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Keywords:

  • allergy prevention;
  • children;
  • cow's milk protein allergy;
  • hypoallergenic formula

Abstract

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

Hypoallergenic formulas are processed by enzymatic hydrolysis of different protein sources such as bovine casein/whey and soy followed by further processing such as heat treatment and/or ultrafiltration, or they are based on amino acid mixtures. The products have been classified according to the degree of protein hydrolysis as ‘extensively’ or ‘partially’ hydrolysed protein products. Product properties may be characterized by biochemical techniques, and reduction of allergenicity may be assessed in vitro with various immunological methods, and in vivo with skin prick tests, patch tests and challenge tests. In vitro tests do not predict the allergenic effects in humans, and at present there is no evidence of a specific threshold of immunogenic protein. Only pure amino acid mixtures are considered to be nonallergenic. Other ‘hypoallergenic’ products contain residual allergenicity. At present, the potential of a product for treatment and prevention of food allergy can only be determined by clinical trials using scientifically appropriate standards. It has been recommended that dietary products for treatment of cow's milk protein allergy in infants should be tolerated by at least 90% (with 95% confidence) of infants with documented cow's milk protein allergy. Some extensively hydrolysed products and amino-acid-based products have met these criteria. Formulas intended for prevention should have a very low, if any, allergenic activity until otherwise proven. So far there are no firm criteria available for the design of hypoallergenic foods for prevention. Newborns included in prevention studies should be from high-risk families; they should be randomized at birth and fed the formula when supplements are needed for at least the first 4–6 months of life. Follow-up should be at least 18 months, and children should be investigated when symptoms appear. Validated clinical criteria, including controlled food challenges, should be used for diagnosis. Infants fed formulas that claim to prevent or delay allergy should have a statistically significant lower prevalence of allergy when compared with infants fed a standard cow's milk formula. Feeding high-risk infants a documented hypoallergenic formula combined with avoidance of solid foods during the first 4–6 months reduces the cumulative incidence of cow's milk protein allergy and atopic dermatitis as compared with a standard cow's-milk-based formula. Partially hydrolysed formulas may have an effect, though it seems to be less than that of extensively hydrolysed formulas at present. Thus, if exclusive breast-feeding for 4–6 months is not possible in high-risk infants, a documented hypoallergenic formula and avoidance of solid foods are recommended for the first 4 months of life.

Hypoallergenic formulas are intended for use by infants with existing allergic symptoms because of documented cow's milk protein allergy (CMPA). For more than 60 years, many children with food protein allergies and other forms of dietary protein intolerance have been treated successfully with extensively hydrolysed formulae (EHF) (1–5) and, more recently, also with products based on amino acid mixtures (5,6). Strategies for the prevention of allergy have been proposed, including the use of EHF. Partially hydrolysed formulae (PHF) have also been proposed and marketed in Europe as hypoallergenic formulae (HF). The European Society for Paediatric Allergology and Clinical Immunology (ESPACI) (7) and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) have commented previously (8) on these issues and the Commission of the European Union has issued a regulation for the requirements of infant formulas with reduced allergenicity or reduced antigenicity (9). Several HF with reduced allergenicity in varying degrees are available. Most of these products are produced by an enzymatic hydrolysis of cow's milk protein. Ideally, a HF should be tolerated by most infants and young children with proven CMPA, and a possible preventive potency should be comparable with that of exclusively breast-feeding. This review will focus on the results of prospective controlled randomized studies on dietary allergy prevention. When randomization is not possible, e.g. as regards the preventive effect of breast-feeding, only prospective controlled studies of high quality have been included. The recommendations given are evidence-based according to recent studies on classification of statements of evidence I–IV and grades of recommendations A–D (10–13).

Food allergy

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

Sensitization to allergens develops in the order of exposure. During early infancy low levels of specific immunoglobulin E (IgE) antibodies to food proteins, especially cow's milk protein and egg, is a normal phenomenon, whereas increased levels of antibodies to foods in early infancy are associated with an increased risk of allergic disease. Later in childhood, sensitization to foods normally disappears and is followed by sensitization to primarily indoor allergens like house dust mites and pets and later also to outdoor allergens such as pollens and moulds. This natural history of sensitization in allergics reflects the well-known allergy march starting in early infancy with atopic dermatitis often related to food allergy during the first 1–3 years of life followed by partial recovery of these allergic diseases, which are replaced by bronchial asthma and allergic rhino-conjunctivitis in later childhood and adolescence (14). CMPA is mainly a problem of infancy and early childhood, and has its onset mostly during infancy. In prospective studies the incidence of CMPA in infancy has been estimated to be about 2–3% based on strict diagnostic criteria (8,15,16). Most of the children with CMPA will be tolerant to milk before the age of 3 years (16). Reproducible clinical abnormal reactions to cow's milk proteins may be the result of the interaction between one or more immune mechanisms. Children with IgE-mediated reactions to cow's milk protein often show immediate reactions after intake of even small amounts of cow's milk protein, and severe anaphylactic reactions may occur (16). The development of food allergy depends on several factors, especially genetic predisposition, early foreign food protein exposure (time, dose, frequency), food protein uptake and handling. The relatively high incidence of food allergy, especially CMPA, in infancy has been suggested to be the result of an incomplete mucosal barrier, increased gut permeability to large molecules, and immaturity of local and systemic immunological responses. Human colostrum/milk facilitates maturation of the gut and provides passive protection against infectious agents and antigens (8). However, food proteins are absorbed from the gut and can be measured in the blood in quantities of micrograms per litre serum both in children and adults. Likewise, foreign food proteins are secreted into the breast milk of lactating women. The cow's milk protein β-lactoglobulin can be detected in the breast milk of 95% of lactating women (0.9–150 μg/l, median 4.2 μg/l) (Table 1) (17–19), when consecutive testing of breast milk is carried out (19). Likewise, low amounts (0.84–14.5 μg/l) of residual cow's milk proteins (β-lactoglobulin) have been determined in EHF, whereas higher amounts, up to 12.400 μg/l, have been determined in PHF (Table 1) (17,20). In infancy sensitization to cow's milk proteins is usually the result of ingestion of cow's milk-based formula, and a significant association between early neonatal exposure to cow's milk formula feeding and subsequent development of CMPA has been documented (16).

Table 1.  Degree of hydrolysis in some hydrolysed formulas, and content of β-lactoglobulin (BLG) (μg/l) in cow's milk, some formulas (ready to use) and breast milk
Cow's milk, some formulas and breast milkDegree of hydrolysisContent of BLG (μg/l)
Ref. 17Ref. 20
  • PHF, partially hydrolysed formula; EHF, extensively hydrolysed formula.

  • nd, not done, i.e. not analysed.

  • PHF contain a higher proportion of unresolved, nondegraded or partially degraded proteins in the range 5–40 kDa. There is no unanimous agreement on firm criteria for classification of EHF and PHF.

  • *

    To the knowledge of the authors, convincing clinical evidence of a high degree of hypoallergenicity of these products has not been published.

Cow's milk 4 000 000nd
Nan1 nd1 320 000
Hydrolysed bovine casein
 NutramigenEHF0.841.1
 PregestimilEHFnd5.0
 AlimentumEHFndnd
Hydrolysed bovine whey
 Alfa-RéEHF14.5198
 ProfylacEHF8.923
 Pepti-JuniorEHF0.9113
 Nutrilon Pepti*EHFnd207
 Nutrilon Pepti Plus*EHFnd18
 Peptidi-TutteliEHFndnd
 Nan HAPHFnd48 180
 Beba HAPHFnd96 250
 Good StartPHF12 400nd
 Nidina HAPHFndnd
 LHAPHF31 200nd
Hydrolysed casein and whey
 Aptamil HA hypoantigenPHFnd359
Hydrolysed soy and bovine collagen
 PregominEHF9.74.7
 Aptamil HAPHFnd77
Amino acid mixture
 Neocate, Nutri-Juniorndnd 
Breastmilk5–33 μg/l, according to ref. 18  
0.9–150 μg/l, according to ref. 19  

Characterization of hypoallergenic formulas

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

The available allergen-reduced dietary products for infants are derived from different protein sources, such as bovine casein, bovine whey and soy exposed to enzymatic hydrolysis and further processing, such as heat treatment or ultrafiltration, or they are based on amino acid mixtures (Table 1). Attempts have been made to classify products according to the degree of protein hydrolysis [‘extensive’ or ‘high degree’ (EHF) vs‘partial’ or ‘low degree’ (PHF) protein hydrolysates] (1,7,8); but there is no unanimous agreement on firm criteria on which to base such a classification (Table 1). For example, product properties may be characterized by biochemical techniques, such as the spectrum of peptide molecular weights or the ratio of α amino nitrogen to total nitrogen. Reduction of allergenicity of dietary products may be assessed in vitro using various immunological methods [e.g. IgE binding tests such as the radioallergosorbent test (RAST), RAST inhibition test, immunoelectrophoresis methods and enzyme-linked immunosorbent assay (ELISA)] and in vivo with skin prick tests, patch tests and challenge tests (20). In vitro characterization of peptide size and determination of allergenicity might be valuable for quality control of the products and assurance of batch-to-batch consistency as well as for labelling. Meanwhile, on the basis of current knowledge, such in vitro tests do not predict the immunogenic or the allergenic effects in the recipient infant. The regulations of the European Union for labelling infant formulas as having reduced allergenicity (or antigenicity) are based arbitrarily on a content of immunoreactive protein of <1% of total nitrogen-containing substances (9) but there is no evidence that such a threshold of immunogenic protein would ensure a reduced clinical allergenicity. Only pure amino acid mixtures are considered to be nonallergenic, other ‘hypoallergenic’ products contain residual allergenicity (8,20,21) (Table 2). At present, the potential of a product for treatment and prevention of food allergy can only be determined by clinical trials using scientifically appropriate standards. The allergenicity, i.e. the ability of an allergen to induce allergic reactions, may vary considerably because thresholds of reactions against allergens may differ intra- and interindividually and with time. Atopic individuals have the capacity to develop sensitization and clinical symptoms against even minute amounts of allergens. In cow's milk the most frequent allergens are native proteins, although new allergenic epitopes may be revealed by technological processing or by digestion. Furthermore, aggregation of smaller peptides to larger particles may explain the occurrence of higher molecular weight particles in HF (20; 21). Several different proteins from cow's milk giving rise to production of IgE antibodies in atopic subjects have been identified. Major allergens are found in both the casein- and the whey-fraction of cow's milk.

Table 2.  Allergenicity of hypoallergenic formulae
Only pure amino acid mixtures are nonallergenic
Other ‘hypoallergenic’ products contain residual allergenicity:
 Residual antigenicity
  inadequate hydrolysis/filtration
  peptides with epitopes derived from cow's milk protein
  aggregation of smaller peptides
  epitopes cross-reacting with those of cow's milk protein
 Contamination
  during production or packing
  from carbohydrate/lipid sources
 Other antigen sources
  from carbohydrate/lipid sources

Hypoallergenic formulas for treatment

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

The basic and only effective treatment of CMPA is complete avoidance of cow's milk protein. During infancy and early childhood an alternative hypoallergenic milk substitute is necessary.

Alternative milk substitutes, such as soybean formula and goat's milk, have been applied, but these unaltered proteins are potentially allergenic and allergic reactions to them have been documented. Soy protein is reported to be at least as allergenic as cow's milk protein, and in young children with CMPA, soy protein allergy has been recorded with frequencies between 17 and 47% (8,22). Soy formula is not generally recommended for infants and young children with CMPA. Most of the proteins of goat's milk share identity with those of cow's milk, resulting in cross-reactivity (23). Thus individuals with CMPA may react at the first exposure to goat's milk, and goat's milk should not be recommended to children with CMPA. HF based on casein from cow's milk have been used and regarded as safe for the treatment of CMPA for several years. Other HF have been introduced and some of these have also been shown to be safe for treatment of CMPA (2–4,8). EHF are recommended for the treatment of infants with CMPA. EHF casein formulae, Nutramigen and Pregestemil, have been widely used in children with CMPA for more than 60 years, and are generally regarded as ‘hypoallergenic’ (1,7,24). These formulas are enzymatically extensively hydrolysed, and the effectiveness of these products is documented in clinical reports on CMPA (1–5,7,24–27). Some of the products are also tested with controlled challenges in children with CMPA. The use of EHF is hampered by a poor, bitter taste. This problem would be reduced by a less complete hydrolysis; however, this may result in increased remaining antigenicity and a higher risk of allergic reactions. PHF whey hydrolysates have been used primarily for prevention for some years. Several cases of allergic reactions to these products have been reported in children with CMPA, and these preparations are not recommended to children with CMPA.

Allergic reactions to EHF products in infants with CMPA have been published (27–32). Adverse reactions to HF may be caused by residual antigenicity, but it may also be caused by contamination with native proteins during fabrication or packing or from contamination of carbohydrate source (e.g. lactose). Also other antigen/allergen sources, e.g. residual vegetable protein from vegetable sources of maltodextrin or lipids, may be considered (Table 2). It has been recommended that dietary products for treatment of CMPA in infants should be tolerated by at least 90% (with 95% confidence) of infants with documented CMPA (1,8). Furthermore, it is recommended that after a successful double-blind challenge the product should be tolerated in a controlled open challenge during a period of 7 days (1). Some EHF (2–5) and amino-acid-based products (5,6), have met these criteria. Recently, a new EHF supplemented with Probiotics has been marketed for children older than 4 months. At present there is no evidence of any further benefit of the addition of probiotics.

Breast-feeding

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

In prospective observational studies (33–49) and one randomized study (50) breast-feeding for at least 3–6 months and late introduction of solid foods (after 4–6 months) is associated with a decreased risk of CMPA/food allergy and atopic dermatitis up to 3 years and recurrent wheeze/asthma up to 6 (− 17) years (Table 3). As recommended by the World Health Organization exclusively breast-feeding for the first 6 months of life should be attempted in all infants and also recommended as an allergy-prevention measure. Two meta-analyses (51,52), using predetermined standardized inclusion criteria for trial appraisal, and a systematic review (53) demonstrated an overall protective effect of exclusive breast-feeding during the first 3–4 months of life on atopic dermatitis and asthma in the first 5–10 years of life, especially in infants with atopic heredity. There is no evidence of preventive effect of special maternal diet, either during pregnancy or lactation (54–57). When breast milk is insufficient or lacking a substitute formula is needed. HF have been employed in studies on prevention/reduction of the incidence of food allergy in high-risk infants.

Table 3.  Preventive effect of dietary measures
InterventionEffectGrades of recommendation
  • Grades of recommendation according to (10–14).

  • Recommendations based on the results of prospective controlled randomized (when possible) studies, grade A. Furthermore, prospective controlled nonrandomized studies of high-quality, grade B, as regards the effect of breast-feeding have been included.

  • *

    Exclusively or as a supplement to breast-feeding.

  • High-risk infants: infants with a well-defined increased risk of developing allergic disease; that is, infants with at least one first-degree relative (parent or sibling) with documented allergic disease.

Exclusively breast-feeding, at least 4 monthsReduced cumulative incidence of cow's milk protein allergy until 18 monthsA
For nutritional reasons WHO recommend  breast-feeding for the first 6 months for all  Children
 Reduced cumulative incidence of atopic dermatitis until 3 yearsB
Reduced recurrent wheeze/asthma until 6 (−16) yearsB
Extensively hydrolysed formula* combined with avoidance of solid foods at least the first 4–6 monthsReduced cumulative incidence of cow's milk protein allergy until 5–7 years and atopic dermatitis until 4 yearsA
Partially hydrolysed formula* combined with avoidance of solid foods at least the first 4–6 monthsSome effect, though less than extensively hydrolysed formulaA
An effect of an allergy-preventive diet has been documented only in high-risk-infants
No convincing evidence for effect of an allergy preventive diet after the age of 4–6 months

Hydrolysed formulas

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

Formulas intended for prevention should have a very low, if any, allergenic activity until otherwise proven (8). In the future, other criteria may be set up for the development of formulas intended for prevention, based on the immuno-stimulatory effect of these products. So far there are no such criteria for the design of hypoallergenic foods for prevention available. Newborns included in prevention studies should be from high-risk families. High-risk infants are defined as infants with at least one first-degree relative (parent or sibling) with documented atopic disease (doctor diagnosed), possibly combined with elevated cord blood IgE in the case of single atopic predisposition. The infants should be randomized at birth and fed the formula when supplements are needed for at least the first 4 months of life [or 6 months according to America Academy of Pediatrics (1)] and observed for at least 18 months. Children should be investigated when symptoms appear and validated clinical criteria, including controlled food challenges, should be used for diagnosis (1). Infants fed formulas that claim to prevent or delay allergy should have a statistically significant lower prevalence of allergy when compared with infants fed a standard cow's milk formula (1).The only useful method for evaluation of the possible preventive ‘potency’ is properly performed studies in matched groups of infants with proven high risk of developing CMPA/allergic diseases, using well-defined and validated methods. As a result of the spontaneous course of food allergy it is important to evaluate the cumulative incidence of food allergy/CMPA during the first 3–4 years of life – and not only the point prevalence at the age of 3–4 years. Moreover the diagnostic criteria are crucial. As reviewed in a position paper of ESPACI (7) and a joint statement of ESPACI and ESPGHAN (8) prospective, randomized, controlled studies on high-risk infants have shown a preventive effect of different dietary allergy prevention programmes. This preventive effect has only been demonstrated in high-risk infants (8,50). As a result of the great variations in study design and diagnostic criteria it is difficult to compare the effects of these programmes. A preventive effect of EHF has been demonstrated (Table 3) in combination with avoidance of cow's milk proteins and solid foods during at least the first 4 months in high-risk infants on the cumulative incidence of atopic dermatitis and food allergy (especially CMPA) until the age of 4 years (58–66). In two prospective studies (61,64), the cumulative incidence of food allergy and CMPA was significantly reduced until the ages of 5 and 7 years. Thus, a real prevention, and not only a postponement of the onset of the disease, was documented.

Also a preventive effect of PHF (Table 3) has been reported in randomized prospective studies (67–73) in high-risk infants. Because of great variations in study design and diagnostic criteria, the relative efficacy of the different interventions tested in the various studies cannot be compared directly (67,69–72). One of these studies (71,72), reported a very high prevalence of CMPA; the reason for this is unclear, but it may be because of less strict diagnostic criteria or selection bias.

Recent data from studies comparing the allergy-prevention effect of PHF and EHF (66,74–76), indicate a greater effect with EHF in studies with well-defined diagnostic criteria (66,74,75). In a recent study (66) the preventive effect, a reduction in the prevalence of atopic dermatitis, was particularly seen in infants with a family history of atopic dermatitis. If these results are confirmed in future studies, dietary preventive measures may be targeted more specifically. There is no evidence that soy formulas or other formulas based on whole proteins other than cow's milk proteins are less allergenic than cow's milk-based formulas (7,8,68,69,77–81).

Duration of the diet

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References

Duration and dietary restrictions vary in different studies. All studies showing a preventive effect have included solely breast-feeding or EHF and avoidance of cow's milk and solid foods for at least 4–6 months. Studies including restrictive diets for a long period >12–24 months and studies with dietary restrictions for only 4–6 months have shown comparable results. Two studies with a preventive diet for the first 6 and 4 months, respectively, resulted in a very low incidence of CMPA and other food allergies until the age of 18 months (59–61,75). In another recent study (82) no significant effect of supplement with EHF compared with cow's milk-based formula after the age of 6 months in breast-fed high-risk infants was found. Controlled studies concerning the possible preventive effect of avoidance of other potential food allergens, e.g. egg, fish, etc., after the age of 4–6 months of life have not been published. Thus, there is no evidence of an allergy-preventing effect of restrictive diets after 6 months of age.

References

  1. Top of page
  2. Abstract
  3. Food allergy
  4. Characterization of hypoallergenic formulas
  5. Hypoallergenic formulas for treatment
  6. Hypoallergenic formulas for prevention of allergy
  7. Breast-feeding
  8. Hydrolysed formulas
  9. Duration of the diet
  10. References
  • 1
    American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics 2000;106: 346349.
  • 2
    Sampson HA, Bernhisel-Broadbent J, Yang E, Scanlon SM. Safety of casein hydrolysate formula in children with cow milk allergy. J Pediatr 1991;118: 520525.
  • 3
    Halken S, Host A, Hansen LG, Osterballe O. Safety of a new, ultrafiltrated whey hydrolysate formula in children with cow milk allergy: a clinical investigation. Pediatr Allergy Immunol 1993;4: 5359.
  • 4
    Giampietro PG, Kjellman NI, Oldaeus G, Wouters-Wesseling W, Businco L. Hypoallergenicity of an extensively hydrolyzed whey formula. Pediatr Allergy Immunol 2001;12: 8386.
  • 5
    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. J Pediatr 1995;127: 550557.
  • 6
    Sampson HA, James JM, Bernhisel-Broadbent J. Safety of an amino acid-derived infant formula in children allergic to cow milk. Pediatrics 1992;90: 463465.
  • 7
    Businco L, Dreborg S, Einarsson R, Giampietro PG, Host A, Keller KM, et al. Hydrolysed cow's milk formulae. Allergenicity and use in treatment and prevention. An ESPACI position paper. Pediatr Allergy Immunol 1993;4: 101111.
  • 8
    Høst A, Koletzko B, Dreborg S, Muraro A, Wahn U, Aggett P, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint statement of the European Society of Paediatric Allergology and Clinical Immunology (ESPACI) Committee of Hypoallergeneic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child 1999;8: 8084.
  • 9
    Commission of the European Communities. Commission directive 96/4 EC of. amending directive 91/321/EEC on infant formulae and follow-on formulae. Official J European Commission 16 February 1996;39: 1216.
  • 10
    Eccles M, Freemantle N, Mason J. North of England evidence based guidelines development project: methods of developing guidelines for efficient drug use in primary care. Br Med J 1998;316: 12321235.
  • 11
    Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. Br Med J, 2001;323: 334336.
  • 12
    Bandolier Library. Bias in Diagnostic Testing. Levels in Evidence. http://www.jr2.ox.ac.uk/bandolier/booth/diagnosis/bias/html.
  • 13
    Oxford Centre for Evidence-based medicine. Levels of Evidence and Grades of Recommendations, updated, May: 2001. http://www.Indigojazz.co/uk/cebm/levels_levels_of_evidence.asp.
  • 14
    Host A, Halken S. Can we apply clinical studies to real life? Evidence-based recommendations from studies on development of allergic diseases and allergy prevention. Allergy 2002;57: 389397.
  • 15
    Host A, Husby S, Gjesing B, Larsen JN, Lowenstein H. Prospective estimation of IgG, IgG subclass and IgE antibodies to dietary proteins in infants with cow milk allergy. Levels of antibodies to whole milk protein, BLG and ovalbumin in relation to repeated milk challenge and clinical course of cow milk allergy. Allergy 1992;47: 218229.
  • 16
    Host A. Cow's milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol 1994;5: 136.
  • 17
    Makinen-Kiljunen S, Sorva R. Bovine beta-lactoglobulin levels in hydrolysed protein formulas for infant feeding. Clin Exp Allergy 1993;23: 287291.
  • 18
    Jakobsson I, Lindberg T, Benediktsson B, Hansson BG. Dietary bovine beta-lactoglobulin is transferred to human milk. Acta Paediatr Scand 1985;74: 342345.
  • 19
    Host A, Husby S, Hansen LG, Osterballe O. Bovine beta-lactoglobulin in human milk from atopic and non-atopic mothers. Relationship to maternal intake of homogenized and unhomogenized milk. Clin Exp Allergy 1990;20: 383387.
  • 20
    Rosendal A, Barkholt V. Detection of potentially allergenic material in 12 hydrolyzed milk formulas. J Dairy Sci 2000;83: 22002210.
  • 21
    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 Pediatr 2002;2: 10.
  • 22
    Zeiger RS, Sampson HA, Bock SA, Burks AW Jr, Harden K, Noone S, et al. Soy allergy in infants and children with IgE-associated cow's milk allergy. J Pediatr 1999;134: 614622.
  • 23
    Ribadeau-Dumas B. Structure and variability of milk proteins. In: Barth, CA, Schlimme, E, editors. Milk Protein. Nutritional, Clinical, Functional and Technological Aspects. New York: Springer Verlag., 1988: 112123.
  • 24
    Aggett PJ, Haschke F, Heine W, Hernell O, Koletzko B, Rey J, et al. Comment on antigen-reduced infant formulae. ESPGAN Committee on Nutrition. Acta Paediatr 1993;82: 314319.
  • 25
    Oldæus G, Björkstén B, Einarsson R, Kjellman N-IM. Antigenicity of cow's milk hydrolysates intended for infant feeding. Pediatr Allergy Immunol 1991;2: 156160.
  • 26
    Rugo E, Wahl R, Wahn U. How allergenic are hypoallergenic infant formulae? Clin Exp Allergy 1992;22: 635639.
  • 27
    Ragno V, Giampietro PG, Bruno G, Businco L. Allergenicity of milk protein hydrolysate formulae in children with cow's milk allergy. Eur J Pediatr 1993;152: 760762.
  • 28
    Kuitunen P, Visakorpi JK, Savilahti E, Pelkonen P. Malabsorption syndrome with cow's milk intolerance. Clinical findings and course in 54 cases. Arch Dis Child 1975;50: 351356.
  • 29
    Ellis MH, Short JA, Heiner DC. Anaphylaxis after ingestion of a recently introduced hydrolyzed whey protein formula. J Pediatr 1991;118: 7477.
  • 30
    Saylor JD, Bahna SL. Anaphylaxis to casein hydrolysate formula. J Pediatr 1991;118: 7174.
  • 31
    Schwartz RH, Amonette MS. Cow milk protein hydrolysate infant formulas not always ‘hypoallergenic’. J Pediatr 1991;119: 839840.
  • 32
    Businco L, Cantani A, Longhi MA, Giampietro PG. Anaphylactic reactions to a cow's milk whey protein hydrolysate (Alfa-Re, Nestle) in infants with cow's milk allergy. Ann Allergy 1989;62: 333335.
  • 33
    Høst A, Husby S, ØSterballe O. A prospective study of cow's milk allergy in exclusively breast-fed infants. Acta Paediatr Scand 1988;77: 663670.
  • 34
    Saarinen UM, Kajosaari M. Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old. Lancet 1995;346: 10651069.
  • 35
    Wright AL, Holberg CJ, Taussig LM, Martinez FD. Relationship of infant feeding to recurrent wheezing at age 6 years. Arch Pediatr Adolesc Med 1995;149: 758763.
  • 36
    Oddy WH, Holt PG, Sly PD, Read AW, Landau LI, Stanley FJ, et al. Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study. Br Med J 1999;319: 815819.
  • 37
    Oddy WH. Breastfeeding and asthma in children. A prospective cohort study. Adv Exp Med Biol 2000;478: 393394.
  • 38
    Oddy WH, Peat JK, De Klerk NH. Maternal asthma, infant feeding, and the risk of asthma in childhood. J Allergy Clin Immunol 2002;110: 6567.
  • 39
    Oddy WH, De Klerk NH, Sly PD, Holt PG. The effects of respiratory infections, atopy, and breastfeeding on childhood asthma. Eur Resp J 2002;19: 899905.
  • 40
    Wilson AC, Forsyth JS, Greene SA, Irvine L, Hau C, Howie P. Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. Br Med J 1998;316: 2125.
  • 41
    Saarinen UM, Kajosaari M, Backman A, Siimes MA. Prolonged breast-feeding as prophylaxis for atopic disease. Lancet 1979;2: 163166.
  • 42
    Gruskay FL. Comparison of breast, cow, and soy feedings in the prevention of onset of allergic disease: a 15-year prospective study. Clin Pediatr (Philadelph) 1982;21: 486491.
  • 43
    Pratt H. Breastfeeding and ezcema. Early Hum Dev 1984;9: 283290.
  • 44
    Moore WJ, Midwinter RE, Morris AF, Colley JR, Soothill JF. Infant feeding and subsequent risk of atopic eczema. Arch Dis Child 1985;60: 722726.
  • 45
    Wright AL, Holberg CJ, Martinez FD, Morgan WJ, Taussig LM. Breast feeding and lower respiratory tract illness in the first year of life. Group Health Medical Associates. Br Med J 1989;299: 946949.
  • 46
    Elder DE, Hagan R, Evans SF, Benninger HR, French NP. Recurrent wheezing in very preterm infants. Arch Dis Child Fetal Neonatal Ed 1996;74: F165F171.
  • 47
    Tariq SM, Matthews SM, Hakim EA, Stevens M, Arshad SH, Hide DW, et al. The prevalence of and risk factors for atopy in early childhood: a whole population birth cohort study. J Allergy Clin Immunol 1998;101: 587593.
  • 48
    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: 192197.
  • 49
    Bergmann RL, Diepgen TL, Kuss O, Bergmann KE, Kujat J, Dudenhausen JW, et al. MAS-study group Breastfeeding duration is a risk factor for atopic eczema. Clin Exp Allergy 2002;32: 205209.
  • 50
    Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF. Early diet of preterm infants and development of allergic or atopic disease: randomized prospective study. Br Med J 1990;300: 837840.
  • 51
    Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding and the onset of atopic dermatitis in childhood. a systematic review and meta-analysis of prospective studies. J Am Acad Dermatol 2001;45: 520527.
  • 52
    Gdalevich M, Mimouni D, Mimouni M. Breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies. J Pediatr 2001;139: 261266.
  • 53
    Van Odijk J, Kull I, Borress MP, Brandtzaeg P, Edberg U, Hanson LA, et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966–2001) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 2003;58: 833843.
  • 54
    Fälth-Magnusson K, ÖHman H, Kjellman N-IM. Maternal abstention from cow milk and egg in allergy risk pregnancies. Allergy 1987;42: 6473.
  • 55
    Fälth-Magnusson K, Kjellman N-IM. Allergy prevention by maternal elimination diet during late pregnancy. J Allergy Clin Immunol 1992;89: 709713.
  • 56
    Hattevig G, Sigurs N, Kjellman B. Effects of maternal dietary avoidance during lactation on allergy in children at 10 years of age. Acta Paediatr 1999;88: 712.
  • 57
    Lilja G, Dannaeus A, Foucard T, Graff LV, Johansson SGO, Ohman 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. Clin Exp Allergy 1989;19: 473479.
  • 58
    Chandra RK, Shakuntla P, Hamed A. Influence of maternal diet during lactation and use of formula feeds on development of atopic ezcema in high risk infants. Br Med J 1989;299: 228230.
  • 59
    Halken S, Høst A, Hansen LG, ØSterballe O. Effect on an allergy prevention programme on incidence of atopic symptoms in infancy. A prospective study of 159 ‘high risk’ infants. Allergy 1992;47: 545553.
  • 60
    Halken S, Høst A, Hansen LG, ØSterballe O. Preventive effect of feeding high-risk infants a casein hydrolysate formula or an ultrafiltrated whey hydrolysate formula. A prospective, randomized, comparative clinical study. Pediatr Allergy Immunol 1993;4: 173181.
  • 61
    Halken S, Høst A, Jacobsen HP, Hansen LG, ØSterballe O. Prevention of food allergy in high-risk infants until the age of 5 years. A prospective dietary intervention study. Allergy 1995;26: 49 (abstract).
  • 62
    Zeiger RS, Heller S, Mellon MH, Forsythe AB, O'Connor RD, Hamburger RN, et al. Effect of combined maternal and infant food-allergen avoidance on development of atopy in early infancy: a randomized study. J Allergy Clin Immunol 1989;84: 7289.
  • 63
    Zeiger RS, Heller S, Sampson HA. Genetic and environmental factors affecting the development of atopy through age 4 in children of atopic parents: a prospective randomized controlled study of food allergen avoidance. Pediatr Allergy Immunol 1992;3: 110127.
  • 64
    Zeiger RS, Heller RS. 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. J Allergy Clin Immunol 1995;95: 11791190.
  • 65
    Mallet E, Henocq A. Long-term prevention of allergic diseases by using protein hydrolysate formula in at-risk infants. J Pediatr 1992;121: S95S100.
  • 66
    Von Berg A, Koletzko S, Grubl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, et al. 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. J Allergy Clin Immunol 2003;111: 533540.
  • 67
    Vandenplas Y, Deneyr M, Sacre L, Loeb H. Preliminary data on a field study with a new hypo-allergenic formula. Eur J Pediatr 1988;148: 274277.
  • 68
    Chandra RK, Singh G, Shridhara B. Effect of feeding whey hydrolysate, soy and conventional cow milk formula on incidence of atopic disease in high risk infants. Ann Allergy 1989;63: 102106.
  • 69
    Chandra RK, Hamed A. Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas. Ann Allergy 1991;67: 129132.
  • 70
    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 fomulas. J Pediatr Gastroenterol Nutr 1997;24: 380388.
  • 71
    Vandenplas Y, Hauser B, Van den Borre C, Sacre L, Dab I. Effect of a whey hydrolysate prophylaxis of atopic disease. Ann Allergy 1992;68: 419424.
  • 72
    Vandenplas Y, Hauser B, Van den Borre C, Clybouw C, Mahler T, Hachimi-Idrissi S, et al. The long-term effect of a partial whey hydrolysate formula on the prophylaxis of atopic disease. Eur J Pediatr 1995;154: 488494.
  • 73
    Chan YH, Shek LP, Aw M, Quak SH, Lee BW. Use of hypoallergenic formula in the prevention of atopic disease among Asian children. J Paediatr Child Health 2002;38: 8488.
  • 74
    Oldæus G, Anjou K, Björksten B, Moran JR, Kjellman N-IM. Extensively and partially hydrolysed infant formulas for allergy prophylaxis. Arch Dis Child 1997;77: 410.
  • 75
    Halken S, Hansen KS, Jacobsen HP, Estmann A, Faelling AE, Hansen LG, et al. Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study. Pediatr Allergy Immunol 2000;11: 149161.
  • 76
    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: 11441156.
  • 77
    Burr ML, Merrett TG, Dunstan FDJ, Magguire MJ. The development of allergy in high-risk children. Clin Exp Allergy 1997;27: 12471253.
  • 78
    Arato A, Horwarth J. Soy formula in the feeding of infants with milk allergy. Orvosi Hetilap 1995;135: 14331437.
  • 79
    Bardare M, Vaccari A, Allievi E, Brunelli L, Coco F, de Gaspari GC, et al. Influence of dietary manipulation on incidence of atopic disease in infants at risk. Ann Allergy 1993;71: 366371.
  • 80
    Businco L, Bruno G, Giampietro PG, Cantani A. Allergenicity and nutritional adequacy of soy protein formulas. J Pediatr 1992;121: S21S28.
  • 81
    Kerner JA Jr. Use of infant formulas in prevention or postponing atopic manifestations. J Pediatr Gastroenterol Nutr 1997;24: 442446.
  • 82
    Odelram H, Vanto T, Jacobsen L, Kjellman N-IM. 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: 192195.