Table 1.
GRADE assessment and summary of key findings of review of studies of hydrolysed formula and risk of allergic or autoimmune disease
| No of studies | Design | Risk of bias | Inconsistency | Indirectness | Imprecision | Publication bias | Other considerations | Odds ratio or relative risk | GRADE of evidence |
|---|---|---|---|---|---|---|---|---|---|
| Outcome: eczema at age 0-4 | |||||||||
| Partially hydrolysed formula: | |||||||||
| 12 studies | 11 RCT, 1 qRCT | Serious. 11 studies with high or unclear overall risk of bias, all studies with high/unclear risk of conflict of interest | Not serious. I2=30%, study estimates varying from 0.33 to 1.44; subgroup analysis suggests difference by study design or population | No | Not serious. 95% CI for OR do not exclude clinically important effect, but exclude large effect sizes and significant harmful effects | No. NB Significant risk when pHF and eHF data combined. Egger’s P<0.05 | All RCTs undertaken in populations at high risk of eczema due to family history of allergic disease | OR 0.84 (0.67 to 1.07) | Moderate |
| Extensively hydrolysed formula: | |||||||||
| 6 studies, 7 interventions | 6 RCT | Serious. 5 studies with high or unclear overall risk of bias, all studies with high/unclear risk of conflict of interest | Serious. I2=74% for analysis of casein eHF; 0% for whey eHF. Study estimates varying from 0.18 to 1.26 | No | Serious 95% CI for OR do not exclude large beneficial or harmful effects | Not tested (n<10) NB Significant risk when pHF and eHF data combined. Egger’s P<0.05 | All RCTs undertaken in populations at high risk of eczema due to family history of allergic disease | Casein eHF OR 0.55 (0.28 to 1.09), whey eHF OR 1.12 (0.88 to 1.42) | Very low |
| Outcome: recurrent wheeze at age 0-4 | |||||||||
| Partially hydrolysed formula: | |||||||||
| 5 studies | 5 RCT | Serious. 4 studies with high or unclear overall risk of bias, all studies with high/unclear risk of conflict of interest | No. I2=15%, study estimates varying from 0.29 to 1.20 | No | Not serious. 95% CI for OR do not exclude clinically important effect, but exclude large effect sizes | Not tested (n<10). NB Significant risk when pHF and eHF data are combined. Egger’s P<0.05 | All RCTs undertaken in populations at high risk of allergy due to family history of allergic disease | OR 0.82 (0.48 to 1.41) | Moderate |
| Extensively hydrolysed formula: | |||||||||
| 5 studies, 6 interventions | 5 RCT | Serious. 5 studies with high or unclear overall risk of bias, all studies with high/unclear risk of conflict of interest | Serious. I2=74% for analysis of casein eHF; 0% for whey eHF. Study estimates varying from 0.18 to 1.26 | Not serious. 2 studies used multifaceted interventions | Not serious. 95% CI for OR do not exclude clinically important effect, but exclude large effect sizes | Not tested (n<10). NB Significant risk when pHF and eHF data combined. Egger’s P<0.05 | All RCTs undertaken in populations at high risk of allergy due to family history of allergic disease | Casein eHF OR 0.76 (0.53 to 1.09), whey eHF OR 1.15 (0.84 to 1.59) | Very low |
| Outcome: allergic sensitisation to cows’ milk at any age | |||||||||
| Partially hydrolysed formula: | |||||||||
| 7 studies | 7 RCT | Serious. 6 studies with high or unclear overall risk of bias, and high/unclear risk of conflict of interest | No. I2=0%, study estimates varying from 0.44 to 9.63 | Not serious. 2 studies used multifaceted interventions | Not serious. 95% CI for RR do not exclude clinically important effect, but exclude very large effect sizes | Not tested (n<10) | All RCTs undertaken in populations at high risk of allergy due to family history of allergic disease | RR 1.30 (0.65 to 2.60) | Moderate |
| Extensively hydrolysed formula: | |||||||||
| 3 studies | 3 RCT | Serious. All studies with high or unclear overall risk of bias, 2 studies with high/unclear risk of conflict of interest | Serious. I2=77%, study estimates varying from 0.08 to 10.13 | Not serious. 1 study used multifaceted intervention | Serious. 95% CI for RR do not exclude large effect sizes | Not tested (n<10) | All RCTs undertaken in populations at high risk of allergy due to family history of allergic disease | RR 0.77 (0.09 to 6.73) | Very low |
| Outcome: type 1 diabetes mellitus at any age | |||||||||
| Extensively hydrolysed formula: | |||||||||
| 5 studies | 5 RCT | Not serious. All studies had low or unclear overall risk of bias, 4 studies had low risk of conflict of interest | Not serious. I2=25%, study estimates varying from 0.62 to 2.02 | No | Not serious. 95% CI for RR do not exclude clinically important effect, but exclude large effect sizes | Not tested (n<10) | All RCTs undertaken in populations at high genetic risk of TIDM, and 4 of 5 studies used casein eHF | RR 1.12 (0.62 to 2.02) | High |
RCT=randomised controlled trial, qRCT=quasi-randomised controlled trial, pHF=partially hydrolysed formula, eHF=extensively hydrolysed formula, RR=risk ratio, OR=odds ratio.