Infant formulas containing hydrolysed protein for prevention of allergic disease and food allergy

David A Osborn; John KH Sinn; Lisa J Jones

doi:10.1002/14651858.CD003664.pub4

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Figure 1

Study flow diagram: review update.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Funnel plot of comparison: 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, outcome: 4.1 Any allergy.

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Figure 5

Funnel plot of comparison: 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, outcome: 4.3 Eczema.

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Figure 6

Funnel plot of comparison: 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, outcome: 4.6 Cow's milk allergy.

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Analysis 1.1

Comparison 1 Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants, Outcome 1 Any allergy.

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Analysis 1.2

Comparison 1 Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants, Outcome 2 Asthma.

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Analysis 1.3

Comparison 1 Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants, Outcome 3 Eczema.

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Analysis 1.4

Comparison 1 Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants, Outcome 4 Food allergy.

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Analysis 1.5

Comparison 1 Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants, Outcome 5 Cow's milk allergy.

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Analysis 2.1

Comparison 2 Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 1 Any allergy.

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Analysis 2.2

Comparison 2 Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 2 Asthma.

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Analysis 2.3

Comparison 2 Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 3 Eczema.

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Analysis 2.4

Comparison 2 Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 4 Food allergy.

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Analysis 2.5

Comparison 2 Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 5 Cow's milk allergy.

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Analysis 4.1

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 4.2

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 4.3

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 4.4

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 4.5

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 5 Food allergy.

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Analysis 4.6

Comparison 4 Prolonged feeding: hydrolysed formula versus cow's milk formula, Outcome 6 Cow's milk allergy.

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Analysis 5.1

Comparison 5 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 1 Any allergy.

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Analysis 5.2

Comparison 5 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 2 Asthma.

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Analysis 5.3

Comparison 5 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 3 Eczema.

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Analysis 5.4

Comparison 5 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants, Outcome 4 Rhinitis.

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Analysis 6.1

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 1 Any allergy.

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Analysis 6.2

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 2 Asthma.

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Analysis 6.3

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 3 Eczema.

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Analysis 6.4

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 4 Rhinitis.

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Analysis 6.5

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 5 Food allergy.

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Analysis 6.6

Comparison 6 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants, Outcome 6 Cow's milk allergy.

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Analysis 7.1

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 7.2

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 7.3

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 7.4

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 7.5

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 5 Food allergy.

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Analysis 7.6

Comparison 7 Prolonged feeding: partially hydrolysed formula versus cow's milk formula, Outcome 6 Cow's milk allergy.

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Analysis 8.1

Comparison 8 Prolonged feeding: extensively hydrolysed formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 8.2

Comparison 8 Prolonged feeding: extensively hydrolysed formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 8.3

Comparison 8 Prolonged feeding: extensively hydrolysed formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 8.4

Comparison 8 Prolonged feeding: extensively hydrolysed formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 8.5

Comparison 8 Prolonged feeding: extensively hydrolysed formula versus cow's milk formula, Outcome 5 Food allergy.

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Analysis 9.1

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 1 Any allergy.

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Analysis 9.2

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 2 Asthma.

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Analysis 9.3

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 3 Eczema.

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Analysis 9.4

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 4 Rhinitis.

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Analysis 9.5

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 5 Food allergy.

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Analysis 9.6

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 6 Cow's milk allergy.

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Analysis 9.7

Comparison 9 Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula, Outcome 7 Urticaria.

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Analysis 10.1

Comparison 10 Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 10.2

Comparison 10 Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 10.3

Comparison 10 Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 10.4

Comparison 10 Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 10.5

Comparison 10 Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula, Outcome 5 Cow's milk allergy.

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Analysis 11.1

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 1 Any allergy.

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Analysis 11.2

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 2 Asthma.

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Analysis 11.3

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 3 Eczema.

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Analysis 11.4

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 4 Rhinitis.

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Analysis 11.5

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 5 Food allergy.

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Analysis 11.6

Comparison 11 Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement, Outcome 6 Cow's milk allergy.

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Analysis 13.1

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 13.2

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 13.3

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 13.4

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 13.5

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 5 Food allergy.

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Analysis 13.6

Comparison 13 Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula, Outcome 6 Cow's milk allergy.

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Analysis 14.1

Comparison 14 Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 14.2

Comparison 14 Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 14.3

Comparison 14 Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 14.4

Comparison 14 Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula, Outcome 4 Rhinitis.

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Analysis 14.5

Comparison 14 Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula, Outcome 5 Food allergy.

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Analysis 15.1

Comparison 15 Prolonged feeding: extensively hydrolysed whey formula versus cow's milk formula, Outcome 1 Any allergy.

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Analysis 15.2

Comparison 15 Prolonged feeding: extensively hydrolysed whey formula versus cow's milk formula, Outcome 2 Asthma.

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Analysis 15.3

Comparison 15 Prolonged feeding: extensively hydrolysed whey formula versus cow's milk formula, Outcome 3 Eczema.

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Analysis 16.1

Comparison 16 Prolonged feeding: extensively hydrolysed casein formula versus cow' milk formula, Outcome 1 Any allergy.

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Analysis 16.2

Comparison 16 Prolonged feeding: extensively hydrolysed casein formula versus cow' milk formula, Outcome 2 Asthma.

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Analysis 16.3

Comparison 16 Prolonged feeding: extensively hydrolysed casein formula versus cow' milk formula, Outcome 3 Eczema.

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Analysis 17.1

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 1 Any allergy.

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Analysis 17.2

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 2 Asthma.

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Analysis 17.3

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 3 Eczema.

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Analysis 17.4

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 4 Rhinitis.

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Analysis 17.5

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 5 Food allergy.

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Analysis 17.6

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 6 Cow's milk allergy.

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Analysis 17.7

Comparison 17 Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula, Outcome 7 Urticaria.

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Summary of findings for the main comparison. Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants for prevention of allergic disease and food allergy

Early short‐term feeding of hydrolysed formula versus human milk for prevention of allergic disease and food allergy
Patient or population: infants not selected for allergy risk Settings: hospitals Intervention: early short‐term feeding: hydrolysed formula versus human milk feeding for prevention of allergic disease and food allergy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Early short‐term feeding: hydrolysed formula vs human milk ‐ low‐risk infants
Any allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 1.43 (0.38 to 5.37)	90 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	75 per 1000	108 per 1000 (29 to 405)
	Moderate
	76 per 1000	109 per 1000 (29 to 408)
Asthma ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 0.48 (0.05 to 4.41)	90 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	57 per 1000	27 per 1000 (3 to 250)
	Moderate
	57 per 1000	27 per 1000 (3 to 251)
Eczema ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 0.48 (0.05 to 4.41)	90 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	57 per 1000	27 per 1000 (3 to 250)
	Moderate
	57 per 1000	27 per 1000 (3 to 251)
Food allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 1.43 (0.38 to 5.37)	90 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	75 per 1000	108 per 1000 (29 to 405)
	Moderate
	76 per 1000	109 per 1000 (29 to 408)
Cow's milk allergy ‐ infancy (incidence) Follow‐up: mean 27 months	Study population		RR 0.87 (0.52 to 1.46)	3559 (1 study)	⊕⊝⊝⊝ very low^c,d,e
	17 per 1000	15 per 1000 (9 to 25)
	Moderate
	17 per 1000	15 per 1000 (9 to 25)
Cow's milk allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 7.11 (0.35 to 143.84)	90 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate
^aMethodological concerns including quasi‐random sequence allocation, incomplete outcome data and imbalances at baseline ^bImprecision of estimate ‐ single small study ^cReported by only a single study ^dMethodological concerns including quasi‐random sequence allocation and incomplete outcome data ^eImpression of estimate ‐ low incidence of outcome

Summary of findings for the main comparison. Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants for prevention of allergic disease and food allergy

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Summary of findings 2. Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants for prevention of allergic disease and food allergy

Early short‐term feeding of hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy
Patient or population: infants not selected for allergy risk Settings: hospitals Intervention: early short‐term feeding of hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Early short‐term feeding: hydrolysed formula vs cow's milk formula ‐ low‐risk infants
Any allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 1.37 (0.33 to 5.71)	77 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	77 per 1000	105 per 1000 (25 to 439)
	Moderate
	77 per 1000	105 per 1000 (25 to 440)
Asthma ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 3.08 (0.13 to 73.26)	77 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Eczema ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 0.34 (0.04 to 3.15)	77 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	77 per 1000	26 per 1000 (3 to 242)
	Moderate
	77 per 1000	26 per 1000 (3 to 243)
Food allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 1.37 (0.33 to 5.71)	77 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	77 per 1000	105 per 1000 (25 to 439)
	Moderate
	77 per 1000	105 per 1000 (25 to 440)
Cow's milk allergy ‐ infancy (incidence) Follow‐up: mean 3 years	Study population		RR 0.62 (0.38 to 1)	3473 (1 study)	⊕⊝⊝⊝ very low^a,c,d
	24 per 1000	15 per 1000 (9 to 24)
	Moderate
	25 per 1000	15 per 1000 (9 to 25)
Cow's milk allergy ‐ childhood (incidence) Follow‐up: mean 3 years	Study population		RR 5.13 (0.25 to 103.43)	77 (1 study)	⊕⊝⊝⊝ very low^a,b,c
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate
^aMethodological concerns including quasi‐random sequence allocation, incomplete outcome data and imbalances at baseline ^bImprecision of estimate ‐ single small study ^cReported only by a single study ^dImprecision of estimate ‐ low incidence of outcome

Summary of findings 2. Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants for prevention of allergic disease and food allergy

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Summary of findings 3. Prolonged feeding: hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy

Prolonged feeding of hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy
Patient or population: infants Settings: infant feeding Intervention: prolonged feeding of hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Prolonged feeding: hydrolysed formula vs cow's milk formula
Any allergy ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.82 (0.72 to 0.95)	2852 (8 studies)	⊕⊝⊝⊝ very low^a,b
	294 per 1000	241 per 1000 (212 to 279)
	Moderate
	395 per 1000	324 per 1000 (284 to 375)
Any allergy ‐ childhood (incidence) Follow‐up: 3 years	Study population		RR 0.85 (0.69 to 1.05)	950 (2 studies)	⊕⊝⊝⊝ very low^a,b,c,d
	353 per 1000	300 per 1000 (244 to 371)
	Moderate
	381 per 1000	324 per 1000 (263 to 400)
Asthma ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.57 (0.31 to 1.04)	318 (4 studies)	⊕⊝⊝⊝ very low^a,b,d
	175 per 1000	100 per 1000 (54 to 182)
	Moderate
	149 per 1000	85 per 1000 (46 to 155)
Eczema ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.86 (0.73 to 1.01)	2896 (9 studies)	⊕⊝⊝⊝ very low^a,b,d
	223 per 1000	191 per 1000 (162 to 225)
	Moderate
	200 per 1000	172 per 1000 (146 to 202)
Rhinitis ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.52 (0.14 to 1.85)	256 (3 studies)	⊕⊝⊝⊝ very low^a,b,d
	58 per 1000	30 per 1000 (8 to 107)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Food allergy ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.95 (0.58 to 1.54)	479 (2 studies)	⊕⊝⊝⊝ very low^a,b,d
	139 per 1000	132 per 1000 (81 to 214)
	Moderate
	119 per 1000	113 per 1000 (69 to 183)
Cow's milk allergy ‐ infancy (incidence) Follow‐up: 2 years	Study population		RR 0.38 (0.16 to 0.86)	405 (2 studies)	⊕⊝⊝⊝ very low^a,b,d
	80 per 1000	30 per 1000 (13 to 68)
	Moderate
	222 per 1000	84 per 1000 (36 to 191)
The basis for the assumed risk* (e.g. median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: We are very uncertain about the estimate
^aSubstantial methodological concerns. Sensitivity analysis found no study considered at low risk of bias ^bNot reported by all studies ^cSignificant heterogeneity between studies ^dImprecision of estimate

Summary of findings 3. Prolonged feeding: hydrolysed formula versus cow's milk formula for prevention of allergic disease and food allergy

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Comparison 1. Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Childhood (incidence)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.38, 5.37]
2 Asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Childhood (incidence)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 4.41]
3 Eczema Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Childhood (incidence)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.05, 4.41]
4 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Childhood (incidence)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.38, 5.37]
5 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	3559	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.52, 1.46]
5.2 Childhood (incidence)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	7.11 [0.35, 143.84]

Comparison 1. Early short‐term feeding: hydrolysed formula versus human milk feeding ‐ low‐risk infants

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Comparison 2. Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Childhood (incidence)	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.33, 5.71]
2 Asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Childhood (incidence)	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	3.08 [0.13, 73.26]
3 Eczema Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Childhood (incidence)	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.04, 3.15]
4 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Childhood (incidence)	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.33, 5.71]
5 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	3473	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.38, 1.00]
5.2 Childhood (incidence)	1	77	Risk Ratio (M‐H, Fixed, 95% CI)	5.13 [0.25, 103.43]

Comparison 2. Early short‐term feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants

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Comparison 4. Prolonged feeding: hydrolysed formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	8	2852	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.72, 0.95]
1.2 Childhood (incidence)	2	950	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.69, 1.05]
1.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	4	318	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.31, 1.04]
2.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.84]
2.3 Childhood (prevalence)	3	1229	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.89, 1.50]
3 Eczema Show forest plot	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	9	2896	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.73, 1.01]
3.2 Childhood (incidence)	2	950	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.63, 1.10]
3.3 Childhood (prevalence)	3	1228	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.60, 1.02]
4 Rhinitis Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	3	256	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.14, 1.85]
4.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.04, 5.03]
4.3 Childhood (prevalence)	2	357	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.78, 1.67]
5 Food allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.58, 1.54]
6 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.86]

Comparison 4. Prolonged feeding: hydrolysed formula versus cow's milk formula

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Comparison 5. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [0.77, 6.26]
3 Eczema Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.03, 2.66]
4 Rhinitis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.53, 3.26]

Comparison 5. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ low‐risk infants

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Comparison 6. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	8	2852	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.72, 0.95]
1.2 Childhood (incidence)	2	950	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.69, 1.05]
2 Asthma Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	4	318	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.31, 1.04]
2.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.84]
2.3 Childhood (prevalence)	2	1167	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.83, 1.44]
3 Eczema Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	9	2896	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.73, 1.01]
3.2 Childhood (incidence)	2	950	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.63, 1.10]
3.3 Childhood (prevalence)	2	1166	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.61, 1.04]
4 Rhinitis Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	3	256	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.14, 1.85]
4.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.04, 5.03]
4.3 Childhood (prevalence)	1	295	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.73, 1.68]
5 Food allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	2	479	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.58, 1.54]
5.2 Childhood (incidence)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Childhood (prevalence)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.86]
6.2 Childhood (prevalence)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 6. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ high‐risk infants

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Comparison 7. Prolonged feeding: partially hydrolysed formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	8	1820	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.72, 0.96]
1.2 Childhood (incidence)	2	510	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.67, 1.10]
2 Asthma Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	4	268	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.28, 1.04]
2.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.84]
2.3 Childhood (prevalence)	3	789	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.91, 1.58]
3 Eczema Show forest plot	9		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	8	1699	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.75, 1.06]
3.2 Childhood (incidence)	2	510	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.61, 1.19]
3.3 Childhood (prevalence)	3	788	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.61, 1.09]
4 Rhinitis Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	3	206	Risk Ratio (M‐H, Fixed, 95% CI)	0.4 [0.09, 1.70]
4.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.04, 5.03]
4.3 Childhood (prevalence)	2	357	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.78, 1.67]
5 Food allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	2	429	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.62, 1.63]
6 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.86]

Comparison 7. Prolonged feeding: partially hydrolysed formula versus cow's milk formula

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Comparison 8. Prolonged feeding: extensively hydrolysed formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	2	1561	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.68, 1.13]
1.2 Childhood (incidence)	1	651	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.71, 1.13]
1.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.18, 2.04]
2.2 Childhood (prevalence)	2	713	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.76, 1.72]
3 Eczema Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	3	1726	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.63, 1.08]
3.2 Childhood (incidence)	1	651	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.63, 1.17]
3.3 Childhood (prevalence)	2	713	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.39, 0.97]
4 Rhinitis Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	2.76 [0.12, 66.22]
4.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.53, 3.26]
5 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.33, 4.02]

Comparison 8. Prolonged feeding: extensively hydrolysed formula versus cow's milk formula

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Comparison 9. Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	3	1806	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.75, 1.16]
1.2 Childhood (incidence)	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.74, 1.18]
2 Asthma Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	2	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.72 [0.74, 3.96]
2.2 Childhood (prevalence)	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.58, 1.35]
3 Eczema Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	4	1865	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.73, 1.10]
3.2 Childhood (incidence)	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.67, 1.26]
3.3 Childhood (prevalence)	1	661	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.54, 1.52]
4 Rhinitis Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	2	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.36, 4.29]
5 Food allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	2	341	Risk Ratio (M‐H, Fixed, 95% CI)	0.43 [0.19, 0.99]
6 Cow's milk allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	1	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.13 [0.01, 1.16]
7 Urticaria Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Infancy (incidence)	1	246	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.26, 6.66]

Comparison 9. Prolonged feeding: extensively hydrolysed formula versus partially hydrolysed formula

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Comparison 10. Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	5	425	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.46, 0.80]
1.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.19, 0.90]
1.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	2	144	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.25, 1.31]
2.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.84]
2.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [0.77, 6.26]
3 Eczema Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	4	271	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.45, 1.21]
3.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.14, 1.26]
3.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.03, 2.66]
4 Rhinitis Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.04, 5.03]
4.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.53, 3.26]
5 Cow's milk allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.15, 0.89]

Comparison 10. Prolonged exclusive feeding: hydrolysed formula versus cow's milk formula

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Comparison 11. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	3	2156	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.69, 1.08]
1.2 Childhood (incidence)	1	872	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.73, 1.14]
1.3 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.17, 1.42]
2.2 Childhood (prevalence)	2	934	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.80, 1.73]
3 Eczema Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	2	2089	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.70, 1.16]
3.2 Childhood (incidence)	1	872	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.66, 1.18]
3.3 Childhood (prevalence)	2	934	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.42, 0.97]
4 Rhinitis Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.06, 35.37]
4.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.53, 3.26]
5 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	141	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.64, 5.16]
6 Cow's milk allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	1	67	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.15, 0.89]

Comparison 11. Prolonged feeding: hydrolysed formula versus cow's milk formula ‐ studies with blinded measurement

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Comparison 13. Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 Infancy (incidence)	7	1729	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.66, 0.94]
1.2 Childhood (incidence)	2	510	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.31, 1.52]
2 Asthma Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	3	177	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.29, 1.28]
2.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.84]
2.3 Childhood (prevalence)	2	727	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.85, 1.51]
3 Eczema Show forest plot	7		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	7	1608	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.72, 1.03]
3.2 Childhood (incidence)	2	510	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.61, 1.19]
3.3 Childhood (prevalence)	2	726	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.63, 1.12]
4 Rhinitis Show forest plot	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	2	115	Risk Ratio (M‐H, Fixed, 95% CI)	0.4 [0.09, 1.70]
4.2 Childhood (incidence)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.04, 5.03]
4.3 Childhood (prevalence)	1	295	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.73, 1.68]
5 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	338	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.44, 1.33]
6 Cow's milk allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	2	405	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.16, 0.86]

Comparison 13. Prolonged feeding: partially hydrolysed whey formula versus cow's milk formula

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Comparison 14. Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.80, 2.31]
1.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.76 [0.76, 4.09]
2 Asthma Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.07, 1.60]
2.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [0.77, 6.26]
3 Eczema Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.66, 2.55]
3.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.03, 2.66]
4 Rhinitis Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Childhood (prevalence)	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.53, 3.26]
5 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	91	Risk Ratio (M‐H, Fixed, 95% CI)	2.56 [0.86, 7.56]

Comparison 14. Prolonged feeding: partially hydrolysed casein‐containing formula versus cow's milk formula

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Comparison 15. Prolonged feeding: extensively hydrolysed whey formula versus cow's milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	1	972	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.71, 1.34]
1.2 Childhood (incidence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.82, 1.38]
2 Asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Childhood (prevalence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.73, 1.94]
3 Eczema Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	1	972	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.72, 1.40]
3.2 Childhood (incidence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.75, 1.49]
3.3 Childhood (prevalence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.46, 1.33]

Comparison 15. Prolonged feeding: extensively hydrolysed whey formula versus cow's milk formula

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Comparison 16. Prolonged feeding: extensively hydrolysed casein formula versus cow' milk formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.54, 1.07]
1.2 Childhood (incidence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.53, 0.97]
2 Asthma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Childhood (prevalence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.49, 1.45]
3 Eczema Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	1	976	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.47, 1.00]
3.2 Childhood (incidence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.44, 0.98]
3.3 Childhood (prevalence)	1	431	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.27, 0.92]

Comparison 16. Prolonged feeding: extensively hydrolysed casein formula versus cow' milk formula

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Comparison 17. Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Any allergy Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Infancy (incidence)	2	1143	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.73, 1.26]
1.2 Childhood (incidence)	1	440	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.50, 0.90]
2 Asthma Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Infancy (incidence)	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	2.28 [0.83, 6.28]
2.2 Childhood (prevalence)	1	440	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.42, 1.19]
3 Eczema Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Infancy (incidence)	2	1143	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.59, 1.10]
3.2 Childhood (incidence)	1	440	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.42, 0.92]
3.3 Childhood (prevalence)	1	440	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.33, 1.21]
4 Rhinitis Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Infancy (incidence)	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	2.08 [0.39, 11.02]
5 Food allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 Infancy (incidence)	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.48, 4.39]
6 Cow's milk allergy Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6.1 Infancy (incidence)	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	5.19 [0.25, 106.38]
7 Urticaria Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 Infancy (incidence)	1	161	Risk Ratio (M‐H, Fixed, 95% CI)	4.15 [0.47, 36.34]

Comparison 17. Prolonged feeding: extensively hydrolysed casein formula versus extensively hydrolysed whey formula

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