Clinical Trials of Lactoferrin in the newborn: Effects on Infection and the Gut Microbiome

Summary

Every year, more than 15 million infants are born premature or with a low birth weight globally [1]. Whilst survival rates are improving, infections remain prevalent. In infants born very preterm, late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) are the commonest reasons for death after the first week [2]. The etiology of NEC and LOS is multifactorial, and various strategies have been employed in an attempt to reduce
their occurrence, especially the provision of mother’s own breast milk, which results in a dose-response reduction in NEC and LOS occurrence.

In recent years, our knowledge of gut microbiota in preterm infants has increased due to next-generation sequencing methodologies. In several studies, the pattern of gut microbial communities differed between preterm and healthy term infants. Furthermore, these patterns appear to change prior to the onset of NEC or LOS, offering hope that earlier disease identification may be possible [3]. However, many healthy preterm
infants exhibit gut community patterns that are not dissimilar to those who develop disease, and many infants show rapid changes in microbial patterns without obvious precipitants. Identification of an enteral immunonutrient such as lactoferrin with a range of enterocyte growth activity and immunomodulation might lead to a reduction in NEC.

Human breast milk has bacteriostatic activity against certain bacteria such as Escherichia coli. It was originally postulated that much of this activity derived from the presence of lactoferrin, an iron-binding glycoprotein present at high concentrations especially in early colostrum. Lactoferrin may also act as a “prebiotic,” and studies also show improved immune cell responses. Typically, preterm infants receive only small
amounts of mother’s own colostrum in the first 1–2 days and usually take several days to achieve full enteral feeds. Providing supplemental lactoferrin at this stage may, therefore, be beneficial. A large multicenter randomized controlled study conducted in Italy showed that overall rates of LOS were significantly lower in those receiving lactoferrin, and there was a reduction in NEC [4].

The ELFIN trial, the largest trial of lactoferrin supplementation, enrolled 2,203 infants [5]. Very preterm infants were recruited before 72 h of age and allocated to lactoferrin or placebo. The primary outcome was LOS, and primary outcome data showed no difference in the rate of LOS between lactoferrin (28.9%) and placebo groups (30.7%). The incidence of NEC stage II/III and all-cause mortality also did not differ. The
ELFIN trial provides high-quality data that show that routine supplementation with lactoferrin does not improve outcome, contradicting findings suggested by previous studies.

The ELFIN trial highlights the importance of adequately powered high-quality trials to provide the most robust evidence base for clinical practice. This requires collaboration at national and international level. Whilst large-scale pragmatic trials are essential, mechanistic studies are needed in order to better understand disease pathology and treatment effects. However, these are practically and ethically challenging in pre-term infants, and studies must be planned, developed, and conducted concomitant with parents and the public. The ELFIN trial reminds us that nutrients do not function in isolation, and that the optimal source of immune nutrients remains fresh human milk. Whilst we search for immune nutrients that improve health and reduce disease, we must continue to better understand how to support mothers to meet their infants’
intake needs using their own milk.

References
1 March of Dimes, PMNCH, Save the Children, WHO: Born Too Soon: The Global
Action Report on Preterm Birth. Geneva, WHO, 2012, vol 13, pp 1–126.
2 Berrington JE, Hearn RI, Bythell M, et al: Deaths in preterm infants: changing pathology over 2 decades. J Pediatr 2012;160:49–53.e1.
3 Stewart CJ, Marrs ECL, Nelson A, et al: Development of the preterm gut microbiome
in twins at risk of necrotising enterocolitis and sepsis. PLoS One 2013;8:e73465.
4 Manzoni P, Rinaldi M, Cattani S, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009;302:1421–1428.
5 ELFIN Trial Investigators Group: Enteral lactoferrin supplementation for very pre-
term infants: a randomised placebo-controlled trial. Lancet 2019;393:423–433.