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Traditional Chinese medicine for septic patients undergoing ulinastatin therapy: A meta-analysis.
Shan, RF, Zhu, YA, Qin, J, Chen, JP
Medicine. 2021;(38):e27151
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Abstract
PURPOSE This study aimed to assess the efficacy of traditional Chinese medicine (TCM) in septic patients treated with ulinastatin. METHODS PubMed, EmBase, and the Cochrane library were searched up to January 2021 to identify randomized controlled trials. The weight mean difference (WMD) and relative risk (RR) with 95% confidence intervals were used with the random-effects model. RESULTS Twenty-three randomized controlled trials with 1903 septic patients were included. TCM significantly reduced the APACHE II score (WMD: -5.18; P < .001), interleukin-6 (WMD: -63.00; P < .001), tumor necrosis factor-α (WMD: -8.86; P < .001), c-reactive protein (WMD: -9.47; P < .001), mechanical ventilation duration (WMD: -3.98; P < .001), intensive care unit stay (WMD: -4.18; P < .001), procalcitonin (WMD: -0.53; P < .001), lipopolysaccharide (WMD: -9.69; P < .001), B-type natriuretic peptide (WMD: -159.87; P < .001), creatine kinase isoenzyme MB (WMD: -45.67; P < .001), cardiac troponin I (WMD: -0.66; P < .001), and all-cause mortality risk (RR: 0.55; P < .001). CONCLUSIONS TCM lowers inflammation levels and reduces the risk of all-cause mortality for septic patients.
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Prediction of sepsis mortality using metabolite biomarkers in the blood: a meta-analysis of death-related pathways and prospective validation.
Wang, J, Sun, Y, Teng, S, Li, K
BMC medicine. 2020;(1):83
Abstract
BACKGROUND Sepsis is a leading cause of death in intensive care units (ICUs), but outcomes of individual patients are difficult to predict. The recently developed clinical metabolomics has been recognized as a promising tool in the clinical practice of critical illness. The objective of this study was to identify the unique metabolic biomarkers and their pathways in the blood of sepsis nonsurvivors and to assess the prognostic value of these pathways. METHODS We searched PubMed, EMBASE, Cochrane, Web of Science, CNKI, Wangfang Data, and CQVIP from inception until July 2019. Eligible studies included the metabolomic analysis of blood samples from sepsis patients with the outcome. The metabolic pathway was assigned to each metabolite biomarker. The meta-analysis was performed using the pooled fold changes, area under the receiver operating characteristic curve (AUROC), and vote-counting of metabolic pathways. We also conducted a prospective cohort metabolomic study to validate the findings of our meta-analysis. RESULTS The meta-analysis included 21 cohorts reported in 16 studies with 2509 metabolite comparisons in the blood of 1287 individuals. We found highly limited overlap of the reported metabolite biomarkers across studies. However, these metabolites were enriched in several death-related metabolic pathways (DRMPs) including amino acids, mitochondrial metabolism, eicosanoids, and lysophospholipids. Prediction of sepsis death using DRMPs yielded a pooled AUROC of 0.81 (95% CI 0.76-0.87), which was similar to the combined metabolite biomarkers with a merged AUROC of 0.82 (95% CI 0.78-0.86) (P > 0.05). A prospective metabolomic analysis of 188 sepsis patients (134 survivors and 54 nonsurvivors) using the metabolites from DRMPs produced an AUROC of 0.88 (95% CI 0.78-0.97). The sensitivity and specificity for the prediction of sepsis death were 80.4% (95% CI 66.9-89.4%) and 78.8% (95% CI 62.3-89.3%), respectively. CONCLUSIONS DRMP analysis minimizes the discrepancies of results obtained from different metabolomic methods and is more practical than blood metabolite biomarkers for sepsis mortality prediction. TRIAL REGISTRATION The meta-analysis was registered on OSF Registries, and the prospective cohort study was registered on the Chinese Clinical Trial Registry (ChiCTR1800015321).
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Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.
Pammi, M, Suresh, G
The Cochrane database of systematic reviews. 2020;(3):CD007137
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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 To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the 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 later. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. MAIN RESULTS Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty 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; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies. AUTHORS' CONCLUSIONS We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.
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Importance of vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis.
Cariolou, M, Cupp, MA, Evangelou, E, Tzoulaki, I, Berlanga-Taylor, AJ
BMJ open. 2019;(5):e027666
Abstract
OBJECTIVES To estimate the prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency and investigate its association with mortality in children with acute or critical conditions. DESIGN Systematic review and meta-analysis of observational studies. DATA SOURCES PubMed, OVID, Google Scholar and the Cochrane Library searched until 21 December 2018. ELIGIBILITY CRITERIA Studies of children hospitalised with acute or critical conditions who had blood 25(OH)D levels measured. DATA EXTRACTION AND SYNTHESIS We obtained pooled prevalence estimates of 25(OH)D deficiency and ORs for mortality. We calculated 95% CI and prediction intervals and investigated heterogeneity and evidence of small-study effects. RESULTS Fifty-two studies were included. Of 7434 children, 3473 (47.0%) were 25(OH)D deficient (<50 nmol/L). The pooled prevalence estimate of 25(OH)D deficiency was 54.6% (95% CI 48.5% to 60.6%, I2=95.3%, p<0.0001). Prevalence was similar after excluding smaller studies (51.5%). In children with sepsis (18 studies, 889 total individuals) prevalence was 64.0% (95% CI 52.0% to 74.4%, I2=89.3%, p<0.0001) and 48.7% (95% CI 38.2% to 59.3%; I2=94.3%, p<0.0001) in those with respiratory tract infections (RTI) (25 studies, 2699 total individuals). Overall, meta-analysis of mortality (18 cohort studies, 2463 total individuals) showed increased risk of death in 25(OH)D deficient children (OR 1.81, 95% CI 1.24 to 2.64, p=0.002, I2=25.7%, p=0.153). Four (22.0%) of the 18 studies statistically adjusted for confounders. There were insufficient studies to meta-analyse sepsis and RTI-related mortality. CONCLUSIONS Our results suggest that 25(OH)D deficiency in acute and critically ill children is high and associated with increased mortality. Small-study effects, reverse causation and other biases may have confounded results. Larger, carefully designed studies in homogeneous populations with confounder adjustment are needed to clarify the association between 25(OH)D levels with mortality and other outcomes. PROSPERO REGISTRATION NUMBER CRD42016050638.
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Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis.
Chi, C, Buys, N, Li, C, Sun, J, Yin, C
European journal of clinical nutrition. 2019;(5):657-670
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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.
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[A Meta-analysis of Qingre Jiedu and Liangxue Sanyu method in the treatment of sepsis].
Cheng, L, Jiang, H, Chen, M, Chen, Q, Wang, X, Lu, J
Zhonghua wei zhong bing ji jiu yi xue. 2019;(1):73-80
Abstract
OBJECTIVE To systematically review the effect of Qingre Jiedu and Liangxue Sanyu method in patients with sepsis, and to discuss its effect in the treatment of sepsis. METHODS The randomized controlled trials (RCTs) on the treatment of Qingre Jiedu and Liangxue Sanyu method for sepsis published on PubMed, Embase, Web of Science, CNKI and Wanfang database from the construction to December 31st, 2017 were searched by electronical way. Conventional treatment measures for sepsis, such as fluid resuscitation, maintenance of hemodynamic stability, anti-infection, improvement of tissue perfusion, maintenance of organ function and nutritional support were used in the control group. While traditional Chinese medicine treatment based on Qingre Jiedu and Liangxue Sanyu method were applied in the experimental group besides the conventional treatment, including Chinese patent medicine or Chinese herbal medicine. The main outcome was 28-day mortality, and the second outcome was acute physiology and chronic health evaluation II (APACHE II), coagulation function, inflammatory mediators, procalcitonin (PCT), lactic acid (Lac), and the length of intensive care unit (ICU) stay. Two researchers independently searched literatures, collected data and evaluated risk bias. The statistical analysis was completed by RevMan 5.3 and STATA 13.0 software. The funnel plot and Egger test were used to evaluate the potential publication bias of the main outcomes. RESULTS A total of 20 RCTs were enrolled in this Meta-analysis, including 1 347 patients, with 667 patients in the control group and 680 patients in the experimental group. Comprehensive risk bias assessment showed that the risk bias of 11 RCT items was unknown, and the risk bias of 9 RCT items was high. Meta-analysis results showed that compared with the control group, the 28-day mortality of the experimental group was significantly lowered [relative risk (RR) = 0.54, 95% confidence interval (95%CI) = 0.45-0.65, P < 0.000 01], the 7-day APACHE II score was significantly lowered [mean difference (MD) = -3.86, 95%CI = -4.82 to -2.90, P < 0.000 01], the 7-day prothrombin time (PT) and activated partial thromboplastin time (APTT) were significantly shortened (PT: MD = -1.72, 95%CI = -2.29 to -1.14, P < 0.000 01; APTT MD = -4.36, 95%CI = -5.81 to -2.91, P < 0.000 01), the 7-day D-dimer was slightly improved (MD = -0.13, 95%CI = -0.37-0.11, P = 0.29), the 10-day interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were significantly decreased (IL-6: MD = -40.33, 95%CI = -59.55 to -21.11, P < 0.000 1; TNF-α: MD = -7.26, 95%CI = -11.31 to -3.21, P = 0.000 4), the 7-day Lac was significantly declined (MD = -1.30, 95%CI = -1.91 to -0.68, P < 0.000 1), but no significance in PCT (MD = -1.57, 95%CI = -3.25-0.11, P = 0.07) or the length of ICU stay (MD = -4.02, 95%CI = -8.60-0.56, P = 0.09) was found. The results of publication bias assessment showed that 19 studies reported 28-day mortality were basically "funnel-shaped" distribution without potential publication bias (P = 0.336). CONCLUSIONS The Meta-analysis showed that Qingre Jiedu and Liangxue Sanyu method may reduce the release of inflammatory mediators, improve the coagulation function, and reduce the 28-day mortality in patients with sepsis.
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Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis.
Ananthan, A, Balasubramanian, H, Rao, S, Patole, S
Advances in nutrition (Bethesda, Md.). 2018;(3):238-246
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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.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis.
Silversides, JA, Major, E, Ferguson, AJ, Mann, EE, McAuley, DF, Marshall, JC, Blackwood, B, Fan, E
Intensive care medicine. 2017;(2):155-170
Abstract
BACKGROUND It is unknown whether a conservative approach to fluid administration or deresuscitation (active removal of fluid using diuretics or renal replacement therapy) is beneficial following haemodynamic stabilisation of critically ill patients. PURPOSE To evaluate the efficacy and safety of conservative or deresuscitative fluid strategies in adults and children with acute respiratory distress syndrome (ARDS), sepsis or systemic inflammatory response syndrome (SIRS) in the post-resuscitation phase of critical illness. METHODS We searched Medline, EMBASE and the Cochrane central register of controlled trials from 1980 to June 2016, and manually reviewed relevant conference proceedings from 2009 to the present. Two reviewers independently assessed search results for inclusion and undertook data extraction and quality appraisal. We included randomised trials comparing fluid regimens with differing fluid balances between groups, and observational studies investigating the relationship between fluid balance and clinical outcomes. RESULTS Forty-nine studies met the inclusion criteria. Marked clinical heterogeneity was evident. In a meta-analysis of 11 randomised trials (2051 patients) using a random-effects model, we found no significant difference in mortality with conservative or deresuscitative strategies compared with a liberal strategy or usual care [pooled risk ratio (RR) 0.92, 95 % confidence interval (CI) 0.82-1.02, I 2 = 0 %]. A conservative or deresuscitative strategy resulted in increased ventilator-free days (mean difference 1.82 days, 95 % CI 0.53-3.10, I 2 = 9 %) and reduced length of ICU stay (mean difference -1.88 days, 95 % CI -0.12 to -3.64, I 2 = 75 %) compared with a liberal strategy or standard care. CONCLUSIONS In adults and children with ARDS, sepsis or SIRS, a conservative or deresuscitative fluid strategy results in an increased number of ventilator-free days and a decreased length of ICU stay compared with a liberal strategy or standard care. The effect on mortality remains uncertain. Large randomised trials are needed to determine optimal fluid strategies in critical illness.
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Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.
Pammi, M, Suresh, G
The Cochrane database of systematic reviews. 2017;(6):CD007137
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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.