Enteral lactoferrin does not reduce late-onset infection in very preterm infants.

Abstract

Late-onset sepsis is a major cause of morbidity and mortality in neonates, but predominantly in preterm infants. In survivors, it can prolong length of hospital stay, worsen long-term neurodevelopmental outcomes and increase the associated social burden of disease.1 Lactoferrin, a mammalian iron-binding whey glycoprotein with important bacteriostatic and anti-inflammatory properties, plays a role in promoting growth of probiotic bacteria in the gut.2 A recent Cochrane review suggested reductions in both sepsis and necrotizing enterocolitis with oral lactoferrin supplementation.3 Many of these studies enrolled small numbers and had limitations in study design and implementation. The ELFIN randomised, placebo-controlled trial is the largest trial of this intervention. A major strength lies in the large number (>2000) of participating babies with more than 99% of outcome data being available. Important consideration was given to limit bias for the study; randomisation was successful in balancing baseline demographic and prognostic characteristics. Measures were put in place to define the spectrum of late-onset infection in order to reduce potential sources of bias. This is in contrast to most previous studies, in which only culture-proven late-onset sepsis was used as a marker.4 This does not necessarily completely rule out bias. The primary outcome used encompasses both microbiologically confirmed and clinically suspected late-onset infection, from trial entry until hospital discharge. Although these results were confirmed, using pre-defined criteria, by masked central end-point review committees, clinically suspected late-onset infection remains a subjective outcome. As it accounts for more than 40% of the cases in this study, this might be considered a confounding factor. Based on the GRADE system (grading of recommendation, assessment, development and evaluation), due to the relative imprecision of the primary outcome and inconsistency of the main result, lactoferrin is not recommended as a routine intervention to prevent late-onset sepsis in very preterm infants. Although other trials of lactoferrin are ongoing (Mooselmokadem trial; NCT01821989, estimated n = 180), NEOLACTO (NCT01525316, n = 414) and LIFT (ACTRN12611000247976, target sample size of 1500), it would be difficult to anticipate that these would bring about a change in the grade of recommendation, unless a substantial positive effect were seen in the largest of these trials. Although the risk of adverse outcomes in more mature preterm infants is generally lower, the effect size, favouring lactoferrin, was larger in this study in infants born at 30 or more weeks of gestation. Although not statistically significant, this finding may be clinically relevant. Lactoferrin promotes growth of probiotic bacteria, so this finding begs the question of whether this effect could be related to lower rates of exclusive breastmilk feeding and more restricted use of broad-spectrum antibiotics in larger infants. Evidently, there is still a need for novel research into the use of alternative interventions as adjuvants in preventing late-onset sepsis, and reducing mortality and morbidity in the very preterm population. Is there, for example, a need for further large scale studies to look at the effectiveness of using lactoferrin in combination with probiotic therapy or other interventions designed to decrease infection risk?5 https://ebneo.org/2019/11/enteral-lactoferrin-late-onset-infection/ None.