Table 1.
Characteristics of the studies included in the systematic review.
| Study | Characteristics of patients | Sample size | OR (95% CI) | Intervention | Results |
|---|---|---|---|---|---|
| NEC preventive factors | |||||
| 1. Probiotics | |||||
| Robertson et al. (3) (OS) NEC is the primary outcome |
<36 w GA + <1,500 g |
n: 982 | 0.44 (0.23–0.85) | Lactobacillus + Bifidobacterium | The incidence of NEC was reduced with the administration of Lactobacillus and Bifidobacterium compared to those who did not receive it. |
| Beghetti et al. (5) (NMA) NEC is the primary outcome |
<37 w GA | n: 10,664 | 0.32 (0.00–0.21) |
Lactobacillus
Bifidobacterium Formula feed vs. breastmilk |
Lactobacillus acidophilus LB had an effect in reducing NEC in both groups, taking breast milk or artificial milk Bifidobacterium lactis Bb12/b94 was associated with decreased NEC in stage >2, especially in the breast milk subgroup. |
| Patel and Underwood (11) (NMA) NEC is the primary outcome |
<34 w GA | n: 10,520 | 0.58 (0.37–0.91) | Lactobacillus o Bifidobacterium | The combination of Lactobacillus acidophilus and Bifidobacterium bifidum implies a lower risk of NEC suggestive of surgical intervention Other combinations of probiotics reduce the risk of NEC, requiring more studies to determine the combination and dose. |
| Baldassarre et al. (12) (NMA) NEC is NOT the primary outcome |
<34 w GA or <1,500 g |
n: not stated | Not defined | Lactobacillus + Bifidobacterium | The use of probiotics (Lactobacillus + Bifidobacerium) reduces the incidence of NEC in premature infants with <34 weeks' gestational age or <1,500 g birth weight. |
| Liu et al. (13) (NMA) NEC is NOT the primary outcome |
<37 w GA | n: 11,045 | 0.36 (0.24–0.53) |
Lactobacillus rhamnosus GG Lactobacillus reuteri Others |
The use of different probiotics in premature patients significantly reduces the risk of NEC compared to untreated patients The use of L. rhamnosus GG and L. reuteri in doses lower than 109 CFU is postulated to be more beneficial, due to the risk of bacterial translocation. |
| Morgan et al. (14) (NMA) NEC is NOT the primary outcome |
<37 w GA <2,500 g |
n: 15,712 | 0.56 (0.39–0.80) |
Lactobacillus + Bifidobacterium
Bacillus + Enterococcus Bifidocbacterium + Streptoccus isolate |
They reviewed 63 clinical trials of probiotic supplementation vs. placebo treatment, finding that the combination of one or more strains of Lactobacillus spp and Bifidobacterium spp reduced all-cause mortality included NEC. |
| Underwood (15) (NMA) NEC is the primary outcome |
<37 w GA <28 w GA >1,000 g |
n: 85,596 n: 4,683 |
p <0.0002 p <0.005 | Lactobacillus + Bifidobacterium | Use of probiotics reduces mortality and NEC incidence in all premature infants, especially in <28 GA and <1,000 g birth weight. |
| 2. Oligosaccharides (HMOS), breast milk, donated milk | |||||
| Nolan et al. (16) (NR) NEC is the primary outcome |
<1,000 g <37 w GA |
n: 291 n: 27,749 |
0.84 (0.79–0.88) | HMOs breastmilk | Higher breast milk concentrations of HMO disialyllacto-N-tetraose (DSLNT) is associated with a lower risk of NEC (Bell stage 2 and 3 combined). |
| Altobelli et al. (17) (NMA and OS) NEC is the primary outcome |
<37 w GA | n: ~10,484 | 0.62 (0.42–0.93) | Breast/donated vs. formula milk | Reduced risk of NEC>2 in preterm infants who received breast or donated milk instead of formula (even when the amount of breast or donated milk was 50%). |
| Miller et al. (18) (NMA and SR) NEC is NOT the primary outcome |
<28 w GA ≤ 1,500 g |
n: 16,422 | Not defined in OR ARR 4.3–3.8% |
Breast vs. formula milk | Maternal milk reduces NEC. |
| Quigley et al. (19) (SR) NEC is NOT the primary outcome |
<37 w GA | n: 1,809 | 1.87 (1.23–2.85) | Breast vs. donated milk | Feeding with formula milk compared with donor human milk, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing NEC. |
| Sánchez-Luna et al. (8) (NR) NEC is NOT the primary outcome |
<37 w GA | n: 659 | Not defined in OR Reduction of NEC from 10.9 to 2.4% |
Personalized nutrition with pasteurized donated milk + /– fortifier | Personalized nutrition with donated milk decreases the risk of NEC. |
| 3. Lactoferrin | |||||
| Pammi and Suresh (20) (SR and OS) NEC is the primary outcome |
<37 w GA | n: 5,370 | 1.10 (0.86–1.41) | Supplementation with lactoferrin | Decreases late-onset sepsis (both suspected and confirmed, and confirmed only) but not NEC ≥ stage II. |
| 4. Inmunomodulators | |||||
| Nolan et al. (21) (SR) NEC is the primary outcome |
<37 w GA | Not specified | Not defined | Immunomodulatory components of breast milk | The dietary intake of the breastfeeding mother has been shown to influence the variability of human milk concentrations of fat-soluble and water-soluble vitamins and other nutrients. These nutrients, including immunoglobulins, growth factors, cytokines, and immune cells, have been demonstrated to transfer from the mother to the neonate through breast milk. |
| Hackam et al. (22) (SR) NEC is the primary outcome |
<37 w GA | Not specified | Not defined | Role of TLR4 in the development of NEC. | Breast milk is a powerful TLR4 inhibitor, while mutations in TLR4 genes lead to increased NEC risk in humans, providing proof-of-concept for its role in NEC. |
| Alganabi et al. (23) (SR) NEC is the primary outcome |
<1,500 g | Not specified | Not defined | TLR4 Factors related to NEC Breast milk and HMOs in the prevention of NEC |
There are factors involved in the pathophysiology of NEC, such as nitric oxide, toll-like receptor 4 (TLR4), microvascular blood flow that produces intestinal ischemia, and reduced activity of stem cells at the intestinal level Breast milk and the supplementation of enteral nutrition with oligosaccharides from breast milk (HMO) cause a greater functioning of stem cells at the intestinal level, significantly reducing the risk of NEC. |
| 5. Other preventive factors | |||||
| Rose and Patel (24) (SR) NEC is the primary outcome |
<37 w GA <37 w GA <2,000 gr <37 w GA <1,500 g <32 w GA |
n: 4,702 n: 1,170 n: 2,869 n: 750 n: 285 n:1,092 |
0.50 (0.32–0.78) 0.30 (0.10–0.89) 0.43 (0.21–0.87) Any stage of NEC:0.38 (0.23–0.64) Death due to NEC: 0.18 (0.03–1) 0.93 (0.64–1.34) 1.07 (0.67–1.70) |
Prenatal steroids Use of progesterone in the mother in preterm labor Hydric restriction Oral or parenteral supplementation with arginine Delay in the start of enteral nutrition Trophic enteral nutrition |
The use of antenatal steroids reduces the risk of NEC by 50%, but in <25 w GA it does not present benefits in this aspect Progesterone given to women at risk for preterm birth decreased the relative risk of NEC Total fluid goals for premature infants are influenced by multiple factors but a restricted approach may decrease NEC risk Meta-analysis of small trials demostrate that oral or parenteral supplementation with arginine decreases the risk for any stage of NEC and death due to NEC Delay in enteral feeding by <1,500 g or <32 w GA does not alter the risk of NEC, including children with RIC Trophic enteral nutrition does not modify the risk of NEC. |
| NEC risk factors | |||||
| Rose and Patel 2018 (24) (SR) NEC is the primary outcome |
≤ 31 w GA <37 w GA <37 w GA |
n: 4,649 n: 5,003 n: 874 |
2.09 (1.30–2.35) 1.25 (0.12–12.50) 0.44 (0.17–0.12) |
Reduced placental flow at delivery Antibiotics administration Anemia |
Reduced placental flow during preterm delivery increases the risk of NEC. A recent meta-analysis of observational studies found prolonged antibiotic exposure was associated with NEC, but no statistically significant effect on NEC when looking at whether or not an infant received prophylactic antibiotics or broad vs. narrow spectrum antibiotics. Anemia ( ≤ 8 g/dl) was associated with an increased risk for NEC but not red cell transfusion or erythropoiesis-stimulating agents used to modify transfusion. |
| NEC predictive factors | |||||
| Sinclair et al. (25) (CC) NEC is the primary outcome |
<32 w GA | n: 995 | p <0.001 | Metabolite levels (aminoacids and acylcarnitine) at birth and in the days of life 1, 7, 28, 42 | Analytical leves of of alanine, phenylalanine, free carnitine, C16, arginine, C14:1/C16, and citrulline/phenylalanine in day 1 were associated with later development of NEC. Over time, differences in individual levels associated with NEC onset changed from predominantly AA at birth to predominantly AC at day 42. Subjects who developed NEC received significantly lower weight-adjusted total calories. |
| Nguyen and Sangild (9) (SR) NEC is the primary outcome |
<37 w GA | Not specified | Not defined | Study of biomarkers (calprotectin, IL6, IL17) for NEC prediction | NEC gut tissues also display increased activation of TLR4 signalingand formation of neutrophil extracellular traps (NETs) with release of antimicrobial neutrophil components, including calprotectin. As a result, fecal calprotectin has been suggested as a potential biomarker for NEC diagnosis. The polarization of CCR9+ Treg into CCR9+ IL17 producing Treg was regulated by IL6 activity. The authors therefore proposed that IL6 receptor antibody can be used to treat NEC. The exciting results from this study may pave the way for future investigations on new disease blood biomarkers as well as therapeutic approaches with inhibition of gut chemokines or IL-6 signaling. |
OS, observational study; NMA, network meta-analysis; NR, narrative review; MA, meta-analysis; SR, systematic review; CC, cases-controls; OR, odds ratio.