Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants.
ABSTRACT: Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood.Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC.Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidémiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidémiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing.Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002).Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.
Project description:BACKGROUND/OBJECTIVES:Prebiotics are increasingly recognized as an effective measure to promote health and prevent adverse health outcomes in preterm infants. We aimed to systematically review the randomized controlled trials (RCTs) in this area. SUBJECTS/METHODS:Relevant studies from January 2000 to June 2018 were searched and selected from PubMed, Medline, Scopus, and the Cochrane Library. RCTs were included if they involved preterm infant participants, included a prebiotic intervention group, measured incidence of sepsis, feeding intolerance, mortality, time to full enteral feeding, necrotizing enterocolitis (NEC), length of hospital stay, and stool frequency as outcomes. RESULTS:Eighteen RCTs (n?=?1322) were included in the final meta-analysis. Participants who took prebiotics showed significant decreases in the incidence of sepsis (with a risk ratio (RR) of 0.64, 95% CI: 0.51, 0.78), mortality (RR?=?0.58. 95% CI: 0.36, 0.94), length of hospital stay (mean difference (MD): -5.18, 95% CI: -8.94, -1.11), and time to full enteral feeding (MD: -0.99, 95% CI: -1.15, 0.83). The pooled effects showed no significant differences between intervention and control groups in relation to the morbidity rate of NEC (RR?=?0.79, 95% CI: 0.44, 1.44) or feeding intolerance (RR?=?0.87, 95% CI: 0.52, 1.45). CONCLUSIONS:The results showed that the use of prebiotics with preterm infants is safe and can decrease the incidence of sepsis, mortality, length of hospital stay, and time to full enteral feeding but not NEC.
Project description:Our goal was to investigate the surgical procedures, postoperative complications, and survival with regard to different onset timing of necrotizing enterocolitis (NEC).We performed a retrospective review of medical records with a diagnosis of NEC between 2005 and 2016. The cutoff was set at 10 days for early onset ≤10 days and late onset over 10 days. Propensity score matching was performed to adjust for any baseline differences. In 53 paired patients, clinical outcomes, including, mortality, postoperative complications, and length of neonatal intensive care unit (NICU) stay, were evaluated on the basis of early or late-onset NEC.Successful 1:1 matching propensity score matching was performed with 208 infants. Mortality for early-onset NEC infants was lower than that of early late NEC infants (P = .026). A lower overall postoperative complication rate, including infectious complications [19 (35.8) vs 29 (54.7); odds ratio, 0.462, confidence interval (CI) 0.212-1.008, P = .039], was noted in patients with early-onset NEC compared with infants with late-onset NEC. NICU stay and major complication were marginal different between the 2 groups. Comparison of feeding outcomes revealed that the time to achieve full enteral feeds was significantly longer for those with late-onset NEC (18.1 ± 11.5 vs 26.3 ± 15.6, P = .008).The infants who develop NEC after 10 days of life do influence postoperative outcome survival or other clinically important outcomes after laparotomy.
Project description:Human milk contains non-nutritional factors that promote intestinal maturation and protect against infectious and inflammatory conditions. In the Neonatal Intensive Care Unit (NICU) setting, donor milk (DM) is recommended when availability of own mother's milk (OMM) is not enough. Our aim was to compare the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) in very preterm infants (VPI) after the introduction of DM. Growth and breastfeeding rates were examined as secondary outcomes. Single center, observational and retrospective cohort study comparing 227 VPI admitted to our neonatal unit before (Group 1, n = 99) and after (Group 2, n = 128) DM introduction. Enteral nutrition was started earlier after DM availability (2.6 ± 1.1 vs. 2.1 ± 1 days, p = 0.001). Incidence of NEC decreased in group 2 (9.1% vs. 3.4%, p = 0.055), especially in those born between 28 and 32 weeks (5.4 vs. 0.0%, p = 0.044). Surgical NEC was also less frequent. Suffering NEC was 4 times more likely in group 1 (multivariate analysis). Availability of DM did not impact breastfeeding rates or preterm growth. Our findings support the protective role of DM against NEC, particularly in non-extreme VPI, a group less frequently included in clinical guidelines and research studies on the use of DM.
Project description:Necrotizing enterocolitis (NEC) is exceptional after the neonatal period. A toddler with encephalopathy, mitochondrial myopathy, and hypertrophic cardiomyopathy developed fatal NEC and multiple organ dysfunction within 48?hours of the introduction of enteral feeding. She was subsequently found to have pathogenic mutations in <i>FBXL4</i> , a cause of mitochondrial DNA depletion syndrome-13. Intestinal dysmotility in the context of deficient mitochondrial respiration may have contributed to the development of NEC. Current paradigms call for early introduction of enteral nutrition to reinstate energy homeostasis. Enteral feeding should be administered with caution during metabolic crises of patients with mitochondrial DNA depletion syndromes.
Project description:Enteral formula feeding is a risk factor for necrotizing enterocolitis (NEC) in premature infants, yet studies are conflicting regarding the safest timing for introduction and advancement of feeds. Our aim was to test the effects of early vs. late initiation and abrupt vs. gradual advancement of enteral feeding of an intact vs. hydrolyzed protein formula on NEC incidence and severity in preterm pigs. In Experiment 1, preterm pigs received total parenteral nutrition (TPN) at birth with abrupt initiation of enteral formula feeds (50% full intake) on d of life (DOL) 2 (EA) or 5 (LA) while PN continued. Pigs were also fed formula containing either intact or hydrolyzed protein. In Experiment 2, preterm pigs received TPN at birth with enteral, hydrolyzed-protein formula feeds introduced on DOL 2 either abruptly (EA; 50% full feeds) or gradually (EG; 10-50% full feeds over 5 d) while PN continued. NEC incidence and severity were assessed based on macroscopic and histological scoring. In Experiment 1, NEC incidence (41% vs. 70%, P<0.05) and severity were reduced in LA vs. EA groups and LA was associated with a higher survival rate, daily weight gain and jejunum villus height. Piglets fed hydrolyzed vs. intact protein formula had lower stomach content weights and similar NEC incidence. In Experiment 2, NEC incidence and severity were not different between pigs the EG vs. EA group. Proinflammatory gene expression (IL-1?, IL-6 and S100A9) in the ileum was lower in both LA and EG vs. EA groups. In conclusion, delayed initiation but not gradual advancement of enteral feeding is protective against NEC in preterm pigs. Feeding hydrolyzed vs. intact protein formula improved gastric transit without affecting the NEC incidence.
Project description:BACKGROUND:Oropharyngeal colostrum (OC) is a novel feeding strategy to prevent complications of prematurity. A meta-analysis was conducted to investigate whether very low birth weight infants (VLBWs) can benefit from OC. METHODS:Randomized controlled trials (RCTs) were searched from Embase, PubMed, Web of Science, and Cochrane Central Register of Controlled Trials from the date of inception until May 2019. RCTs were eligible if they used OC therapy on VLBW infants. The primary outcomes included ventilator-associated pneumonia (VAP), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), late-onset sepsis, and death. The secondary outcomes included the time of full enteral feeding and the length of stay. RESULTS:Eight RCTs involving 682 patients (OC group: 332; non-OC group: 350) were included in the meta-analysis. The results suggested that OC was associated with a significantly reduced incidence of VAP [odds ratio (OR)?=?0.39, 95% confidence interval (CI): 0.17-0.88, P?=?0.02] and full enteral feeding days (mean difference?=?-2.66, 95% CI: -4.51 to -0.80, P?=?0.005), a potential significance of NEC (OR?=?0.51, 95% CI: 0.26-0.99, P?=?0.05), a trend toward downregulating mortality (OR?=?0.60, 95% CI: 0.34-1.08, P?=?0.09) and proven sepsis (OR?=?0.64, 95% CI: 0.40-1.01, P?=?0.06). CONCLUSIONS:OC could significantly reduce the occurrence of VAP, and consequently, its routine use should be considered for VLBWs to prevent infectious diseases. IMPACT:OC significantly reduces the occurrence of VAP and NEC in VLBW infants. OC may reduce the incidence of VAP and NEC by increasing IgA levels. Early OC therapy for mechanical ventilation of low-weight infants may prevent the occurrence of VAP.
Project description:Clostridia-especially Clostridium butyricum-are among the taxa most frequently identified from stool samples of preterm neonates with necrotizing enterocolitis (NEC). Recently, Clostridium neonatale has also been detected from epidemic cases, but using a culture-based approach we were unable to confirm this discovery in a local cohort. In order to investigate this link by a molecular approach, a specific rpoB-based quantitative real-time PCR was developed to detect C. neonatale directly from patients' stool specimens. Design of this rpoB-based quantitative real-time PCR was based on the genomic analysis of seven clinical isolates of C. neonatale. It was tested on stool samples from 88 preterm neonates with necrotizing enterocolitis and 71 matched controls. C. neonatale was significantly more prevalent in stools from preterm neonates with necrotizing enterocolitis than in controls (respectively 30/88 (34%) versus 9/71 (13%); p 0.003). Whole-genome analysis also allowed the identification of three genomic clusters of C. neonatale. This clustering was associated with a geographical location regardless of isolation from the NEC or control, suggesting asymptomatic carriage. Although less prevalent than C. butyricum in our cohort, C. neonatale is significantly associated with the occurrence of necrotizing enterocolitis.
Project description:OBJECTIVE:To assess the effects of earlier vs. later re-initiation of enteral feeds after necrotizing enterocolitis (NEC). STUDY DESIGN:We reviewed the literature to assess timing of enteral feeding after NEC using fixed effects models. RESULTS:Three studies met inclusion criteria; no randomized trials. After removal of Bell's Stage I infants, the earlier refeeding group (<5-7 or median 4 days) included 79 infants and later refeeding group (?5-7 or median 10 days) included 119 infants. Pooled analysis revealed earlier re-initiation reduced the incidence in the composite outcome of recurrent NEC and/or post-NEC stricture (OR?=?0.27; 95% Cl?=?0.10-0.75; p?=?0.012). Individually, NEC recurrence (pooled OR?=?0.34; 95% Cl?=?0.09-1.29; p?=?0.112) or stricture (OR?=?0.34; 95% Cl?=?0.09-1.26; p?=?1.06) did not differ between groups. CONCLUSIONS:There was no increase in negative outcomes with earlier refeeding after NEC. Earlier initiation of enteral feeds resulted in a significantly lower risk for the combined outcome of recurrent NEC and/or post-NEC stricture.
Project description:Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
Project description:BACKGROUND:Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES:Primary objective 1. To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates Secondary objectives 1. To determine the effects of lactoferrin supplementation to enteral feeds to prevent neonatal sepsis and/or NEC on duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later2. To determine the adverse effects of lactoferrin supplementation for prophylaxis of neonatal sepsis and/or NECWhen data were available, we analyzed the following subgroups.1. Gestational age < 32 weeks and 32 to 36 weeks2. Birth weight < 1000 g (extremely low birth weight (ELBW) infants) and birth weight < 1500 g (very low birth weight (VLBW) infants)3. Type of feeding: breast milk versus formula milk SEARCH METHODS: We used the search strategy of the Cochrane Neonatal Review Group (CNRG) to update our search in December 2016. We searched the databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PREMEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as trial registries and conference proceedings. SELECTION CRITERIA:Randomized controlled trials (RCTs) evaluating oral lactoferrin at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS:Review authors used standard methods of the CNRG. MAIN RESULTS:This review includes six RCTs. Trial results show that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical risk ratio (RR) 0.59, 95% confidence interval (CI) 0.40 to 0.87; typical risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 17, 95% CI 10 to 50; six trials, 886 participants; low-quality evidence) and NEC stage II or III (typical RR 0.40, 95% CI 0.18 to 0.86; typical RD -0.04, 95% CI -0.06 to -0.01; NNTB 25, 95% CI 17 to 100; four studies, 750 participants; low-quality evidence). Lactoferrin supplementation did not have an effect on "all-cause mortality" (typical RR 0.65, 95% CI 0.37 to 1.11; typical RD -0.02, 95% CI -0.05 to 0; six studies, 1041 participants; low-quality evidence).Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.27, 95% CI 0.12 to 0.60; RD -0.13, 95% CI -0.19 to -0.06; NNTB 8, 95% CI 5 to 17; one study, 321 participants; low-quality evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; one study, 496 participants; low-quality evidence), but not "all-cause mortality" (low-quality evidence).Lactoferrin supplementation to enteral feeds with or without probiotics decreased bacterial and fungal sepsis but not CLD or length of hospital stay (low-quality evidence). Investigators reported no adverse effects and did not evaluate long-term neurological outcomes and PVL. AUTHORS' CONCLUSIONS:Evidence of low quality suggests that lactoferrin supplementation to enteral feeds with or without probiotics decreases late-onset sepsis and NEC stage II or III in preterm infants without adverse effects. Completed ongoing trials will provide data from more than 6000 preterm neonates, which may enhance the quality of the evidence. Clarification regarding optimal dosing regimens, types of lactoferrin (human or bovine), and long-term outcomes is needed.