Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants

Abstract

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.

The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income Countries: A Systematic Review

“…This finding is echoed in a recent Cochrane review of studies in high- and low-resource settings, which concluded there was low-certainty evidence that lactoferrin supplementation could reduce late-onset sepsis, though not NEC or all-cause mortality. 37 Contrary to another previous Cochrane review, we did not find strong evidence for KMC as an intervention to reduce BSI in LMICs—only 2 studies fulfilled the ICROMS criteria and only 1 had some evidence of impact on BSI. 20,38 For studies that analyzed the impact of bundled interventions, the strongest evidence was generated from studies aiming to prevent device-associated infection.…”

The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income Countries: A Systematic Review

“…This finding is echoed in a recent Cochrane review of studies in high- and low-resource settings, which concluded there was low-certainty evidence that lactoferrin supplementation could reduce late-onset sepsis, though not NEC or all-cause mortality. 37 Contrary to another previous Cochrane review, we did not find strong evidence for KMC as an intervention to reduce BSI in LMICs—only 2 studies fulfilled the ICROMS criteria and only 1 had some evidence of impact on BSI. 20,38 For studies that analyzed the impact of bundled interventions, the strongest evidence was generated from studies aiming to prevent device-associated infection.…”

Preventing Sepsis in Preterm Infants with Bovine Lactoferrin: A Randomized Trial Exploring Immune and Antioxidant Effects

“…However, in line with contemporary NICU, the primary endpoint is to maximize diagnostic specificity and cross-study comparability [ 39 ]. Our findings agree with several small trials and meta-analyses reporting lower LOS rates with bLf [ 14 , 15 , 16 , 18 , 19 , 20 , 40 ], likely due to its combined antimicrobial and immunomodulatory actions. However, these findings contrast with those of two large multicenter megatrials, ELFIN [ 12 ] and LIFT [ 13 ], that found no reduction in infection-related outcomes.…”

“…Both LOS and BPD are multifactorial conditions that overlap with other morbidities such as NEC, hsPDA, ROP, and brain injury. In line with other studies [ 9 , 12 , 13 , 20 , 41 , 43 ], we did not detect clear effects of bLf on these outcomes. The combination of multifaceted pathogenesis, their lower baseline incidence in contemporary NICUs, and our modest sample size, primarily powered to detect differences in LOS, probably limited our ability to detect smaller effects in these secondary outcomes.…”

Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials

“…Although anti-infective drugs are currently available for the treatment of sepsis in preterm infants, the mortality rate of sepsis in preterm infants remains high ( Stoll et al., 2002 ). However, the findings of our meta-analysis revealed that enteral lactoferrin supplementation did not affect all-cause mortality, which is consistent with the previous studies ( Pammi and Suresh, 2017 ; He et al., 2018 ). Furthermore, the results also showed that lactoferrin had no significant benefit on the bronchopulmonary dysplasia, retinopathy of prematurity, invasive fungal infection, intraventricular hemorrhage, and urinary tract infection.…”

The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income Countries: A Systematic Review

“…This finding is echoed in a recent Cochrane review of studies in high- and low-resource settings, which concluded there was low-certainty evidence that lactoferrin supplementation could reduce late-onset sepsis, though not NEC or all-cause mortality. 37 Contrary to another previous Cochrane review, we did not find strong evidence for KMC as an intervention to reduce BSI in LMICs—only 2 studies fulfilled the ICROMS criteria and only 1 had some evidence of impact on BSI. 20,38 For studies that analyzed the impact of bundled interventions, the strongest evidence was generated from studies aiming to prevent device-associated infection.…”

Preventing Sepsis in Preterm Infants with Bovine Lactoferrin: A Randomized Trial Exploring Immune and Antioxidant Effects

“…However, in line with contemporary NICU, the primary endpoint is to maximize diagnostic specificity and cross-study comparability [ 39 ]. Our findings agree with several small trials and meta-analyses reporting lower LOS rates with bLf [ 14 , 15 , 16 , 18 , 19 , 20 , 40 ], likely due to its combined antimicrobial and immunomodulatory actions. However, these findings contrast with those of two large multicenter megatrials, ELFIN [ 12 ] and LIFT [ 13 ], that found no reduction in infection-related outcomes.…”

“…Both LOS and BPD are multifactorial conditions that overlap with other morbidities such as NEC, hsPDA, ROP, and brain injury. In line with other studies [ 9 , 12 , 13 , 20 , 41 , 43 ], we did not detect clear effects of bLf on these outcomes. The combination of multifaceted pathogenesis, their lower baseline incidence in contemporary NICUs, and our modest sample size, primarily powered to detect differences in LOS, probably limited our ability to detect smaller effects in these secondary outcomes.…”

Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials

“…Although anti-infective drugs are currently available for the treatment of sepsis in preterm infants, the mortality rate of sepsis in preterm infants remains high ( Stoll et al., 2002 ). However, the findings of our meta-analysis revealed that enteral lactoferrin supplementation did not affect all-cause mortality, which is consistent with the previous studies ( Pammi and Suresh, 2017 ; He et al., 2018 ). Furthermore, the results also showed that lactoferrin had no significant benefit on the bronchopulmonary dysplasia, retinopathy of prematurity, invasive fungal infection, intraventricular hemorrhage, and urinary tract infection.…”

The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income Countries: A Systematic Review

“…This finding is echoed in a recent Cochrane review of studies in high- and low-resource settings, which concluded there was low-certainty evidence that lactoferrin supplementation could reduce late-onset sepsis, though not NEC or all-cause mortality. 37 Contrary to another previous Cochrane review, we did not find strong evidence for KMC as an intervention to reduce BSI in LMICs—only 2 studies fulfilled the ICROMS criteria and only 1 had some evidence of impact on BSI. 20,38 For studies that analyzed the impact of bundled interventions, the strongest evidence was generated from studies aiming to prevent device-associated infection.…”

Preventing Sepsis in Preterm Infants with Bovine Lactoferrin: A Randomized Trial Exploring Immune and Antioxidant Effects

“…However, in line with contemporary NICU, the primary endpoint is to maximize diagnostic specificity and cross-study comparability [ 39 ]. Our findings agree with several small trials and meta-analyses reporting lower LOS rates with bLf [ 14 , 15 , 16 , 18 , 19 , 20 , 40 ], likely due to its combined antimicrobial and immunomodulatory actions. However, these findings contrast with those of two large multicenter megatrials, ELFIN [ 12 ] and LIFT [ 13 ], that found no reduction in infection-related outcomes.…”

“…Both LOS and BPD are multifactorial conditions that overlap with other morbidities such as NEC, hsPDA, ROP, and brain injury. In line with other studies [ 9 , 12 , 13 , 20 , 41 , 43 ], we did not detect clear effects of bLf on these outcomes. The combination of multifaceted pathogenesis, their lower baseline incidence in contemporary NICUs, and our modest sample size, primarily powered to detect differences in LOS, probably limited our ability to detect smaller effects in these secondary outcomes.…”

Enteral Lactoferrin Supplementation for Preventing Sepsis and Necrotizing Enterocolitis in Preterm Infants: A Meta‑Analysis With Trial Sequential Analysis of Randomized Controlled Trials

“…Although anti-infective drugs are currently available for the treatment of sepsis in preterm infants, the mortality rate of sepsis in preterm infants remains high ( Stoll et al., 2002 ). However, the findings of our meta-analysis revealed that enteral lactoferrin supplementation did not affect all-cause mortality, which is consistent with the previous studies ( Pammi and Suresh, 2017 ; He et al., 2018 ). Furthermore, the results also showed that lactoferrin had no significant benefit on the bronchopulmonary dysplasia, retinopathy of prematurity, invasive fungal infection, intraventricular hemorrhage, and urinary tract infection.…”