von Berg 2003.

Methods	Multi‐centre randomised controlled trial in Germany.
Participants	Inclusion criteria: high risk of allergic disease in healthy infants with at least one first‐degree family member with allergic disease Exclusion criteria: severe acquired or congenital diseases, gestation < 37 weeks, birth weight < 2500 g, > 14 days, intake cow's milk‐based formula before inclusion, incapability of parent to comply with study protocol.
Interventions	Mothers encouraged to breast feed for at least 4 months. Study formula provided for when sole breast feeding no longer continued and provided until infant 6 months of age. Infants (all centres: N = 2252; Wessel: n = 1087) randomised to: Treatment 1 (all centres: n = 557; Wessel: n = 273): partially hydrolysed 100% whey formula (Beba HA, Nestle, Vevey, Switzerland) Treatment 2 (all centres: n = 559; Wessel: n = 265): extensively hydrolysed 100% whey formula (Hipp HA, Hipp, Pfaffenhofen, Germany) Treatment 3 (all centres: n = 580; Wessel: n = 281): lactose‐free, extensively hydrolysed 100% casein formula (Nutramigen, Mead Johnson, Diezenbach, Germany) Control (all centres: n = 556; Wessel: n = 268): CMF with casein:whey ratio 40:60 (Nutrilon Premium, Nutricia/Numico, Zoetermeer, the Netherlands) Co‐interventions: all groups received advice about breast feeding for at least 4 months, preferably 6; no dietary restrictions during lactation; not to feed solids during study period, and thereafter to add 1 food a week and avoid common allergenic foods in first year. 58.4% of infants received study formula
Outcomes	Primary outcome(s): allergic disease. Other outcomes: allergic disease (atopic manifestations), asthma and eczema. Definitions Allergic disease (atopic manifestations) diagnosed at 12 months (infant allergic disease) as atopic dermatitis, allergic urticaria or gastrointestinal food allergy. Atopic dermatitis: typical morphology and distribution of skin lesions; pruritus; chronicity (duration ≥ 14 days, chronically relapsing or both); confirmed on skin examination by a second specially trained allergist; severity rated using the SCORAD method. Allergic urticaria: at least 2 episodes of itching eruptions or swelling with typical appearance, observed by parents or physician, caused by the same allergen. In case of a single episode, immunological evidence (specific SPT or allergen‐specific IgE level ≥ 0.35 KU/L or positive provocation response). Gastrointestinal food allergy: suspected if GI symptoms not explained by any other condition, and if unblinded elimination challenge reproduced symptoms. GI allergic disease definite if a positive standardised elimination/challenge procedure. Double‐blind, placebo‐controlled food challenge performed in cases of uncertain reactions. At 3 years, childhood allergic disease included atopic dermatitis, urticaria, food allergy with manifestation in the gastrointestinal tract and asthma. Allergic asthma: diagnosed from parental report of relevant symptoms (wheeze and/or cough without infection) or regular use of asthma medication in the child's third year of life. Asthma symptoms included wheezing or cough for at least 2 weeks (acute laryngotracheitis excluded); exercise‐induced wheeze or cough at any time (with crying, laughing or activity); and episodes of wheezing or dry night‐time cough. At 6 years, reported physician‐diagnosed allergic diseases (atopic dermatitis, food allergy, allergic urticaria, asthma and hay fever/allergic rhinitis). At 10 years, reported physician‐diagnosed asthma, allergic or atopic eczema/dermatitis, hay fever/allergic rhinitis, urticaria and food allergy. Also, if present, at 10 years, parents reported a physician’s diagnosis during past 4 years, treatment in past 12 months or both. At 15 years, parent‐reported physician‐diagnosed asthma, allergic rhinitis (AR) and eczema, spirometric indices and sensitisation.
Notes	Data for intention‐to‐treat analyses of all infants (including breast fed infants) according to study centre provided by study authors for all allergic disease, asthma and eczema. Intention‐to‐treat 3‐year data for food allergy not provided. Analyses meeting inclusion criteria for the review are intention‐to‐treat analyses including breast fed infants for all study centres at 1 year and infants enrolled in Wesel for 3‐year outcomes. Excess losses beyond 3 years, so data not included in analyses. Trial of prolonged breast feeding with supplemental or sole formula feeding when required comparing use of CMF, pHWF, extensively hydrolysed whey formula and lactose‐free extensively hydrolysed casein formula. Sponsor: study supported by Federal Ministry for Education, Science, Research and Technology and the Child Health Research Foundation. Formulas provided by Nestle, Hipp, Milupa, Numico and Mead Johnson.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list stratified for single or double parental atopy and study region.
Allocation concealment (selection bias)	Low risk	Random sequence generation and blinded intervention.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Blinding of parents and the study team was guaranteed by using identically labelled tins for the study formula coded with 4 different letters for each of the 4 formulas".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	In intention‐to‐treat analyses for study centres (Munich and Wesel) that included breast fed infants: 1 year: 304/2252 (13.5% lost to follow‐up). 3 years: 692/2254 (31% lost to follow‐up). 6 years: 572/2252 (25% lost to follow‐up). 10 years: 1115 to 1145/2522 (44% to 45% lost to follow‐up). 15 years: Response rates were 61.1% (1377/2252) ‐ lost to follow‐up 875/2252 (39%) Breast fed infants randomised to interventions who did not receive interventions were followed up only in Wesel. In intention‐to‐treat analyses for Wesel only: 1 year: 158/1087 (14.5% lost to follow‐up). 3 years: 206/1087 (19% lost to follow‐up).
Selective reporting (reporting bias)	Low risk	Primary endpoints and specific timings stated in the methods were reported in the results in the original study report (von Berg 2003).
Other bias	High risk	Quote: ".. significant bias in the eHF‐C group because disproportionally more children had to be excluded as a result of noncompliance with the study formula (18% [47/257] in the eHF‐C group vs 10% to 12% in the other study formula groups, P = 0.02)".