, 0.90). Meta-analysis (two studies, 510 infants) found no significant difference in childhood allergy incidence (typical RR 0.68, 95% CI 0.31, 1.52). Significant (p = 0.04) and substantial (I² = 75.2%) heterogeneity was found. Meta-analysis (three studies, 177 infants) found no significant difference in infant asthma (typical RR 0.61, 95% CI 0.29, 1.28). Marini 1996 (78 infants) reported no significant difference in childhood asthma incidence (typical RR 0.38, 95% CI 0.08, 1.84). von Berg 2003 (432 infants) reported no significant difference in childhood allergy prevalence (typical RR 1.15, 95% CI 0.70, 1.88). Meta-analysis (six studies, 1270 infants) found no significant difference in infant eczema (typical RR 0.84, 95% CI 0.65, 1.09). Meta-analysis (two studies, 510 infants) found no significant difference in childhood eczema incidence (typical RR 0.85, 95% CI 0.61, 1.19). von Berg 2003 (432 infants) reported no significant difference in childhood allergy incidence (typical RR 0.71, 95% CI 0.41, 1.22). Meta-analysis (2 studies 115 infants) found no significant difference in infant rhinitis (typical RR 0.4, 95% CI 0.09,1.70) and Marini 1996 reported no significant difference in childhood rhinitis incidence (typical RR 0.48, 95% CI 0.04,5.03). Vandenplas 1992 reported a significant reduction in infant CMA (RR 0.36, 95% CI 0.15, 0.89). Meta-analysis of two studies, 46 infants (Picaud 2001, Szajewska 2001) comparing preterm infant formulas found no significant difference in weight gain (WMD weight gain -1.15 g/kg/day, 95% CI -2.9, 0.60) for infants on hydrolysed preterm infant formula.

COMPARISON 15: PROLONGED FEEDING: PARTIALLY HYDROLYSED CASEIN CONTAINING FORMULA VERSUS COW'S MILK FORMULA
Oldaeus 1997 (91 infants) reported no significant difference in infant allergy (RR 1.36, 95% CI 0.80, 2.31), infant asthma (RR 0.34, 95% CI 0.07, 1.60), infant eczema (RR 1.30, 95% CI 0.66, 2.55) and infant food allergy (RR 2.56, 95% CI 0.86, 7.56). No infant was reported with rhinitis. Szajewska 2001 (30 infants) reported no significant difference in weight gain (MD weight gain -1.32 g/kg/day, 95% CI -4.83, 2.19) for infants on a partially hydrolysed casein containing preterm infant formula.

COMPARISON 16: PROLONGED FEEDING: EXTENSIVELY HYDROLYSED WHEY FORMULA VERSUS COW'S MILK FORMULA
von Berg 2003 (972 infants) reported no significant difference in infant allergy (RR 0.97, 95% CI 0.71, 1.34) and (431 infants) childhood allergy incidence (RR 1.07, 95% CI 0.82, 1.38). von Berg 2003 (431 infants) reported no significant difference in childhood asthma prevalence (RR 1.19, 95% CI 0.73, 1.94), infant eczema (972 infants, RR 1.00, 95% CI 0.72, 1.40), childhood eczema incidence (431 infants, RR 1.06, 95% CI 0.75, 1.49) and childhood eczema prevalence (431 infants, RR 0.78, 95% CI 0.46, 1.33).

COMPARISON 17: PROLONGED FEEDING: EXTENSIVELY HYDROLYSED CASEIN CONTAINING FORMULA VERSUS COW'S MILK FORMULA
Meta-analysis (two studies, 1072 infants) found no significant difference in infant allergy (typical RR 0.79, 95% CI 0.58, 1.06). von Berg 2003 (431 infants) reported a significant reduction in childhood allergy incidence (RR 0.72, 95% CI 0.53, 0.97). Oldaeus 1997 (96 infants) reported no significant difference in infant asthma (RR 0.61, 95% CI 0.18, 2.04) and von Berg 2003 (431 infants) reported no significant difference in childhood asthma prevalence (RR 0.84, 95% CI 0.49, 1.45). Meta-analysis (three studies, 1237 infants) found a significant reduction in infant eczema (typical RR 0.71, 95% CI 0.51, 0.97). von Berg 2003 reported a significant reduction in childhood eczema incidence (RR 0.66, 95% CI 0.44, 0.98) and prevalence (RR 0.50, 95% CI 0.27, 0.92). Oldaeus 1997 (96 infants) reported no significant difference in infant rhinitis (RR 2.76, 95% CI 0.12, 66.22) and infant food allergy (RR 1.15, 95% CI 0,33, 4.02). Szajewska 2001 (30 infants) reported no significant difference in weight gain (MD weight gain -2.02 g/kg/day, 95% CI -5.76, -1.72) for infants on an extensively hydrolysed casein containing preterm infant formula.

ADVERSE EFFECTS OF HYDROLYSED FORMULAS
No study reported mortality or serious adverse events. No study reported neurodevelopment outcomes. All studies provided the infant formulas used in the study so data for the effect of infant formula cost on compliance is not available. No study reported a cost analysis of using a hydrolysed infant formula. Growth was reported by seven studies with four studies reporting growth in high risk infants (Mallet 1992; Marini 1996; Nentwich 2001; Tsai 1991) and five studies reporting growth in low risk infants (Maggio 2005; Picaud 2001; Szajewska 2001; Vandenplas 1993), with three of these studies (Maggio 2005; Picaud 2001; Szajewska 2001) enrolling low birthweight or preterm infants. Reports of growth and infant refusal of hydrolysed formula are summarised below.
 

• Growth:

Mallet 1992 reported a significantly reduced mean weight gain at four months but not 12 months in infants receiving an extensively hydrolysed formula compared to an adapted cow's milk formula (4 months: hydrolysed formula group 3060 g; adapted cow's milk formula 3290 g, p < 0.05). No difference in head circumference or length was found (data not given).

Marini 1996 reported no significant differences in weights or lengths at six months, one and three years or head circumferences at six months and one year for infants fed sole or supplemental partially hydrolysed formula versus adapted cow's milk formula.

Nentwich 2001 reported no significant difference in weights of infants (data not given) up to 12 months in infants fed a partially or extensively hydrolysed formula.

Picaud 2001 reported preterm infants fed a partially hydrolysed whey cow's milk formula were significantly lighter than infants fed an isocaloric adapted whey cow's milk formula (3193 +/- 384 g versus 3559 +/- 362 g, p = 0.04). The partially hydrolysed cow's milk formula had slightly lower nitrogen content.

Szajewska 2001 studied low birth weight infants at low risk of allergy and reported no significant difference in weight gain over the first 12 weeks comparing infants on a partially hydrolysed formula versus an adapted cow's milk formula (MD weight gain -2.02 g/day, 95% CI -5.76, 1.72), infants on an extensively hydrolysed formula compared to an adapted cow's milk formula (MD weight gain -0.70 g/day, 95% CI -4.57, 3.17) or infants on an extensively hydrolysed formula compared to a partially hydrolysed formula (MD weight gain -0.70 g/day, 95% CI -4.57, 3.17).

Tsai 1991 reported no significant difference in weight or height at 6 and 12 months in infants fed prolonged supplementary or sole hydrolysed formula versus a cow's milk formula (12 months weight: 9.91 kg SD 0.82 versus 9.74 kg SD 0.88; height 73.6 cm SD 3.7 versus 75.5 cm SD 4.0).

Vandenplas 1993 reported no significant difference in weight gain up to 13 weeks in healthy term infants fed prolonged sole 'intermediate' hydrolysed formula versus cow's milk formula (weight gain 27.2 g/day both groups).
 

• Infant refusal of hydrolysed formula:

Nentwich 2001 at six months reported two 'dropouts' from the partially hydrolysed group due to "parental non-compliance' and one from the extensively hydrolysed formula group due to "poor acceptance of the hydrolysed formula".

Oldaeus 1997 reported "infant feeding problems" in three infants fed an extensively hydrolysed formula, six fed a partially hydrolysed formula and two fed an adapted cow's milk formula.

Vandenplas 1993 reported 4/25 infants fed an 'intermediate' hydrolysed formula with "refusal to drink" and 0/21 fed an adapted cow's milk formula.
 

Discussion

Meta-analysis of seven trials reporting 2514 infants found a significant reduction in infant allergy from use of a hydrolysed formula compared to a cow's milk formula in infants at high risk of allergy. Hydrolysed infant formula would need to be given to 25 infants (95% CI 12.5, 100) to prevent one infant developing allergy. This effect was no longer significant when allergy was measured after two years of age. These findings should be viewed with caution. Infant and childhood allergy had different definitions, timing of measurement and methods for measurement from study to study. Most studies were small or had methodological limitations with benefits not persisting when analysis was restricted to trials with blinding of measurement to study formula or to studies of adequate methodology. There was no significant difference in incidence of childhood allergy. Only one small study (Vandenplas 1992) reported a significant reduction in a specific allergy (CMA). Another trial (Oldaeus 1997) reported no significant difference in food allergy. There was no significant difference incidence of infant or childhood asthma, eczema or rhinitis. Several subgroup analyses were performed to determine if effects of hydrolysed formula varied according to intensity of exposure to cow's milk, method of allergy measurement and study quality.

Subgroup analysis of studies of sole formula feeding found a significant reduction in infant allergy (five studies, 425 infants), childhood allergy (one study, 78 infants) and infant CMA (one study, 67 infants), but no significant difference in infant or childhood asthma or eczema and childhood rhinitis. Subgroup analysis of studies where there was blinding to study formula for measurement of allergy and food intolerance, found no significant difference in infant or childhood allergy, asthma, eczema, rhinitis or food intolerance. Few studies reported testing for atopy using skin prick tests or specific IgE, food intolerance using DBPCFC, or bronchial hyperresponsiveness separately in infants with clinical symptoms of allergy or food intolerance. Tests were frequently performed on all enrolled infants and reported irrespective of symptomatology. This review focused on reports of probable or obvious allergy and food intolerance. Where atopy was confirmed by testing, the review focused on symptomatic infants only. Subgroup analysis of studies confirming allergy or food intolerance by testing, found only one study (Vandenplas 1992) reported a significant reduction in infant allergy and CMA. Subgroup analysis of studies of adequate methodology (adequate randomisation, allocation concealment and < 10% losses) found no significant difference in infant allergy, asthma, eczema, rhinitis or food allergy.

Further subgroup analyses were performed to determine if there were differences in effects between different types of hydrolysed formulas. Subgroup analysis comparing partially hydrolysed infant formulas with cow's milk formula found a significant reduction in infant allergy (six studies, 1391 infants), but no significant difference in childhood allergy (two studies, 510 infants), infant or childhood asthma, eczema or rhinitis. Vandenplas 1992 reported a reduction in infant CMA. Subgroup analysis comparing extensively hydrolysed infant formulas with partially hydrolysed formula found no significant difference in infant or childhood allergy, asthma or eczema, infant rhinitis or CMA. However, meta-analysis of two studies (Halken 2000; Oldaeus 1997) with 341 infants found a significant reduction in food allergy in infants receiving an extensively hydrolysed formula.

Additional subgroup analyses were performed to determine if there were differences in effects between different types of hydrolysed protein (100% whey or casein containing formulas). Most trials of partially hydrolysed formulas used partially hydrolysed 100% whey formula with analyses finding a significant reduction in infant allergy (six studies, 1391 infants), but no significant difference in childhood allergy (two studies, 510 infants), infant or childhood asthma, eczema or rhinitis. Again, Vandenplas 1992 was the only study to report CMA. Only one small trial (Oldaeus 1997) with 91 infants compared a partially hydrolysed casein formula with a cow's milk formula with no benefits reported. von Berg 2003 in 972 infants compared feeding with an extensively hydrolysed whey formula to a cow's milk formula and reported no significant difference in infant or child allergy and eczema, or childhood asthma. Three trials with 1237 infants compared feeding with an extensively hydrolysed casein containing formula to a cow's milk formula. One of these trials (von Berg 2003) reported a significant reduction in childhood allergy due largely to a reduction in infant and childhood eczema. Meta-analysis of two trials found no significant difference in infant allergy, but meta-analysis of three trials found a significant reduction in infant eczema. This finding is predominately due to the large von Berg 2003 study. These results should be viewed with caution given the losses to follow up at one and three years and the fact that no other eligible trial has demonstrated a significant benefit from use of an extensively hydrolysed formula. This large trial was conducted in a population of breast fed infants where formula was used as supplemental or sole formula feeding in those infants unable to fully breast feed. Under 60% of infants in the standard formula group were exposed to cow's milk formula, reducing the power of this study to detect an important difference in outcomes.

No trial without differential allergy preventing co-interventions reported use of a hydrolysed soy formula. Further trials are required to determine the role of hydrolysed soy formulas for allergy prevention in high risk infants.

Costs were not reported by any of the included studies. As the studies mostly provided the infant formulas, the effect of cost on compliance with treatment is not able to be determined. As no study prespecified or systematically measured infant acceptance of the formulas, the effect of formula on infant food refusal is not able to be determined. No study reported any adverse effect of hydrolysed formula on infant growth in term infants. However, there is consistent evidence that growth in weight, but not head circumference or length, of preterm or low birthweight infants fed a preterm hydrolysed formulas is significantly reduced. This is despite one study (Maggio 2005) comparing formulas that were isocaloric for protein, carbohydrate and fat. Whether this is of clinical importance is unclear given that formula intake can be adjusted according to growth parameters. None of the eligible studies reported neurodevelopmental or other health outcomes.

Given the limitations to the evidence supporting the use of hydrolysed formulas, further large well conducted trials with adequate randomisation procedures, blinding of intervention and complete follow up incorporating objective measures of allergy and food intolerance are needed. Given the findings of this review relating to potential benefits from partially hydrolysed 100% whey formulas and extensively hydrolysed casein formula, these trials should address the question of whether these formula types are better than cow's milk formula for prevention of allergy or food intolerance in high risk infants.
 

Reviewers' conclusions

Implications for practice

Implications for research

Acknowledgements

Potential conflict of interest

Characteristics of included studies

Characteristics of excluded studies

References to studies

References to included studies

* Chirico G, Gasparoni A, Ciardelli L, De Amici M, Colombo A, Rondini G. Immunogenicity and antigenicity of a partially hydrolyzed cow's milk infant formula. Allergy 1997;52:82-8.

de Seta 1994 {published data only}

* de Seta L, Siani P, Cirillo G, Di Gruttola M, Cimaduomo L, Coletta S. The prevention of allergic diseases with a hypoallergenic formula: a follow-up at 24 months. The preliminary results. [Italian]. La Pediatria Medica e chirurgica : Medical and Surgical Pediatrics 1994;16:251-4.

Halken 2000 {published data only}

* Halken S, Hansen KS, Jacobsen HP, Estmann A, Faelling AE, Hansen LG, Kier SR, Lassen K, Lintrup M, Mortensen S, Ibsen KK, Osterballe O, Host A. Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study. Pediatric Allergy and Immunology 2000;11:149-61.

Juvonen 1996 {published data only}

* Juvonen P, Mansson M, Andersson C, Jakobsson I. Allergy development and macromolecular absorption in infants with different feeding regimens during the first three days of life. A three-year prospective follow-up. Acta Paediatrica 1996;85:1047-52.

Juvonen P, Mansson M, Jakobsson I. Does early diet have an effect on subsequent macromolecular absorption and serum IgE? Journal of Pediatric Gastroenterology and Nutrition 1994;18:344-9.

Juvonen P, Mansson M, Kjellman NI, Bjorksten B, Jakobsson I. Development of immunoglobulin G and immunoglobulin E antibodies to cow's milk proteins and ovalbumin after a temporary neonatal exposure to hydrolyzed and whole cow's milk proteins. Pediatric Allergy and Immunology 1999;10:191-8.

Lam 1992 {unpublished data only}

* Lam BCC, Yeung CY. The effect of breast milk, infant formula and hypoallergenic formula on incidence of atopic manifestation in high risk infants. Nestle Internal Report 1992.

Maggio 2005 {published data only}

* Maggio L, Zuppa AA, Sawatzki G, Valsasina R, Schubert W, Tortorolo G. Higher urinary excretion of essential amino acids in preterm infants fed protein hydrolysates. Acta Paediatrica 2005;94:75-84.

Mallet 1992 {published data only}

* Mallet E, Henocq A. Long-term prevention of allergic diseases by using protein hydrolysate formula in at-risk infants. Journal of Pediatrics 1992;121:S95-100.

Marini 1996 {published data only}

* Marini A, Agosti M, Motta G, Mosca F. Effects of a dietary and environmental prevention programme on the incidence of allergic symptoms in high atopic risk infants: three years' follow-up. Acta Paediatrica (Supp) 1996;414:1-21.

Nentwich 2001 {published data only}

* Nentwich I, Michkova E, Nevoral J, Urbanek R, Szepfalusi Z. Cow's milk-specific cellular and humoral immune responses and atopy skin symptoms in infants from atopic families fed a partially (pHF) or extensively (eHF) hydrolyzed infant formula. Allergy 2001;56:1144-56.

Oldaeus 1997 {published data only}

* Oldaeus G, Anjou K, Bjorksten B, Moran JR, Kjellman NI. Extensively and partially hydrolysed infant formulas for allergy prophylaxis. Archives of Disease in Childhood 1997;77:4-10.

Oldaeus G, Bjorksten B, Jenmalm MC, Kjellman NI. Cow's milk IgE and IgG antibody responses to cow's milk formulas. Allergy 1999;54:352-7.

Picaud 2001 {published data only}

* Picaud JC, Rigo J, Normand S, Lapillonne A, Reygrobellet B, Claris O, Salle BL. Nutritional efficacy of preterm formula with a partially hydrolyzed protein source: a randomized pilot study. Journal of Pediatric Gastroenterology and Nutrition 2001;32:555-61.

Saarinen 1999 {published data only}

Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Klemetti P, Kuitunen P, Lope L, Renlund M, Siivola M, Vaarala O, Savilahti E. Breast-feeding and the development of cows' milk protein allergy. Advances in Experimental Medicine and Biology 2000;478:121-30.

* Saarinen KM, Juntunen-Backman K, Jarvenpaa AL, Kuitunen P, Lope L, Renlund M, Siivola M, Savilahti E. Supplementary feeding in maternity hospitals and the risk of cow's milk allergy: A prospective study of 6209 infants. Journal of Allergy and Clinical Immunology 1999;104:457-61.

Saarinen KM, Savilahti E. Infant feeding patterns affect the subsequent immunological features in cow's milk allergy. Clinical and Experimental Allergy 2000;30:400-6.

Saarinen KM, Suomalainen H, Savilahti E. Diagnostic value of skin-prick and patch tests and serum eosinophil cationic protein and cow's milk-specific IgE in infants with cow's milk allergy. Clinical and Experimental Allergy 2001;31:423-9.

Szajewska 2001 {published data only}

* Szajewska H, Albrecht P, Stoinska B, Prochowska A, Gawecka A, Laskowska-Klita T. Extensive and partial protein hydrolysate preterm formulas: the effect on growth rate, protein metabolism indices, and plasma amino acid concentrations. Journal of Pediatric Gastroenterology and Nutrition 2001;32:303-9.

Tsai 1991 {published data only}

Tsai YT, Chou CC, Hsieh KH. The effect of hypoallergenic formula on the occurrence of allergic diseases in high risk infants. Chung-Hua Min Kuo Hsiao Erh Ko i Hsueh Hui Tsa Chih 1991;32:137-44.

* Tsai YT, Chou CC, Hsieh KH. The effect of hypoallergenic formula on the occurrence of allergic diseases in high risk infants. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1991;32:137-44.

Vandenplas 1992 {published data only}

Vandenplas Y, Hauser B, Van den Borre C, Clybouw C, Mahler T, Hachimi-Idrissi S, Deraeve L, Malfroot A, Dab I. The long-term effect of a partial whey hydrolysate formula on the prophylaxis of atopic disease. European Journal of Pediatrics 1995;154:488-94.

* Vandenplas Y, Hauser B, Van den Borre C, Sacre L, Dab I. Effect of a whey hydrolysate prophylaxis of atopic disease. Annals of Allergy 1992;68:419-24.

Vandenplas Y. Atopy at 3 years in high-risk infants fed whey hydrolysate or conventional formula. Lancet 1992;339:1118.

Vandenplas 1993 {published data only}

Hauser B, Blecker U, Keymolen K, Suys B, Gerlo E, Vandenplas Y. Plasma amino acid concentrations in term-born infants fed a whey predominant or a whey hydrolysate formula. Journal of Parenteral and Enteral Nutrition 1997;21:27-30.

Hauser B, Keymolen K, Blecker U, Suys B, Bougatef A, Loeb H, Vandenplas Y. A comparative evaluation of whey hydrolysate and whey-predominant formulas. How well do infants accept and tolerate them? Clinical Pediatrics 1993;62:433-7.

* Vandenplas Y, Hauser B, Blecker U, Suys B, Peeters S, Keymolen K, Loeb H. The nutritional value of a whey hydrolysate formula compared with a whey-predominant formula in healthy infants. Journal of Pediatric Gastroenterology and Nutrition 1993;17:92-6.

von Berg 2003 {published data only}

Laubereau B, Brockow I, Zirngibl A, Koletzko S, Gruebl A, von Berg A, et al. Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life--results from the GINI-birth cohort study.[see comment]. Journal of Pediatrics 2004;144:602-7.

Laubereau B, Filipiak-Pittroff B, von Berg A, Grubl A, Reinhardt D, Wichmann HE, et al. Caesarean section and gastrointestinal symptoms, atopic dermatitis, and sensitisation during the first year of life. Archives of Disease in Childhood 2004;89:993-7.

Schoetzau A, Filipiak-Pittroff B, Franke K, Koletzko S, Von Berg A, Gruebl A, et al. Effect of exclusive breast-feeding and early solid food avoidance on the incidence of atopic dermatitis in high-risk infants at 1 year of age. Pediatric Allergy and Immunology 2002;13:234-42.

Schoetzau A, Gehring U, Franke K, Grubl A, Koletzko S, von Berg A, et al. Maternal compliance with nutritional recommendations in an allergy preventive programme. Archives of Disease in Childhood 2002;86:180-4.

* von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, Reinhardt D, Berdel D; German Infant Nutritional Intervention Study Group. The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: The German Infant Nutritional Intervention Study, a randomized double-blind trial. Journal of Allergy and Clinical Immunology 2003;111:533-40.

von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, et al. The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. Journal of Allergy and Clinical Immunology 2003;111:533-40.

Willems 1993 {published data only}

* Willems R, Duchateau J, Magrez P, Denis R, Casimir G. Influence of hypoallergenic milk formula on the incidence of early allergic manifestations in infants predisposed to atopic diseases. Annals of Allergy 1993;71:147-50.

References to excluded studies

Agosti M, Pugni L, Ramenghi LA, Mosca F, Marini A. Hydrolysed proteins in preterm formula: influence on plasma aminoacids, blood fatty acids and insulinaemia. Acta Paediatrica Supplement 2003;91:34-8.

Akimoto 1993 {published data only}

Akimoto K, Saito H, Akasawa A, Iikura Y. [Preventative effect of a whey hydrolyzed formula (Nestle, NAN H.A.) on the development of allergic symptoms in infants]. [Japanese]. Arerugi - Japanese Journal of Allergology 1997;46:1044-51.

Arshad 1992a {published data only}

Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomised controlled study. Thorax 2003;58:489-93.

* Arshad SH, Matthews S, Gant C, Hide DW. Effect of allergen avoidance on development of allergic disorders in infancy. Lancet 1992;339:1493-7.

Hide DW, Matthews S, Matthews L, Stevens M, Ridout S, Twiselton R, Gant C, Arshad SH. Effect of allergen avoidance in infancy on allergic manifestations at age two years. Journal of Allergy and Clinical Immunology 1994;93:842-6.

Hide DW, Matthews S, Tariq S, Arshad SH. Allergen avoidance in infancy and allergy at 4 years of age. Allergy 1996;51:89-93.

Arshad 1992b {published data only}

Arshad SH, Hide DW. Effect of environmental factors on the development of allergic disorders in infancy. Journal of Allergy and Clinical Immunology 1992;90:235-41.

Arshad 1993 {published data only}

Arshad SH, Stevens M, Hide DW. The effect of genetic and environmental factors on the prevalence of allergic disorders at the age of two years. Clinical and Experimental Allergy 1993;23:504-11.

Arshad 2001 {published data only}

Arshad SH, Tariq SM, Matthews S, Hakim E. Sensitization to common allergens and its association with allergic disorders at age 4 years: a whole population birth cohort study. Pediatrics 2001;108:E33.

Atherton 1978 {published data only}

Atherton DJ, Sewell M, Soothill JF, Wells RS, Chilvers CE. A double-blind controlled crossover trial of an antigen-avoidance diet in atopic eczema. Lancet 1978;1:401-3.

Barberi 1993 {unpublished data only}

* Barberi I, Salpietro DC, Catalioto G, Fulia F. Clinical trial of a new hypoallergenic formula for risk infants. In: 2nd World Congress of Perinatal Medicine. 1993.

Bellioni 1999 {published data only}

Bellioni-Businco B, Paganelli R, Lucenti P, Giampietro PG, Perborn H, Businco L. Allergenicity of goat's milk in children with cow's milk allergy. J Allergy Clin Immunol 1999;103:1191-4.

Bergmann 1994 {published data only}

Bergmann RL, Bergmann KE, Lau-Schadensdorf S, Luck W, Dannemann A, Bauer CP, Dorsch W, Forster J, Schmidt E, Schulz J. Atopic diseases in infancy. The German multicenter atopy study (MAS-90). Pediatric Allergy and Immunology 1994;5 Suppl 6:19-25.

Bergmann 1996a {published data only}

Bergmann RL, Dannemann A, Edenharter G, Bergmann KE, Monch E, Dudenhausen JW, Wahn U. Influence of ultrafiltrated, partially hydrolysed formula on growth and health of young infants. [German]. Monatsschrift fur Kinderheilkunde 1996;144:152-8.

Brand 1977 {published data only}

Brand JC, Miller JJ, Vorbach EA, Edwards RA. A trial of lactose hydrolysed milk in Australian Aboriginal children. Medical Journal of Australia 1977;2 (Suppl. 4):10-3.

Bruno 1996 {published data only}

Bruno G, Giampietro PG, Businco L. Results of a multicentric study for the prevention of atopic allergy. 48 months of follow up. [Italian]. Minerva Pediatrica 1996;48:413-9.

Burr 1993 {published data only}

Burr ML, Limb ES, Maguire MJ, Amarah L, Eldridge BA, Layzell JC, Merrett TG. Infant feeding, wheezing, and allergy: a prospective study. Archives of Disease in Childhood 1993;68:724-8.

Businco 1983 {published data only}

Businco L, Marchetti F, Pellegrini G, Cantani A, Perlini R. Prevention of atopic disease in "at-risk newborns" by prolonged breast-feeding. Annals of Allergy 1983;51:296-9.

Businco 1987 {published data only}

Businco L, Cantani A, Meglio P, Bruno G. Prevention of atopy: results of a long-term (7 months to 8 years) follow-up. Annals of Allergy 1987;59:183-6.

Campbell 1989 {published data only}

Campbell JP. Dietary therapy of infant colic: a double-blind study. [Czech]. Ceskoslovenska Pediatrie 1993;48:199-202.

* Campbell JP. Dietary treatment of infant colic: a double-blind study. Journal of the Royal College of General Practitioners 1989;39:11-4.

Carroccio 1997 {published data only}

Carroccio A, Cavataio F, Montalto G, Soresi M, Lorello D, Notarbartolo A, Iacono G. Evaluation of pancreatic function development after hydrolyzed protein-based and soy-based formulas in unweaned infants. Scandinavian Journal of Gastroenterology 1997;32:273-7.

Carroccio 2000b {published data only}

Carroccio A, Cavataio F, Montalto G, D'Amico D, Alabrese L, Iacono G. Intolerance to hydrolysed cow's milk proteins in infants: clinical characteristics and dietary treatment. Clinical and Experimental Allergy 2000;31:1597-603.

Carroccio 2000c {published data only}

Carroccio A, Montalto G, Custro N, Notarbartolo A, Cavataio F, D'Amico D, Alabrese D, Iacono G. Evidence of very delayed clinical reactions to cow's milk in cow's milk-intolerant patients. Allergy 2000;55:574-9.

Chan 2002 {published data only}

Chan YH, Shek LP, Aw M, Quak SH, Lee BW. Use of hypoallergenic formula in the prevention of atopic disease among Asian children. Journal of Paediatrics and Child Health 2002;38:84-8.

Chan-Yeung 2000 {published data only}

Becker A, Watson W, Ferguson A, Dimich-Ward H, Chan-Yeung M. The Canadian asthma primary prevention study: outcomes at 2 years of age. Journal of Allergy and Clinical Immunology 2004;113:650-6.

* Chan-Yeung M, Manfreda J, Dimich-Ward H, Ferguson A, Watson W, Becker A. A randomized controlled study on the effectiveness of a multifaceted intervention program in the primary prevention of asthma in high-risk infants. Archives of Pediatrics and Adolescent Medicine 2000;154:657-63.

Chandra 1986 {published data only}

Chandra RK, Puri S, Suraiya C, Cheema PS. Influence of maternal food antigen avoidance during pregnancy and lactation on incidence of atopic eczema in infants. Clinical Allergy 1986;16:563-9.

Chandra 1989a {published data only}

* Chandra RK, Puri S, Hamed A. Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants. BMJ 1989;299:228-30.

Chandra 1989b {published data only}

* Chandra RK, Hamed A. Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas. Annals of Allergy 1991;67:129-32.

Chandra RK, Singh G, Shridhara B. Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic disease in high risk infants. Annals of Allergy 1989;63:102-6.

Chandra RK. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hydrolysate, soy, and conventional cow's milk formulas. Journal of Pediatric Gastroenterology and Nutrition 1997;24:380-8.

Custovic 2000 {published data only}

Custovic A, Simpson BM, Simpson A, Hallam C, Craven M, Brutsche M, Woodcock A. Manchester Asthma and Allergy Study: low-allergen environment can be achieved and maintained during pregnancy and in early life. Journal of Allergy and Clinical Immunology 2000;105:252-8.

* Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A. NAC Manchester Asthma and Allergy Study Group. Effect of environmental manipulation in pregnancy and early life on respiratory symptoms and atopy during first year of life: a randomised trial. Lancet 2001;358:188-93.

D'Agata 1996 {published data only}

D'Agata A, Betta P, Sciacca P, Morano C, Pratico G, Curreri R, et al. Role of dietary prevention in newborns at risk for atopy. Results of a follow-up study]. Pediatria Medica e Chirurgica 1996;18:469-72.

de Jong 1998 {published data only}

de Jong MH, Scharp-Van Der Linden VT, Aalberse R, Heymans HS, Brunekreef B. The effect of brief neonatal exposure to cows' milk on atopic symptoms up to age 5. Archives of Disease in Childhood. 2002;86:365-9.

* de Jong MH, Scharp-van der Linden VT, Aalberse RC, Oosting J, Tijssen JG, de Groot CJ. Randomised controlled trial of brief neonatal exposure to cows' milk on the development of atopy. Archives of Disease in Childhood. 1998;79:126-30.

Decsi 1998 {published data only}

Decsi T, Veitl V, Burus I. Plasma amino acid concentrations, indexes of protein metabolism and growth in healthy, full-term infants fed partially hydrolyzed infant formula. Journal of Pediatric Gastroenterology and Nutrition 1998;27:12-6.

Exl 1998 {published data only}

Exl BM, Deland U, Secretin MC, Preysch U, Wall M, Shmerling DH. Improved general health status in an unselected infant population following an allergen reduced dietary intervention programme. The ZUFF-study-programme. Part I: Study design and 6-month nutritional behaviour. European Journal of Nutrition 2000;39:89-102.

* Exl BM, Deland U, Secretin MC, Preysch U, Wall M, Shmerling DH. Improved general health status in an unselected infant population following an allergen-reduced dietary intervention programme: the ZUFF-STUDY-PROGRAMME. Part II: infant growth and health status to age 6 months. European Journal of Nutrition 2000;39:145-56.

Exl BM, Deland U, Wall M, Preysch U, Secretin MC, Shmerling DH. Zug-Frauenfeld nutritional survey ('Zuff Study'): Allergen-reduced nutrition in a normal infant population and its health-related effects: Results at the age of six months. Nutrition Research 1998;18:1443-62.

Fukushima 1997 {published data only}

Fukushima Y, Iwamoto K, Takeuchi-Nakashima A, Akamatsu N, Fujino-Numata N, Yoshikoshi M, Onda T, Kitagawa M. Preventive effect of whey hydrolysate formulas for mothers and infants against allergy development in infants for the first 2 years. Journal of Nutritional Science and Vitaminology 1997;43:397-411.

Giampietro 2001 {published data only}

Giampietro PG, Kjellman NI, Oldaeus G, Wouters-Wesseling W, Businco L. Hypoallergenicity of an extensively hydrolyzed whey formula. Pediatric Allergy and Immunology 2001;12:83-6.

Giovannini 1994 {published data only}

Giovannini M, Agostoni C, Fiocchi A, Bellu R, Trojan S, Riva E. Antigen-reduced infant formulas versus human milk: growth and metabolic parameters in the first 6 months of life. Journal of the American College of Nutrition 1994;13:357-63.

Gruskay 1982 {published data only}

Gruskay FL. Comparison of breast, cow, and soy feedings in the prevention of onset of allergic disease: a 15-year prospective study. Clinical Pediatrics 1982;21:486-91.

Gustafsson 1992 {published data only}

Gustafsson D, Lowhagen T, Andersson K. Risk of developing atopic disease after early feeding with cows' milk based formula. Archives of Disease in Childhood 1992;67:1008-10.

Halken 1992 {published data only}

Halken S, Host A, Hansen LG, Osterballe O. Effect of an allergy prevention programme on incidence of atopic symptoms in infancy. A prospective study of 159 "high-risk" infants. Allergy 1992;47:545-53.

* Halken S, Host A, Hansen LG, Osterballe O. Preventive effect of feeding high-risk infants a casein hydrolysate formula or an ultrafiltrated whey hydrolysate formula. A prospective, randomized, comparative clinical study. Pediatric Allergy and Immunology 1993;4:173-81.

Halken S, Host A, Hansen LG, Osterballe O. Prevention of allergy in infants. A prospective study of 159 high-risk children [German]. Ugeskrift for Laeger 1994;156:308-12.

Hartman 1994 {unpublished data only}

* Hartman CT, Fredericks GL, Katz ES, Brown CA. Prevalence of symptomatic formula intolerance and allergy in a general infant population. In: Journal of Allergy and Clinical Immunology. 1994:210.

Hattevig 1989 {published data only}

* Hattevig G, Kjellman B, Sigurs N, Bjorksten B, Kjellman NI. Effect of maternal avoidance of eggs, cow's milk and fish during lactation upon allergic manifestations in infants. Clinical and Experimental Allergy 1989;19:27-32.

Hattevig G, Kjellman B, Sigurs N, Grodzinsky E, Hed J, Bjorksten B. The effect of maternal avoidance of eggs, cow's milk, and fish during lactation on the development of IgE, IgG, and IgA antibodies in infants. Journal of Allergy and Clinical Immunology 1990;85:108-15.

Hattevig G, Sigurs N, Kjellman B. Effects of maternal dietary avoidance during lactation on allergy in children at 10 years of age. Acta Paediatrica 1999;88:7-12.

Paronen J, Bjorksten B, Hattevig G, Akerblom HK, Vaarala O. Effect of maternal diet during lactation on development of bovine insulin-binding antibodies in children at risk for allergy. Journal of Allergy and Clinical Immunology 2000;106:302-6.

Sigurs N, Hattevig G, Kjellman B. Maternal avoidance of eggs, cow's milk, and fish during lactation: effect on allergic manifestations, skin-prick tests, and specific IgE antibodies in children at age 4 years. Pediatrics 1992;89:735-9.

Hernell 2003 {published data only}

* Hernell O, Lonnerdal B. Nutritional evaluation of protein hydrolysate formulas in healthy term infants: plasma amino acids, hematology, and trace elements. American Journal of Clinical Nutrition 2003;78:296-301.

Hill 1995a {published data only}

Hill DJ, Cameron DJ, Francis DE, Gonzalez-Andaya AM, Hosking CS. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. Journal of Allergy and Clinical Immunology 1995;96:386-94.

Hill 1995b {published data only}

Hill DJ, Hudson IL, Sheffield LJ, Shelton MJ, Menahem S, Hosking CS. A low allergen diet is a significant intervention in infantile colic: results of a community-based study. Journal of Allergy and Clinical Immunology 1995;96:886-92.

Hill 1999 {published data only}

Hill DJ, Heine RG, Cameron DJ, Francis DE, Bines JE. The natural history of intolerance to soy and extensively hydrolyzed formula in infants with multiple food protein intolerance. Journal of Pediatrics 1999;135:118-21.

Hill 2000 {published data only}

Hill DJ, Heine RG, Cameron DJ, Catto-Smith AG, Chow CW, Francis DE, Hosking CS. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. Journal of Pediatrics 2000;136:641-7.

Hill 2000b {published data only}

Hill D. A report on the analysis of the Melbourn Atopy Cohort Study. A study designed to test the effectiveness of different formula types on the development of atopic symptoms and signs on a cohort of atopy-at-risk infants. Report at year 2. Nestec Internal Report.

* Hill DJ, Sporik R, Thorburn J, Hosking CS. The association of atopic dermatitis in infancy with immunoglobulin E food sensitization. Journal of Pediatrics 2000;137:475-9.

Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC. Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants. Clinical and Experimental Allergy 2004;34:194-200.

Host 1988 {published data only}

Host A, Samuelsson EG. Allergic reactions to raw, pasteurized, and homogenized/pasteurized cow milk: a comparison. A double-blind placebo-controlled study in milk allergic children. Allergy 1988;43:113-8.

Host 1991 {published data only}

Host A. Importance of the first meal on the development of cow's milk allergy and intolerance. Allergy Proceedings 1991;12:227-32.

Iacono 1998 {published data only}

Iacono G, Cavataio F, Montalto G, Florena A, Tumminello M, Soresi M, Notarbartolo A, Carroccio A. Intolerance of cow's milk and chronic constipation in children. New England Journal of Medicine 1998;339:1100-4.

Iikura 1995 {unpublished data only}

* Iikura Y, Akimoto K, Ebisawa M, Onda T, Akazawa A, Saito H, Kimura T, Ishizawa K, Koya N. Effect of hydrolyzed whey protein formula for babies on development of allergic symptoms during infancy. In: Nestle Nutrition Workshop Intestinal Immunology and Food Allergy. Vol. 34. Raven Press, 1995:269-75.

Isolauri 1995 {published data only}

Isolauri E, Sutas Y, Makinen-Kiljunen S, Oja SS, Isosomppi R, Turjanmaa K. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. Journal of Pediatrics 1995;127:550-7.

Keller 1996 {published data only}

Keller KM, Burgin-Wolff A, Lippold R, Wirth S, Lentze MJ. The diagnostic significance of IgG cow's milk protein antibodies re-evaluated. European Journal of Pediatrics. 155(4):331-7, 1996. European Journal of Pediatrics 1996;155:331-7.

Klemola 2002 {published data only}

Klemola T, Vanto T, Juntunen-Backman K, Kalimo K, Korpela R, Varjonen E. Allergy to soy formula and to extensively hydrolyzed whey formula in infants with cow's milk allergy: a prospective, randomized study with a follow-up to the age of 2 years. Journal of Pediatrics 2002;140:219-24.

Lilja 1989 {published data only}

* Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, Johansson SG, Oman H. Effects of maternal diet during late pregnancy and lactation on the development of atopic diseases in infants up to 18 months of age--in-vivo results. Clinical and Experimental Allergy. 1989;19:473-9.

Lilja G, Dannaeus A, Foucard T, Graff-Lonnevig V, Johansson SG, Oman H. Effects of maternal diet during late pregnancy and lactation on the development of IgE and egg- and milk-specific IgE and IgG antibodies in infants. Clinical and Experimental Allergy 1991;21:195-202.

Lindfors 1988 {published data only}

Lindfors A. Enocksson E. Development of atopic disease after early administration of cow milk formula. Allergy 1988;43:11-6.

Lothe 1982 {published data only}

Lothe L, Lindberg T, Jakobsson I. Cow's milk formula as a cause of infantile colic: a double-blind study. Pediatrics 1982;70:7-10.

Lucas 1984a {published data only}

Lucas A, Brooke OG, Cole TJ, Morley R, Bamford MF. Food and drug reactions, wheezing, and eczema in preterm infants. Archives of Disease in Childhood 1990;65:411-5.

* Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. Early diet of preterm infants and development of allergic or atopic disease: randomised prospective study. BMJ 1990;300:837-40.

Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I, Dicarlo L, Cork S, Lucas PJ. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Archives of Disease in Childhood 1984;59:722-30.

Lucas A, McLaughlan P, Coombs RR. Latent anaphylactic sensitisation of infants of low birth weight to cows' milk proteins. British Medical Journal Clinical Research Ed 1984;289:1254-6.

Lucassen 2000 {published data only}

Lucassen PL, Assendelft WJ, Gubbels JW, van Eijk JT, Douwes AC. Infantile colic: crying time reduction with a whey hydrolysate: A double-blind, randomized, placebo-controlled trial. Pediatrics 2000;106:1349-54.

Martinez-Valverde {unpublished data only}

* Martinenez-Valverde A, Aljma-Garcia JM. Study and evaluation of serum IgE and specific total IgE against alpha-lactalbumin, beta-lactoglobulin and casein with hypoallergenic formulas (HA) and other types of feeding (Spanish). Thesis, Universidad de Malaga, Spain 1993.

McLeish 1995 {published data only}

McLeish CM, MacDonald A, Booth IW. Comparison of an elemental with a hydrolysed whey formula in intolerance to cows' milk. Archives of Disease in Childhood 1995;73:211-5.

Medjad-Guillou 1992 {published data only}

Medjad-Guillou N, Henocq A, Arnaud-Battandier F. Does the hydrolysis of proteins change the acceptability and the digestive tolerance of milk for infants? The results of a comparative and randomized prospective study. [French]. Annales de Pediatrie 1992;39:202-6.

Mihatsch 1999 {published data only}

Mihatsch WA, Hogel J, Pohlandt F. Hydrolysed protein accelerates the gastrointestinal transport of formula in preterm infants. Acta Paediatrica 2001;90:196-8.

* Mihatsch WA, Pohlandt F. Protein hydrolysate formula maintains homeostasis of plasma amino acids in preterm infants. Journal of Pediatric Gastroenterology and Nutrition 1999;29:406-10.

Mihatsch 2002 {published data only}

Mihatsch WA, Franz AR, Hogel J, Pohlandt F. Hydrolyzed protein accelerates feeding advancement in very low birth weight infants. Pediatrics 2002;110:1199-203.

Miskelly 1988 {published data only}

Burr ML, Limb ES, Maguire MJ, Amarah L, Eldridge BA, Layzell JC, Merrett TG. Infant feeding, wheezing, and allergy: a prospective study. Archives of Disease in Childhood 1993;68:724-8.

Burr ML, Miskelly FG, Butland BK, Merrett TG, Vaughan-Williams E. Environmental factors and symptoms in infants at high risk of allergy. Journal of Epidemiology and Community Health 1989;43:125-32.

Merrett TG, Burr ML, Butland BK, Merrett J, Miskelly FG, Vaughan-Williams E. Infant feeding and allergy: 12-month prospective study of 500 babies born into allergic families. Annals of Allergy 1988;61:13-20.

* Miskelly FG, Burr ML, Vaughan-Williams E, Fehily AM, Butland BK, Merrett TG. Infant feeding and allergy. Archives of Disease in Childhood 1988;63:388-93.

Mitchell 1977 {published data only}

Mitchell JD, Brand J, Halbisch J. Weight-gain inhibition by lactose in Australian Aboriginal children. A controlled trial of normal and lactose hydrolysed milk. Lancet 1977;1:500-2.

Moran 1992 {published data only}

Moran JR. Effects of prolonged exposure to partially hydrolyzed milk protein. Journal of Pediatrics 1992;121:S90-4.

Nentwich 2003 {published data only}

Nentwich I, Pazdirkova A, Koberska I, Pokojska E, Szepfalusi Z, Lokaj J. Cow milk-specific humoral and cellular immune response in infants with high risk of atopy under feeding a whey hydrolysate infant formula. Klinische Padiatrie 2003;215:275-9.

Niggemann 2001 {published data only}

Niggemann B, Binder C, Dupont C, Hadji S, Arvola T. Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis. Pediatric Allergy and Immunology 2001;12:78-82.

Odelram 1996 {published data only}

Odelram H, Vanto T, Jacobsen L, Kjellman NI. Whey hydrolysate compared with cow's milk-based formula for weaning at about 6 months of age in high allergy-risk infants: effects on atopic disease and sensitization. Allergy 1996;51:192-5.

Oggero 1994 {published data only}

Oggero R, Garbo G, Savino F, Mostert M. Dietary modifications versus dicyclomine hydrochloride in the treatment of severe infantile colics. Acta Paediatrica 1994;83:222-5.

Palma 1996 {published data only}

Palma M, Rosado JL, Lopez P, Gonzalez C, Valencia ME. Lactose intolerance. Its definition, its prevalence in Mexico, and its implications in milk consumption. [Spanish]. Revista de Investigacion Clinica 1996;48:S25-31.

Paronen 2000 {published data only}

Paronen J, Knip M, Savilahti E, Virtanen SM, Ilonen J, Akerblom HK, Vaarala O. Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group. Diabetes 2000;49:1657-65.

Pauls 1996 {published data only}

Pauls J, Bauer K, Versmold H. Randomized controlled trial of formulas with hydrolyzed versus non-hydrolyzed protein for starting enteral feedings in preterm infants <1500g body weight. Journal of Pediatric Gastroenterology and Nutrition 1996;22:450 (abstract 164).

Polberger 1999 {published data only}

Polberger S, Raiha NC, Juvonen P, Moro GE, Minoli I, Warm A. Individualized protein fortification of human milk for preterm infants: comparison of ultrafiltrated human milk protein and a bovine whey fortifier. Journal of Pediatric Gastroenterology and Nutrition 1999;29:332-8.

Raupp 1995 {published data only}

Raupp P, Von Kries R, Gobel C, Fox A, Lemburg P, Schmidt E, Koletzko B, Kunz C, Manz F. Bone density and biochemical parameters of bone mineral metabolism and acid load in preterm infants. Cow's milk formula versus hydrolysed protein preparation. Monatsschr Kinderheilkd 1995;143 (S2):S140-146.

Riezzo 2001 {published data only}

Riezzo G, Indrio F, Montagna O, Tripaldi C, Laforgia N, Chiloiro M, Mautone A. Gastric electrical activity and gastric emptying in preterm newborns fed standard and hydrolysate formulas. Journal of Pediatric Gastroenterology and Nutrition 2001;33:290-5.

Rigo 1994a {published data only}

Rigo J, Salle BL, Picaud JC, Putet G, Senterre J. Nutritional evaluation of protein hydrolysate formulas. European Journal of Clinical Nutrition 1995;49 (suppl. 1):S26-38.

* Rigo J, Salle BL, Putet G, Senterre J. Nutritional evaluation of various protein hydrolysate formulae in term infants during the first month of life. Acta Paediatrica. Supplement 1994;402:100-4.

Rigo 1994b {published data only}

Rigo J, Senterre J. Metabolic balance studies and plasma amino acid concentrations in preterm infants fed experimental protein hydrolysate preterm formulas. Acta Paediatrica (Supp) 1994;405:98-104.

Sack 1994 {published data only}

Sack RB, Castrellon J, Della Sera E, Goepp J, Burns B, Croll J, Tseng P, Reid R, Carrizo H, Santosham M. Hydrolyzed lactalbumin-based oral rehydration solution for acute diarrhoea in infants. Acta Paediatrica 1994;83:819-24.

Sampson 1991 {published data only}

Sampson HA, Bernhisel-Broadbent J, Yang E, Scanlon SM. Safety of casein hydrolysate formula in children with cow milk allergy. Journal of Pediatrics 1991;118:520-5.

Savino 2003 {published data only}

Savino F, Cresi F, Maccario S, Cavallo F, Dalmasso P, Fanaro S, et al. "Minor" feeding problems during the first months of life: effect of a partially hydrolysed milk formula containing fructo- and galacto-oligosaccharides. Acta Paediatrica Supplement 2003;91:86-90.

Schmelzle 2003 {published data only}

Schmelzle H, Wirth S, Skopnik H, Radke M, Knol J, Bockler HM, et al. Randomized double-blind study of the nutritional efficacy and bifidogenicity of a new infant formula containing partially hydrolyzed protein, a high beta-palmitic acid level, and nondigestible oligosaccharides.[see comment]. Journal of Pediatric Gastroenterology and Nutrition 2003;36:343-51.

Schmidt 1995 {published data only}

Schmidt E, Eden-Kohler J, Tonkaboni F, Tolle J. Alimentary allergy prevention in infants with increased allergic risk: The effect of different feeding regimens in the first 6 months on atopic manifestations during the first year of life. A large scale feeding trial. In: Nestle Nutritional Workshop: Intestinal Immunology and Food Allergy. Vol. 34. Raven Press, 1995:231-48.

Schmitz 1992 {published data only}

Schmitz J, Digeon B, Chastang C, Dupouy D, Leroux B, Robillard P, Strobel S. Effects of brief early exposure to partially hydrolyzed and whole cow milk proteins. Journal of Pediatrics 1992;121:S85-9.

Schrander 1993 {published data only}

Schrander JJ, van den Bogart JP, Forget PP, Schrander-Stumpel CT, Kuijten RH, Kester AD. Cow's milk protein intolerance in infants under 1 year of age: a prospective epidemiological study. European Journal of Pediatrics 1993;152:640-4.

Seppo 2005 {published data only}

Seppo L, Korpela R, Lonnerdal B, Metsaniitty L, Juntunen-Backman K, Klemola T, et al. A follow-up study of nutrient intake, nutritional status, and growth in infants with cow milk allergy fed either a soy formula or an extensively hydrolyzed whey formula. American Journal of Clinical Nutrition 2005;82:140-5.

Sicherer 2001 {published data only}

Sicherer SH, Noone SA, Koerner CB, Christie L, Burks AW. Sampson HA. Hypoallergenicity and efficacy of an amino acid-based formula in children with cow's milk and multiple food hypersensitivities. Journal of Pediatrics 2001;138:688-93.

Silva Rey 1996 {unpublished data only}

Silva Rey AL, Garcia G, Nogales A. Preventatibve effect of a partially hydrolyzed milk formula. Thesis, Madrid, Spain. 1996.

Szajewska 2004 {published data only}

Szajewska H, Mrukowicz JZ, Stoinska B, Prochowska A. Extensively and partially hydrolysed preterm formulas in the prevention of allergic diseases in preterm infants: a randomized, double-blind trial. Acta Paediatrica 2004;93:1159-65.

Tariq 1998 {published data only}

Tariq SM, Matthews SM, Hakim EA, Stevens M, Arshad SH, Hide DW. The prevalence of and risk factors for atopy in early childhood: a whole population birth cohort study. Journal of Allergy and Clinical Immunology 1998;101:587-93.

Taubman 1988 {published data only}

Taubman B. Parental counseling compared with elimination of cow's milk or soy milk protein for the treatment of infant colic syndrome: a randomized trial. Pediatrics 1988;81:756-61.

Terheggen-Lagro 2002 {published data only}

Terheggen-Lagro SW, Khouw IM, Schaafsma A, Wauters EA. Safety of a new extensively hydrolysed formula in children with cow's milk protein allergy: a double blind crossover study. BMC Pediatrics 2002;2:10.

Vaarala 1995 {published data only}

Paronen J, Vaarala O, Savilahti E, Saukkonen T, Akerblom HK. Soluble adhesion molecules and oral antigen feeding in infants. Pediatric Research 1996;40:276-9.

* Vaarala O, Saukkonen T, Savilahti E, Klemola T, Akerblom HK. Development of immune response to cow's milk proteins in infants receiving cow's milk or hydrolyzed formula. Journal of Allergy and Clinical Immunology 1995;96:917-23.

Vandenplas 1988 {published data only}

* Vandenplas Y, Deneyer M, Sacre L, Loeb H. Preliminary data on a field study with a new hypo-allergenic formula. European Journal of Pediatrics 1988;148:274-7.

Vandenplas 1989 {published data only}

* Vandenplas Y, Malfroot A, Dab I. Short-term prevention of cow's milk protein allergy in infants. Immunology and Allergy Practice 1989;11:430-7.

Zeiger 1989 {published data only}

* Zeiger RS, Heller S, Mellon MH, Forsythe AB, O'Connor RD, Hamburger RN, Schatz M. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. Journal of Allergy and Clinical Immunology 1989;84:72-89.

Zeiger RS, Heller S, Mellon MH, Halsey JF, Hamburger RN, Sampson HA. Genetic and environmental factors affecting the development of atopy through age 4 in children of atopic parents: A prospective randomized study of food allergen avoidance. Pediatric Allergy and Immunology 1992;3:110-27.

Zeiger RS, Heller S. Development of nasal basophilic cells and nasal eosinophils from age 4 months through 4 years in children of atopic parents. Journal of Allergy and Clinical Immunology 1993;91:723-34.

Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. Journal of Allergy and Clinical Immunology 1995;95:1179-90.

* indicates the primary reference for the study

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Wright AL, Holberg CJ, Taussig LM, Martinez FD. Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood. Thorax 2001;56:192-7.

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Other published versions of this review

Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2003.

Comparisons and data

01.01 Any allergy

01.01.01 Infancy (incidence)
01.01.02 Childhood (incidence)

01.01.03 Childhood (prevalence)

01.02 Asthma

01.02.01 Infancy (incidence)
01.02.02 Childhood (incidence)

01.02.03 Childhood (prevalence)

01.03 Eczema

01.03.01 Infancy (incidence)
01.03.02 Childhood (incidence)

01.03.03 Childhood (prevalence)

01.04 Food allergy

01.04.01 Infancy (incidence)
01.04.02 Childhood (incidence)

01.04.03 Childhood (prevalence)

01.05 Cow's milk allergy

01.05.01 Infancy (incidence)

01.05.02 Childhood (incidence)

01.05.03 Childhood (prevalence)
 

02 Prolonged feeding: Hydrolysed formula vs human milk feeding

02.01 Any allergy

03 Early short term feeding: Hydrolysed formula vs cow's milk formula

03.01 Any allergy

03.01.01 Infancy (incidence)
03.01.02 Childhood (incidence)

03.01.03 Childhood (prevalence)

03.02 Asthma

03.02.01 Infancy (incidence)
03.02.02 Childhood (incidence)

03.02.03 Childhood (prevalence)

03.03 Eczema

03.03.01 Infancy (incidence)
03.03.02 Childhood (incidence)

03.03.03 Childhood (prevalence)

03.04 Food allergy

03.04.01 Infancy (incidence)
03.04.02 Childhood (incidence)

03.04.03 Childhood (prevalence)

03.05 Cow's milk allergy

03.05.01 Infancy (incidence)

03.05.02 Childhood (incidence)

03.05.03 Childhood (prevalence)

04 Prolonged feeding: Hydrolysed formula vs cow's milk formula

04.01 Any allergy

04.01.01 Infancy (incidence)

04.01.02 Childhood (incidence)

04.01.03 Childhood (prevalence)

04.02 Asthma

04.02.01 Infancy (incidence)

04.02.02 Childhood (incidence)

04.02.03 Childhood (prevalence)

04.03 Eczema

04.03.01 Infancy (incidence)

04.03.02 Childhood (incidence)

04.03.03 Childhood (prevalence)

04.04 Rhinitis

04.04.01 Infancy (incidence)

04.04.02 Childhood (incidence)

04.04.03 Childhood (prevalence)

04.05 Food allergy

04.05.01 Infancy (incidence)

04.05.02 Childhood (incidence)
04.05.03 Childhood (prevalence)

04.06 Cow's milk allergy

04.06.01 Infancy (incidence)

04.06.02 Childhood (incidence)
04.06.03 Childhood (prevalence)
 

05 Prolonged feeding: Hydrolysed formula vs cow's milk formula - Low risk infants

05.01 Weight gain (g/kg/day)

05.01.01 Preterm formula

05.02 Head circumference change (cm/week)

05.02.01 Preterm formula

05.03 Length gain (cm/week)

05.03.01 Preterm formula

06 Prolonged feeding: Hydrolysed formula vs cow's milk formula - High risk infants

06.01 Any allergy

06.01.01 Infancy (incidence)

06.01.02 Childhood (incidence)

06.01.03 Childhood (prevalence)

06.02 Asthma

06.02.01 Infancy (incidence)

06.02.02 Childhood (incidence)

06.02.03 Childhood (prevalence)

06.03 Eczema

06.03.01 Infancy (incidence)

06.03.02 Childhood (incidence)

06.03.03 Childhood (prevalence)

06.04 Rhinitis

06.04.01 Infancy (incidence)

06.04.02 Childhood (incidence)

06.04.03 Childhood (prevalence)

06.05 Food allergy

06.05.01 Infancy (incidence)

06.05.02 Childhood (incidence)
06.05.03 Childhood (prevalence)

06.06 Cow's milk allergy

06.06.01 Infancy (incidence)

06.06.02 Childhood (incidence)
06.06.03 Childhood (prevalence)

07 Prolonged feeding: Extensively hydrolysed formula vs cow's milk formula

07.01 Any allergy

07.01.01 Infancy (incidence)

07.01.02 Childhood (incidence)

07.01.03 Childhood (prevalence)

07.02 Asthma

07.02.01 Infancy (incidence)

07.02.02 Childhood (incidence)
07.02.03 Childhood (prevalence)

07.03 Eczema

07.03.01 Infancy (incidence)

07.03.02 Childhood (incidence)

07.03.03 Childhood (prevalence)

07.04 Rhinitis

07.04.01 Infancy (incidence)

07.04.02 Childhood (incidence)
07.04.03 Childhood (prevalence)

07.05 Food allergy

07.05.01 Infancy (incidence)

07.05.02 Childhood (incidence)
07.05.03 Childhood (prevalence)

07.06 Weight gain (g/day)

07.06.01 Preterm formula

08 Prolonged feeding: Partially hydrolysed formula vs cow's milk formula

08.01 Any allergy

08.01.01 Infancy (incidence)

08.01.02 Childhood (incidence)

08.01.03 Childhood (prevalence)

08.02 Asthma

08.02.01 Infancy (incidence)

08.02.02 Childhood (incidence)

08.02.03 Childhood (prevalence)

08.03 Eczema

08.03.01 Infancy (incidence)

08.03.02 Childhood (incidence)

08.03.03 Childhood (prevalence)

08.04 Rhinitis

08.04.01 Infancy (incidence)

08.04.02 Childhood (incidence)

08.04.03 Childhood (prevalence)

08.05 Food allergy

08.05.01 Infancy (incidence)

08.05.02 Childhood (incidence)
08.05.03 Childhood (prevalence)

08.06 Cow's milk allergy

08.06.01 Infancy (incidence)

08.06.02 Childhood (incidence)
08.06.03 Childhood (prevalence)

08.07 Weight gain (g/day)

08.07.01 Preterm formula

09 Prolonged feeding: Extensively hydrolysed formula vs partially hydrolysed formula

09.01 Any allergy

09.01.01 Infancy (incidence)

09.01.02 Childhood (incidence)

09.01.03 Childhood (prevalence)

09.02 Asthma

09.02.01 Infancy (incidence)

09.02.02 Childhood (incidence)
09.02.03 Childhood (prevalence)

09.03 Eczema

09.03.01 Infancy (incidence)

09.03.02 Childhood (incidence)

09.03.03 Childhood (prevalence)

09.04 Rhinitis

09.04.01 Infancy (incidence)

09.04.02 Childhood (incidence)
09.04.03 Childhood (prevalence)

09.05 Food allergy

09.05.01 Infancy (incidence)

09.05.02 Childhood (incidence)
09.05.03 Childhood (prevalence)

09.06 Cow's milk allergy

09.06.01 Infancy (incidence)

09.06.02 Childhood (incidence)
09.06.03 Childhood (prevalence)

09.07 Weight gain (g/day)

09.07.01 Preterm formula

10 Prolonged sole feeding: Hydrolysed formula vs cow's milk formula

10.01 Any allergy

10.01.01 Infancy (incidence)

10.01.02 Childhood (incidence)

10.01.03 Childhood (prevalence)

10.02 Asthma

10.02.01 Infancy (incidence)

10.02.02 Childhood (incidence)

10.02.03 Childhood (prevalence)

10.03 Eczema

10.03.01 Infancy (incidence)

10.03.02 Childhood (incidence)

10.03.03 Childhood (prevalence)

10.04 Rhinitis

10.04.01 Infancy (incidence)

10.04.02 Childhood (incidence)

10.04.03 Childhood (prevalence)

10.05 Cow's milk allergy

10.05.01 Infancy (incidence)

10.05.02 Childhood (incidence)
10.05.03 Childhood (prevalence)

11 Prolonged feeding: Hydrolysed formula vs cow's milk formula - Allergy / intolerance confirmed by test

11.01 Any allergy

11.01.01 Infancy (incidence)

11.01.02 Childhood (incidence)
11.01.03 Childhood (prevalence)

11.02 Atopic rhinitis

11.02.01 Infancy (incidence)

11.02.02 Childhood (incidence)
11.02.03 Childhood (prevalence)

11.03 Atopic eczema

11.03.01 Infancy (incidence)

11.03.02 Childhood (incidence)
11.03.03 Childhood (prevalence)

11.05 Food allergy

11.05.01 Infancy (incidence)

11.05.02 Childhood (incidence)
11.05.03 Childhood (prevalence)

11.06 Cow's milk allergy

11.06.01 Infancy (incidence)

11.06.02 Childhood (incidence)
11.06.03 Childhood (prevalence)

11.07 Food intolerance

11.07.01 Infancy (incidence)

11.07.02 Childhood (incidence)
11.07.03 Childhood (prevalence)

12 Prolonged feeding: Hydrolysed formula vs cow's milk formula - Blinded measurement

12.01 Any allergy

12.01.01 Infancy (incidence)

12.01.02 Childhood (incidence)

12.01.03 Childhood (prevalence)

12.02 Asthma

12.02.01 Infancy (incidence)

12.02.02 Childhood (incidence)
12.02.03 Childhood (prevalence)

12.03 Eczema

12.03.01 Infancy (incidence)

12.03.02 Childhood (incidence)

12.03.03 Childhood (prevalence)

12.04 Rhinitis

12.04.01 Infancy (incidence)

12.04.02 Childhood (incidence)
12.04.03 Childhood (prevalence)

12.05 Food allergy

12.05.01 Infancy (incidence)

12.05.02 Childhood (incidence)
12.05.03 Childhood (prevalence)

12.06 Cow's milk allergy

12.06.01 Infancy (incidence)

12.06.02 Childhood (incidence)
12.06.03 Childhood (prevalence)

13 Prolonged feeding: Hydrolysed formula vs cow's milk formula - Adequate methodology

13.01 Any allergy

13.01.01 Infancy (incidence)

13.01.02 Childhood (incidence)
13.01.03 Childhood (prevalence)

13.02 Asthma

13.02.01 Infancy (incidence)

13.02.02 Childhood (incidence)
13.02.03 Childhood (prevalence)

13.03 Eczema

13.03.01 Infancy (incidence)

13.03.02 Childhood (incidence)
13.03.03 Childhood (prevalence)

13.04 Rhinitis

13.04.01 Infancy (incidence)

13.04.02 Childhood (incidence)
13.04.03 Childhood (prevalence)

13.05 Food allergy

13.05.01 Infancy (incidence)

13.05.02 Childhood (incidence)
13.05.03 Childhood (prevalence)

13.06 Weight gain (g/kg/day)

13.06.01 Preterm formula

14 Prolonged feeding: Partially hydrolysed whey formula vs cow's milk formula

14.01 Any allergy

14.01.01 Infancy (incidence)

14.01.02 Childhood (incidence)

14.01.03 Childhood (prevalence)

14.02 Asthma

14.02.01 Infancy (incidence)

14.02.02 Childhood (incidence)

14.02.03 Childhood (prevalence)

14.03 Eczema

14.03.01 Infancy (incidence)

14.03.02 Childhood (incidence)

14.03.03 Childhood (prevalence)

14.04 Rhinitis

14.04.01 Infancy (incidence)

14.04.02 Childhood (incidence)

14.04.03 Childhood (prevalence)

14.05 Cow's milk allergy

14.05.01 Infancy (incidence)

14.05.02 Childhood (incidence)
14.05.03 Childhood (prevalence)

14.06 Weight gain (g/day)

14.06.01 Preterm formula

15 Prolonged feeding: Partially hydrolysed casein containing formula vs cow's milk formula

15.01 Any allergy

15.01.01 Infancy (incidence)

15.01.02 Childhood (incidence)
15.01.03 Childhood (prevalence)

15.02 Asthma

15.02.01 Infancy (incidence)

15.02.02 Childhood (incidence)
15.02.03 Childhood (prevalence)

15.03 Eczema

15.03.01 Infancy (incidence)

15.03.02 Childhood (incidence)
15.03.03 Childhood (prevalence)

15.04 Rhinitis

15.04.01 Infancy (incidence)

15.04.02 Childhood (incidence)
15.04.03 Childhood (prevalence)

15.05 Food allergy

15.05.01 Infancy (incidence)

15.05.02 Childhood (incidence)
15.05.03 Childhood (prevalence)

15.06 Weight gain (g/day)

15.06.01 Preterm formula

16 Prolonged feeding: Extensively hydrolysed whey formula vs cow's milk formula

16.01 Any allergy

16.01.01 Infancy (incidence)

16.01.02 Childhood (incidence)

16.01.03 Childhood (prevalence)

16.02 Asthma

16.02.01 Infancy (incidence)
16.02.02 Childhood (incidence)
16.02.03 Childhood (prevalence)

16.03 Eczema

16.03.01 Infancy (incidence)

16.03.02 Childhood (incidence)

16.03.03 Childhood (prevalence)

17 Prolonged feeding: Extensively hydrolysed casein formula containing vs cow's milk formula

17.01 Any allergy

17.01.01 Infancy (incidence)

17.01.02 Childhood (incidence)

17.01.03 Childhood (prevalence)

17.02 Asthma

17.02.01 Infancy (incidence)

17.02.02 Childhood (incidence)
17.02.03 Childhood (prevalence)

17.03 Eczema

17.03.01 Infancy (incidence)

17.03.02 Childhood (incidence)

17.03.03 Childhood (prevalence)

17.04 Rhinitis

17.04.01 Infancy (incidence)

17.04.02 Childhood (incidence)
17.04.03 Childhood (prevalence)

17.05 Food allergy

17.05.01 Infancy (incidence)

17.05.02 Childhood (incidence)
17.05.03 Childhood (prevalence)

17.06 Weight gain (g/day)

17.06.01 Preterm formula

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