| Study | Reason for exclusion |
|---|---|
| Agosti 2003 | AGA preterm infants allocated to low hydrolysed protein formula vs intact protein formula. Method of allocation not reported. Did not measure allergy. n = 20. |
| Akerblom 2005 | 242 newborn infants who had a first‐degree relative with type 1 diabetes and carried risk‐associated HLA‐DQB1 alleles. After exclusive breast feeding, the infants underwent a double‐blind, randomised pilot trial of either casein hydrolysate or conventional cow's milk‐based formula until the age of 6‐8 months. Did not report allergic disease or food allergy. |
| Akimoto 1997 | Cohort study. |
| Arikan 2008 | Randomised families with colicky infants to 4 different intervention groups ‐ massage, sucrose solution, herbal tea and hydrolysed formula and control group. Did not report allergy. n = 35 per group. |
| Arshad 1990 | Randomised controlled trial in infants at high risk of allergy (family history of allergy in two or more of mother/father/sibling) receiving formula (n = 60 in each group). Cow’s milk formula versus hydrolysed formula (extensively hydrolysed casein formula Aptamil HA, Milupa) for the prevention of allergy. Reported allergy at 12 months. Completed, however author unable to get approval from sponsor to release data. |
| Arshad 1992a | Had multiple allergies preventing co‐interventions in treatment group and not in control group |
| Baldassarre 2017 | RCT of infants 28‐33 weeks' gestational age; birth weight of 700 g to 1750 g and AGA within 24 hours of first enteral feeding (n = 65). Cow's milk protein versus EHF feeding. Did not report allergy. Reported feeding advancement and markers of feeding tolerance. |
| Barberi 1993 | Infants at high risk of atopy randomised to HF vs CMF. 440 received allocated formula. Method of allocation not reported. Excess post‐randomisation losses ‐ 278/815 (34%). No intention‐to‐treat analysis. n = 815. |
| Bergmann 1996a | Infants at risk of atopy were assigned to 1 of 3 nutritional groups and were followed up through the first 6 months of life: 20 infants were breast fed, 28 received a predominantly whey protein‐based infant formula, 53 received an ultrafiltrated partially hydrolysed whey protein formula. Non‐random allocation. n = 101. |
| Berseth 2009 | Double‐blind randomised controlled trial in healthy formula‐fed term infants with no family history of allergy of 70% lactose, partially hydrolyzed cow's milk protein formula supplemented with docosahexaenoic acid and arachidonic acid vs full lactose intact cow milk protein formula supplemented with docosahexaenoic acid and arachidonic acid. Did not report allergy. Measured adverse effects and tolerance. n = 335. |
| Borschel 2013 | Healthy term infants randomised to an amino acid–based formula or an extensively hydrolysed casein‐based formula. Did not report allergy. n = 213. |
| Borschel 2014a | RCT in healthy term infants fed whey‐based, palm olein oil–free PHF vs whey‐based, palm olein oil‐containing PHF (not eligible comparison). Did not report allergy. n = 209. |
| Borschel 2014b | RCT in healthy term infants fed ready‐to‐feed or powdered form of an extensively hydrolysed casein‐based formula (not eligible comparison). Did not report allergy. n = 195. |
| Boyle 2016 | RCT in infants at high risk of allergy fed PHF supplemented with prebiotic vs standard CMF without prebiotic. Not an eligible comparison. Reported allergy. n = 863. |
| Burks 2008 | Randomised healthy term infants to amino acid‐based formula vs EHF. Excess post‐randomisation losses (33%). Reported adverse events. Did not report allergy. n = 165. |
| Campbell 1989 | Enrolled infants with colic. Not randomised. |
| Chan 2002 | Trial of sole prolonged partially hydrolysed CMF vs CMF in infants at high risk of atopy. Excess losses (28%). n = 110. |
| Chan‐Yeung 2000 | Infants at high risk of allergy. Had multiple allergy‐preventing co‐interventions in treatment group and not in control group. n = 545. |
| Chandra 1989a | Original data unable to be verified. |
| Chandra 1989b | Original data unable to be verified. |
| Corvaglia 2013 | Randomised preterm infants with symptomatic gastroesophageal reflux to extensively hydrolysed preterm formula vs standard preterm formula. Did not report allergy. n = 40. |
| D'Agata 1996 | Infants at high risk of allergy. 30 exclusively breast fed, 50 hypoallergenic milk‐fed, 30 soy milk‐fed and 15 fed with conventional milk formula. Method of allocation unspecified. Substantial imbalances in numbers. Reported allergy. |
| de Jong 1998 | Trial of early supplementation of CMF vs a protein‐free placebo formula (not hydrolysed protein) in breast fed infants |
| Decsi 1992 | Healthy term infants who were breast fed or received conventional formula (Mildibe, EGIS; Pre‐Aptamil, Milupa), or a formula containing hydrolysed proteins (Aptamil H.A., Milupa). Did not report allergy. n = 10 per group. |
| Decsi 1998 | Term infants fed conventional formula or PHF. Excess losses (27% hydrolysed formula group and 21% CMF group). Did not report allergy. n = 11 per group. |
| Exl 1998 | Allocated to intervention (breast feeding, hydrolysed formula and delayed weaning) according to geographical area. |
| Florendo 2009 | Preterm infants randomised to feeds with a standard non‐hydrolysed whey–casein vs partially hydrolysed whey preterm infant formula. Reported feed intolerance. Did not report allergy. n = 80. |
| Fukushima 1997 | Trial of maternal allergen avoidance and infant supplemental or sole hydrolysed or CMF feeding when required. Differential losses with excess losses in maternal and infant hydrolysed formula group (27%) and in maternal hydrolysed formula and infant CMF group (23%). |
| Giovannini 1994 | Study in infants at high risk of atopy given human milk vs soy formula vs whey‐based low‐degree hydrolysate vs casein‐based high‐degree hydrolysate vs soy plus collagen‐based high‐degree hydrolysate formula. Did not report allergy. Excess post allocation losses (56/138) not analysed in group of assignment (solely breast fed infants reported separately). n = 138. |
| Halken 1992 | Trial of prolonged supplementary or sole extensively vs partially hydrolysed ultrafiltrated formula in high‐risk infants. Only infants who received hydrolysed formula included in analysis. Excess losses after allocation (24%). n = 158. |
| Hartman 1994 | Randomised trial in healthy infants allocated to soy formula, CMF or PHF. Abstract only. Losses unclear. Reported intolerance and allergy but data not extractable from abstract. n = 510. |
| Hattevig 1989 | Trial of maternal allergen avoidance. The diet for infants was the same in both groups. During first 6 months, only breast milk and or formula based on hydrolysed casein (Nutramigen) given. |
| Hernell 2003 | Breast fed infants, infants fed hydrolysate formulas, infants fed milk formula. Method of allocation not reported. Allergy not reported. n = 55. |
| Hill 1995b | Enrolled infants with 'colic'. Randomised to casein hydroIysate or CMF. Did not report allergy. n = 151. |
| Høst 1991 | Cohort study. Casein hydrolysate (Nutramigen) used in elimination/challenge. |
| Iikura 1995 | Abstract form only. Method of allocation unclear. Substantial differences in group sizes. |
| Keller 1996 | Allocation to various feeding regimens including hydrolysed formula performed by nurses 'at random'. "Maternal decision respected". Unlikely to be random allocation. Allergy reported. |
| Knip 2010 | Randomised trial 230 infants with HLA‐conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional cow’s‐milk–based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Did not report allergy outcomes. |
| Knip 2011 | Enrolled infants at risk of type 1 diabetes mellitus. Intervention commenced at weaning. Excess losses reported: 2997 / 5156 randomised infants not included in analysis = 58%. Reported adverse events including asthma, other forms of allergy at 10 years of age. |
| Kuo 2011 | Prospective, observational, uncontrolled cohort study in newborns who had at least 1 first‐degree family member with a history of atopy and could not breast feed. Fed with HF or CM for at least 6 months and monitored prospectively at 6, 18 and 36 months of age. |
| Lasekan 2006 | Assessed growth efficacy, gastrointestinal tolerance and plasma biochemical measurements of healthy infants receiving a partially hydrolysed rice protein‐based formula vs CMF for the first 16 weeks after birth. Did not report allergy. n = 65. |
| Lucassen 2000 | Enrolled infants with excessive crying. Randomised healthy, thriving, formula‐fed infants, < 6 months old, crying > 3 hours per day on at least 3 days per week to whey hydrolysate formula or standard formula. Did not report allergy. n = 43. |
| Maggio 2005 | Randomised controlled trial of preterm formula with hydrolysed cow’s milk proteins reporting short‐term growth and urinary and plasma amino acid levels. Did not report allergy. n = 21. |
| Martinez‐Valverde 1993 | No definition of allergic symptoms reported in first 4 months. In Spanish version of thesis, method of treatment allocation not extractable independently. |
| Medjad‐Guillou 1992 | Cross‐over trial of CMF vs hydrolysed formula in healthy term infants. Did not report allergy. |
| Mennella 2011a | Healthy infants randomly assigned to CMF or PHF between 0.5 and 7.5 months of age. Did not report allergy. n = 79. |
| Mihatsch 1999 | Cross‐over trial examining effects of hydrolysed formula on plasma amino acids and gastrointestinal transit time in preterm infants. Did not report allergy. |
| Mihatsch 2002 | Randomised trial of partially hydrolysed preterm infant formula vs CMF in VLBW infants at low risk of atopy establishing enteral feeds. Excess post‐randomisation exclusions 48/135 (36%). Did not report allergy. n = 135. |
| Mitchell 1977 | Trial of lactose hydrolysed milk, not protein hydrolysed. Enrolled slightly undernourished Aboriginal children < 3 years of age. |
| Moran 1992 | Trial of supplementary or sole hydrolysed formula vs CMF in low‐risk infants. Excessive losses > 20% in both groups. n = 205. |
| NCT00936637 | Enrolled health term infants assigned to one of three nutritional groups: 20 infants were breast fed, 28 received an adapted predominantly whey protein based infant formula, 53 received an ultrafiltrated, partially hydrolysed whey protein formula. Did not report allergy. |
| NCT01987154 | Enrolled infants with presumptive cow’s milk allergic colitis. Randomly assigned to EHCF with LGG (Nutramigen LGG) or without (Nutramigen) (EHCF LGG). |
| Nentwich 2003 | Observational study of infants fed a whey hydrolysate formula compared with exclusively breast fed controls. |
| Nocerino 2012 | Randomised trial of standard formula vs partially hydrolysed whey formula in infants with diagnosed infant colic. Did not report allergy. Published as conference abstract only. n = unclear (52 reported). |
| Odelram 1996 | Trial of extensively hydrolysed vs CMF for weaning of high‐risk infants. Excluded trial, as 13 losses in addition to 9 post‐randomisation exclusions (total 27%). n = 91. |
| Paronen 2000 | Enrolled infants at high genetic risk for diabetes. Did not report allergy. n = 119. |
| Pauls 1996 | Trial of formulas with hydrolysed vs non‐hydrolysed protein for starting enteral feedings in preterm infants < 1500 g. Did not report allergy. Only outcomes to day 6 reported. Reported in abstract format only. |
| Picaud 2001 | Preterm infants randomly assigned to PHF or conventional formula. Did not report allergy. n = 16. |
| Porch 1998 | Infants at high risk of allergy randomly assigned extensively hydrolysed casein formula (Nutramigen); partially hydrolysed whey formula (Good Start); and soy formula. Excess losses 51/181 (28%). n = 181. |
| Raupp 1995 | Trial of sole hydrolysed formula vs CMF in low birth weight infants. Excess post‐randomisation losses. Allergy not reported. n = 39 |
| Riezzo 2001 | Randomised trial of standard and hydrolysate formulas in preterm infants. Allergy not reported. n = 36. |
| Rigo 1994a | Method of treatment allocation unclear. Allocated successive infants to formulas. Trial of 5 different types of hydrolysed formula in healthy term infants. Extent of hydrolysis not reported. Allergy not reported. n = 74. |
| Rigo 1994b | Trial of hydrolysate formula in preterm infants. Method of allocation not stated. Allergy not reported. n = 19. |
| Savino 2003 | Observational study of whey hydrolysate formula enrolling infants with "minor feeding problems". |
| Savino 2006 | Randomised to receive formula containing partially hydrolysed whey proteins, prebiotic oligosaccharides, with a high beta‐palmitic acid content, or standard formula and simethicone (multiple formula differences). |
| Scalabrin 2009 | RCT of healthy term infants who received extensively hydrolysed casein formula, the same formula supplemented with Lactobacillus rhamnosus GG or partially hydrolysed whey:casein (60:40) formula supplemented with LGG (PHFLGG). Excess losses at all time points. Reported adverse events including allergy. n = 289. |
| Schmelzle 2003 | Randomised healthy formula‐fed term infant trial of partially hydrolysed whey infant formula vs standard infant CMF. Excess losses ‐ 52 (34%). Allergy not reported. n = 154. |
| Schmidt 1995 | Observational study in high‐risk infants (infants allocated formula at parents' discretion). |
| Schmitz 1992 | Trial in normal breast fed infants of early supplementary hydrolysed formula vs CMF. Did not report allergy. Excess losses at 1 year. n = 256. |
| Schrander 1993 | Cohort study of newborn infants to determine incidence of CMPI and response to Pregomin (Milupa) protein hydrolysate formula. |
| Shao 2006 | Multiple dietary interventions including hydrolysed formula in treatment group for infants at high risk of atopy who were not able to be breast fed. |
| Silva Rey 1996 | Trial of partially hydrolysed milk formula. Excess losses ‐ 124/276 (45%) ‐ 42 losses by 6 months and further 82 excluded post allocation. Method of allocation not reported. n = 276. |
| Sorensen 2007 | Infants (n = 242) with a family history of allergy assigned to one of 3 randomised groups: weaned to either CMF, EHW or PHW formula. All infants were breast fed for 3 months, then study formulas was were given for 1 month. Published as abstract only. Allergy not reported to date. |
| Staelens 2008 | Double‐blind randomised cross‐over study in healthy newborns fed CMF vs PHF vs EHF. Allergy not reported. n = 17. |
| Szajewska 2001 | Low birth weight infants were assigned randomly to receive extensive protein hydrolysate preterm formula, partial protein hydrolysate preterm formula and standard preterm formula. Allergy not reported. n = 61. |
| Szajewska 2004 | Randomised trial of extensively hydrolysed preterm formula vs partially hydrolysed preterm formula vs CMF in high risk for atopy preterm infants. Excess post‐randomisation losses at all times ‐ 22/90 (24%) at 4 to 5 months. n = 90. |
| Tariq 1998 | Cohort study. |
| Taubman 1988 | Enrolled infants with excessive crying ('colic'). Randomised to hydrolysed casein formula or counselling. Allergy not reported. n = 20. |
| Vaarala 1995 | Double‐blind trial; 10 infants received cow's milk‐based formula and 10 received a casein hydrolysate formula until the age of 9 months. Allergy not reported. n = 20. |
| Vaarala 2012 | Infants with HLA‐conferred susceptibility to type 1 diabetes randomly assigned to receive CMF (n = 389), whey‐based hydrolysed formula (WHF) (n = 350) or whey‐based FINDIA formula essentially free of bovine insulin (n = 365). Allergy not reported. n = 1104. |
| Vandenplas 1988 | Retrospective study. Embedded intervention study. Trial of formula, breast milk or a hypoallergenic formula. Method of allocation reported to be "chronological". Losses unclear. n = 75 |
| Vandenplas 1993 | Randomised healthy term infants to whey intermediate hydrolysed formula vs CMF. Allergy not reported. n = 45. |
| Wopereis 2014 | Infants at high risk of allergy randomised to PHF containing a specific mixture of oligosaccharides or to standard CMF for the first 6 months of life. Allergy not reported to date. Published abstract only. n = 108. |
| Xinias 2017 | Enrolled infants with colic allocated to formula containing partially hydrolyzed whey protein, reduced lactose, Bifidobacterium lactis (B lactis) and galacto‐oligosaccharides. Allergy not reported. |
| Yu 2014 | Likely non‐random allocation. Cross‐over design. Enrolled preterm infants. Did not report allergy. |
| Zeiger 1989 | Trial in mothers and infants at high risk of atopy of maternal dietary avoidance in pregnancy and lactation, and infant allergen avoidance through encouragement of breast feeding with supplemental or weaning formula use and subsequent dietary restriction vs usual maternal diet and infant feeding with use of supplementary or weaning CMF. Excluded as multiple co‐interventions and excess losses. |
AGA: appropriate for gestational age CM: cow’s milk CMF: cow’s milk formula CMPI: cow’s milk protein intolerance EHF: extensively hydrolysed formula HF: hydrolysed formula HLA: human leukocyte antigen PHF: partially hydrolysed formula PHFLGG: partially hydrolysed formula supplemented with LGG RCT: randomised controlled trial VLBW: very low birth weight WHF: whey‐based hydrolysed formula