Hypoallergenic formula milk versus cow's milk for prevention of wheeze and asthma in children with a family history of atopy

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of dietary avoidance of cow's milk protein on the development of early wheezing or later asthma in infants at high risk of developing atopy. More specifically, we wish to quantify the risk of asthma and wheezing in infants fed standard cow's milk based formula, compared to infants in whom standard cow's milk was replaced with either soya-based or extensively or partially hydrolysed milk formulae.


Description of the condition

Wheeze is an abnormal, usually high-pitched whistling sound made during breathing, especially during expiration. This sound is produced as the air passes through narrowed airways and is caused by vibration of the airway wall at a site of flow limitation. It is, thus, a marker of narrowing at some point in the airway, as a result of infection, inflammation or other causes of obstruction (e.g. foreign body inhalation). Generalised wheezing in infants and toddlers may be precipitated by various infectious or allergenic agents: commonly viruses, less commonly house dust mite or foods.

Asthma is a chronic condition characterised by the triad of symptoms: wheeze, cough and breathlessness. It is associated with hyper-responsiveness of the airways due to inflammation. At least half of the children who wheeze in infancy grow out of this tendency; however, some go on to develop chronic asthma (von Mutius 2001; Frank 2008; Turner 2008) and the risk of such progression is increased by a family or personal history of atopy.

The exact causes of recurrent wheezing and airway hyper-responsiveness are poorly understood, but they may develop as a response to allergen exposure in susceptible individuals. Infants may be exposed to allergens through their diet in the initial few months of life. In particular, there is some evidence that early exposure to cow's milk, which contains powerful allergens such as beta-lactoglobulin and casein (Taylor 1986; Savilahti 1992) may be associated with the development of allergies in infants (Foucard 1985).

Description of the intervention

In children with a family history of atopy, maternal allergen exposure can be reduced during pregnancy, lactation or both (Zeiger 1989), by periods of exclusive breast feeding (Gruskay 1982; Saarinen 1995; Oddy 1999; Saarinen 2000), and avoidance of potential allergens including food and environmental antigens (Custovic 2001). Exposure to milk protein allergens may be avoided by substituting cow's milk with other hypoallergenic formulae in the infant's diet in the early months of life ( Vandenplas 1992).These 'hypoallergenic' formulae include:

  1. soya-based formulae, which are also somewhat allergenic and may present some cross-reactivity with cow's milk proteins; and

  2. extensively or partially hydrolysed formulae, in which the protein source (cow's milk – casein or whey) has been enzymatically hydrolysed and heat-denatured, resulting in smaller molecules with reduced allergenic potential (Pahud 1985; Mäkinen-Kiljunen 1993; Ragno 1993).

How the intervention might work

Substituting cow's milk with hypoallergenic formulae in the infant's diet might reduce the risk of sensitisation occurring via the infant's immature gut, and thus reduce the risk of atopic and other allergic diseases developing.

Why it is important to do this review

There is sufficient evidence of other benefits of breast feeding that all mothers should be advised to breast feed (Howie 1990; Wilson 1998), and this is not suitable for assessment by randomised controlled trials. However, there will always be some women who are unable, or choose not to breast feed. The choice of formula feed becomes particularly important for these mothers, particularly in infants at high-risk of atopy owing to a family history.

A number of methodological issues complicate the evaluation of the available evidence; many studies have a cohort design and are therefore subject to sampling, and other types of, bias (Kramer 1988).

Two reviews have studied avoidance of cow's milk in infants. Baumgartner 1998 studied the effect of cow's milk avoidance on the development of atopic symptoms (not asthma or wheeze). A Cochrane review that studied the effect of cow's milk avoidance along with a range of other potentially active co-interventions in infants has been withdrawn because it is out of date (Ducharme 2007) and due to concerns over the reliability of one of the included studies. Subsequently, a further large randomised study on this topic has been published. It is therefore appropriate and timely to carry out a new review to study the effect of one specific intervention (cow's milk avoidance in infancy) on the development of wheeze and asthma in children with family history of atopy, and this protocol forms a basis for this endeavour.


To assess the effects of dietary avoidance of cow's milk protein on the development of early wheezing or later asthma in infants at high risk of developing atopy. More specifically, we wish to quantify the risk of asthma and wheezing in infants fed standard cow's milk based formula, compared to infants in whom standard cow's milk was replaced with either soya-based or extensively or partially hydrolysed milk formulae.


Criteria for considering studies for this review

Types of studies

We will include prospective randomised controlled trials (RCTs). We will not exclude trials on the basis of blinding because we consider that, given the difference in taste and appearance of various formulae, full blinding of the parent/carer is, in practice, not always possible.

Types of participants

We will include infants with a family history of atopy (asthma or atopic eczema or hay fever) in at least one first-degree relative, who had been randomised at or before birth, or before weaning from exclusive breast feeding. For the purpose of this study, a first-degree relative is defined as either a parent or a sibling.

Types of interventions

The intervention group should consist of infants who received one of the hypoallergenic formulae, either:

  • exclusively from birth; or

  • as supplement to, and during weaning from, breast milk.

The control group should consist of infants who received unhydrolysed cow’s milk formula, either:

  • exclusively from birth; or

  • as supplement to, and during weaning from, breast milk.

We will include the following interventions (hypoallergenic infant formulae):

  • soya-based formulae;

  • partially hydrolysed formulae; and

  • extensively hydrolysed formulae.

We will include only studies in which either:

  • randomisation was done at or before birth or before weaning from exclusive breast feeding; or

  • the intervention was started within the first six months of life and continued for a minimum of four months.

We will include trials where mothers continued to breast feed their infant occasionally. We will also include trials which have other co-interventions aimed at reducing allergens (e.g. house dust mite avoidance), as long as the co-intervention is the same in both treatment and control arms.

We will make the following comparisons:

  • hypoallergenic formula versus cow's milk as the only difference between groups; and

  • hypoallergenic formula and other interventions versus cow's milk and the same additional interventions.

We will exclude studies comparing exclusive breast feeding with cow's milk based formula or any other formula.

Types of outcome measures

Primary outcomes

Proportion of children who developed wheezing. Cumulative incidence of wheezing shall be assessed at < 18 months, at < 2 years and at < 3 years of age.

Secondary outcomes

Prevalence of physician-diagnosed asthma at more than four years of age.

Historically, the term 'asthma' has been used to describe wheezing at an early age. However, it was agreed (in line with current consensus) that it is very difficult to definitively diagnose asthma at less than four years of age. It was therefore decided that the terms 'asthma' and 'wheeze', when used as outcome descriptors below four years of age, would be regarded as equivalent.

Search methods for identification of studies

Electronic searches

We will identify trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts (see Appendix 1 for further details). We will search all records in the CAGR coded as 'asthma', using the following terms:

(feed* or food* or milk or formula* or bottle or soy or soya or hydrolysate or hydrolysed or hydrolyzed or hypoallergenic*) and (child* or paediat* or pediat* or adolesc* or infan* or toddler* or bab* or young* or preschool* or "pre school*" or pre-school* or newborn* or "new born*" or new-born* or neo-nat* or neonat*)

We will also conduct additional searches of CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov (see Appendix 2 for the proposed MEDLINE strategy). All databases will be searched from their inception to the present and there will be no restriction on language of publication.

Searching other resources

We will check reference lists of all primary studies and review articles for additional references. Since trials like these are likely to be done in partnership with various infant feed manufacturing companies, we plan to search their websites and contact them to find any unpublished data.

Data collection and analysis

Selection of studies

One review author (YK) will review and identify each abstract obtained as either 1) an RCT; 2) clearly not an RCT or 3) unclear. We will obtain full text papers of all abstracts identified as RCTs or unclear, and two authors (YK and PS) will independently evaluate the full text for inclusion. We will resolve disagreement through discussion or, if required, we will consult a third person.

Data extraction and management

Two independent review authors (YK and PS) will extract data using a data extraction form. We will collect information on the type of intervention, population, study design, details of the risk of bias and the outcome measures at each specified age.

Assessment of risk of bias in included studies

Two review authors will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the risk of bias according to the following domains:

  1. Random sequence generation;

  2. Allocation concealment;

  3. Blinding of participants and personnel;

  4. Blinding of outcome assessment;

  5. Incomplete outcome data;

  6. Selective outcome reporting;

  7. Other bias.

We will grade each potential source of bias as high risk, low risk or unclear. Any disagreement will be resolved by discussion or by involving a third assessor.

Measures of treatment effect

Since data so obtained will be in the form of dichotomous variables, we will use a fixed-effect model to estimate relative risk (RR) for each outcome measure. We shall report all estimates with a 95% confidence interval (CI) and equivalence will be assumed if the 95% CI is contained within RR of 0.9 to 1.1.

Unit of analysis issues

The unit of analysis will be the patient (with one or more episodes of wheezing) rather than the number of episodes of wheezing.

Dealing with missing data

We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible.

Assessment of heterogeneity

We will use the I2 statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will explore it by pre-specified subgroup analysis. 

Assessment of reporting biases

Where we suspect reporting bias, we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis

Data synthesis

We plan to create a 'Summary of findings' table using the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook (Higgins 2011) and using GRADEpro software. We plan to include both the primary and secondary outcome measures.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analysis:

  • different types of hypoallergenic formula (soya-based or partially hydrolysed or extensively hydrolysed formula).

  • feeding method (exclusive formula fed or mixed breast/formula fed)

Sensitivity analysis

We plan to perform sensitivity analyses by comparing the resulting treatment effect with the effect before:

  • including studies in which the authors have been found to be involved in research fraud in other work; and

  • excluding studies considered to be of poor methodological quality.


We are grateful to Toby Lasserson and Emma Welsh for their help and guidance in formulating this review.


Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

DatabaseFrequency of search
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
CENTRAL (The Cochrane Library)Quarterly
PsycINFO (Ovid)Monthly


Hand-searches: core respiratory conference abstracts

ConferenceYears searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards


MEDLINE search strategy used to identify trials for the CAGR

Asthma search

1. exp Asthma/

2. asthma$.mp.

3. (antiasthma$ or anti-asthma$).mp.

4. Respiratory Sounds/

5. wheez$.mp.

6. Bronchial Spasm/

7. bronchospas$.mp.

8. (bronch$ adj3 spasm$).mp.

9. bronchoconstrict$.mp.

10. exp Bronchoconstriction/

11. (bronch$ adj3 constrict$).mp.

12. Bronchial Hyperreactivity/

13. Respiratory Hypersensitivity/

14. ((bronchial$ or respiratory or airway$ or lung$) adj3 (hypersensitiv$ or hyperreactiv$ or allerg$ or insufficiency)).mp.

15. ((dust or mite$) adj3 (allerg$ or hypersensitiv$)).mp.

16. or/1-15

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases.

Appendix 2. MEDLINE search strategy

1. exp asthma/

2. asthma$.tw.

3. respiratory sounds/

4. wheez$.tw.

5. atop$.tw.

6. or/1-5

7. exp Infant Food/

8. Bottle Feeding/

9. exp Milk Substitutes/

10. Milk Hypersensitivity/

11. ((hydrolysate or hydrolysed or hydrolyzed hypoallergenic$ or soy or soya) adj3 (milk or formula or feed or food)).tw.

12. (infant adj3 (formula$ or milk$)).tw.

13. or/7-12

14. 6 and 13

This search will be combined with the RCT filter described in Appendix 1.

Contributions of authors

YK and PS wrote the protocol together.

Declarations of interest

None known