Table 14.
Enteral feeding interventions reducing NEC incidence or mortality in human studies.
| Enteral Feeding Intervention | Effect on NEC Incidence | ||||
|---|---|---|---|---|---|
| Intervention | Study, N | Observed Relative Effect | Anticipated Absolute Effects | Certainty of Evidence (GRADE) | |
| Risk with No Enteral Feeding Intervention | Risk with Enteral Feeding Intervention (95% CI) | ||||
| Fat-Based Interventions | |||||
| n-3 PUFA | Meta-analysis, 11 RCTs, N = 1753 neonates | RR 1.17 (95% CI 0.77–1.79) (incidence all neonates) [223] |
28 per 1000 | 5 more per 1000 more (from 6 less per 1000 to 50 more per 1000) |
Low ⊕⊕⊝⊝ (risk of bias, imprecision) |
| RR 0.50 (95% CI 0.23–1.10) (incidence neonates ≤32 weeks) [223] |
58 per 1000 | 29 less per 1000 (from 45 less per 1000 to 6 more per 1000) |
Low ⊕⊕⊝⊝ (risk of bias, imprecision) |
||
| DHA | RCT, N = 1205 neonates | RR1.16 (95% CI 0.79–1.69) (incidence) [224] |
71 per 1000 | 11 more per 1000 (from 15 less per 1000 to 49 more per 1000) |
Low ⊕⊕⊝⊝ (imprecision) |
| Carbohydrate or sugar-based interventions | |||||
| Prebiotics | Meta-analysis, 6 RCTs, N = 737 neonates | RR 0.79 (95% CI 0.44–1.44) (incidence) [225] |
112 per 1000 | 24 less per 1000 (from 63 less per 1000 to 49 more per 1000) |
Low ⊕⊕⊝⊝ (inconsistency, imprecision) |
| Protein or amino acid-based interventions | |||||
| Lactoferrin | Meta-analysis, 7 RCTs, N = 4874 neonates | RR 0.90 (95% CI 0.69–1.17) (incidence stage II or III NEC) [226] |
47 per 1000 | 5 per 1000 less (from 15 per 1000 less to 8 per 1000 more) |
Low ⊕⊕⊝⊝ (risk of bias, imprecision) |
| Arginine | Meta-analysis, 3 RCTs, N = 285 neonates | RR 0.38 (95% CI 0.23–0.64) (incidence) [227] |
303 per 1000 | 188 per 1000 less (from 233 less per 1000 to 109 less per 1000) |
Moderate ⊕⊕⊕⊝ (imprecision) |
| RR 0.18 (95% CI 0.03–1.00) (death due to NEC) [227] |
55 per 1000 | 45 less per 1000 (from 53 less per 1000 to 0 less per 1000 |
Low ⊕⊕⊝⊝ (imprecision) |
||
| Glutamine | Meta-analysis, 7 RCTs, N = 1172 neonates | RR 0.73 (95% CI 0.49–1.08) (incidence) [228] |
90 per 1000 | 24 less per 1000 (from 46 less per 1000 to 8 more per 1000) |
Low ⊕⊕⊝⊝ (imprecision, publication bias) |
| IgG or IgG + IgA | meta-analysis, 3 clinical trials, N = 2095 neonates | RR 0.84 (95% CI 0.57–1.25) (incidence) [229] |
55 per 1000 | 9 less per 1000 (from 24 less per 1000 to 14 more per 1000) |
Low ⊕⊕⊝⊝ (risk of bias) |
| RR 0.21 (95% CI 0.02–1.75) (NEC related surgery) [229] |
25 per 1000 | 20 less per 1000 (from 25 less per 1000 to 19 more per 1000) |
Very low ⊕⊝⊝⊝ (risk of bias, imprecision) |
||
| RR 1.10 (95% CI 0.47–2.59) (death due to NEC) [229] |
10 per 1000 | 1 per 1000 more (from 5 less per 1000 to 16 more per 1000) |
Very low ⊕⊝⊝⊝ (risk of bias, imprecision) |
||
| Hormone/growth factor/vitamin-based interventions | |||||
| EPO | Meta-analysis, 2 RCTs, N = 110 neonates | RR 0.62 (95% CI 0.15–2.59) (incidence stage II or III NEC) (NS) [230] |
61 per 1000 | 24 less per 1000 (from 52 less per 1000 to 97 more per 1000) |
Very low ⊕⊝⊝⊝ (inconsistency imprecision) |
| RCT, N = 120 neonates | 2.8pp increase (11.1% control group, 13.9% EPO group (NS) (incidence) [232] |
111 per 1000 | 28 less per 1000 (no CI reported) |
Very low ⊕⊝⊝⊝ (risk of bias, inconsistency imprecision) |
|
| RCT, N = 100 neonates | 2 pp reduction (8% control group, 6% EPO group) (NS) (incidence) [231] |
80 per 1000 | 20 less per 1000 (no CI reported) |
||
| EPO + G-CSF | RCT, N = 50 neonates | 10 pp reduction (10% control group, 0% EPO group) (NS) (incidence) [233] |
100 per 1000 | 100 per 1000 less (no CI reported) |
Low ⊕⊕⊝⊝ (imprecision) |
| G-CSF | RCT, N = 50 neonates | 10 pp reduction (10% control group, 0% EPO group) (NS) (incidence) [233] |
100 per 1000 | 100 per 1000 less (no CI reported) |
Low ⊕⊕⊝⊝ (imprecision) |
| G-CSF (in artificial amniotic fluid) |
RCT, N = 100 neonates | 2 pp reduction (8% control group, 6% EPO group) (NS) (incidence) [231] |
80 per 1000 | 20 per 1000 less (no CI reported) |
Very low ⊕⊝⊝⊝ (risk of bias, imprecision) |
| Vitamin A | RCT, N = 154 neonates | RR 1.14 (95% CI 0.66–1.66) (incidence) [234] |
91 per 1000 | 13 per 1000 more (from 31 per 1000 less to 60 per 1000 more) |
Low ⊕⊕⊝⊝ (risk of bias, imprecision) |
| RCT, N = 262 neonates | RR 0.69 (95% CI 0.27–1.76) (incidence) [235] |
77 per 1000 | 24 per 1000 less (from 56 per 1000 less to 59 per 1000 more) |
||
| Probiotic interventions | |||||
| Probiotics | (network) meta-analysis, 56 RCTs, N = 12,738 neonates | ||||
|
Lactobacillus spp. and Bifidobacterium spp. 11 RCTs, N = 1878 neonates |
OR 0.35 (95% CI 0.20–0.59) (incidence stage II or III NEC) [238] |
63 per 1000 | 41 per 1000 less (from 51 per 1000 less to 26 per 1000 less) |
Moderate ⊕⊕⊕⊝ (indirectness) |
|
|
Bifodobacterium animalis subsp. Lactis 5 RCTs, 628 neonates |
OR 0.31 (95% CI 0.13–0.74) (incidence stage II or III NEC) [238] |
94 per 1000 | 44 per 1000 less (from 56 per 1000 less to 16 per 1000 less) |
Moderate ⊕⊕⊕⊝ (imprecision) |
|
|
Lactobacillus reuteri 5 RCTs, N = 1388 neonates |
OR 0.55 (95% CI 0.34–0.91) (incidence stage II or III NEC) [238] |
71 per 1000 | 28 per 1000 less (from 42 per 1000 less to 5 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision, indirectness) |
|
|
Lactobacillus rhamnosus 5 RCTs, N = 839 neonates |
OR 0.44 (95% CI 0.21–0.90) (incidence stage II or III NEC) [238] |
60 per 1000 | 35 per 1000 less (from 50 per 1000 less to 5 per 1000 less) |
Moderate ⊕⊕⊕⊝ (imprecision) |
|
| Combination of Lactobacillus ssp., Bifidobacterium spp. and Enterococcus ssp. 7 RCTs, N = 1950 neonates |
OR 0.28 (95% CI 0.16–0.49) (incidence stage II or III NEC) [238] |
63 per 1000 | 46 per 1000 less (from 54 per 1000 less to 32 per 1000 less) |
Low ⊕⊕⊝⊝ (risk of bias) |
|
| Combination of Bacillus spp. and Enterococcus spp. 1 RCT, N = 355 neonates |
OR 0.23 (95% 0.08–0.63) (incidence stage II or III NEC) [238] |
110 per 1000 | 49 per 1000 less (from 59 per 1000 less to 23 per 1000 less) |
Moderate ⊕⊕⊕⊝ (imprecision) |
|
| Network meta-analysis 43 RCTs, N = 10,651 neonates |
|||||
|
Bifidobacterium lactis Bb-12 or B-94 5 RCTs, N = 828 neonates |
RR 0.25 (95% CI 0.10–0.56) (incidence) [239] |
100 per 10000 | 75 per 1000 less (from 90 per 1000 less to 44 per 1000 less |
Moderate ⊕⊕⊕⊝ (imprecision) |
|
|
Lactobacillus reuteri ATCC55730 or DSM17938 4 RCTs, N = 1459 neonates |
RR 0.43 (95% CI 0.16–0.98) (incidence) [239] |
92 per 1000 | 52 per 1000 less (from 77 per 1000 less to 2 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision, indirectness) |
|
|
Lactobacillus rhamnosus GG 6 RCTs, N = 1507 neonates |
RR 0.24 (95% CI 0.064–0.67) (incidence) [239] |
24 per 1000 | 18 per 1000 less (from 22 per 1000 less to 8 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision, indirectness) |
|
| Combination of Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacteirum longum and Lactobacillus acidophilus 2 RCTs, N = 247 neonates |
RR 0.25 (95% CI 0.051–0.89) (incidence) [239] |
129 per 1000 | 97 per 1000 less (from 122 per 1000 less to 14 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision) |
|
| Combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12 and Streptococcus thermophilus TH-4 2 RCTs, N = 1244 neonates |
RR 0.29 (95% CI 0.073–0.78) (incidence) [239] |
54 per 1000 | 38 per 1000 less (from 50 per 1000 less to 12 per 1000 less) |
Low ⊕⊕⊝⊝ (inconsistency, imprecision) |
|
|
Bifidobacterium longum 35624 and Lacobacillus rhamnosus GG 2 RCTs, N = 285 neonates |
RR 0.18 (95% CI 0.020–0.89) (incidence) [239] |
42 per 1000 | 34 per 1000 less (from 41 per 1000 less to 5 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision) |
|
| Other interventions | |||||
| Carotenoids | RCT, N = 229 neonates | OR 0.34 (95% CI 0.07–1.66) (incidence stage II or III NEC) [241] |
52 per 1000 | 34 per 1000 less (from 48 per 1000 less to 60 per 1000 more) |
Low ⊕⊕⊝⊝ (imprecision) |
| Mixture of probiotics, prebiotics and lactoferrin | RCT, N = 208 neonates | RR 0.16 (95% CI 0.03–0.77) (incidence) [242] |
106 per 1000 | 89 per 1000 less (from 103 per 1000 less to 24 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision) |
| RR 0.56 (95% CI 0.47–0.67) (incidence stage II or III NEC) [242] |
38 per 1000 | 17 per 1000 less (from 20 per 1000 less to 13 per 1000 less) |
Low ⊕⊕⊝⊝ (imprecision) |
||
⊕⊕⊕⊕ depicts high certainty of evidence, ⊕⊕⊕⊝ depicts moderate certainty of evidence, ⊕⊕⊝⊝ depicts low certainty of evidence, ⊕⊝⊝⊝ depicts very low certainty of evidence; PUFA, polyunsaturated fatty acids; DHA, docosahexaenoic acid; SC-GOS, short chain galacto-oligosaccharides; LC-FOS, long chain fructo-oligosaccharides; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; OR, odds ratio; RR, relative risk; CI, confidence interval.