Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial.
OBJECTIVE
NEC is a common and severe complication in premature neonates, particularly those with very-low-birth-weight (VLBW, <1500 g at birth). Probiotics including lactobacillus rhamnosus GG (LGG) proved effective in preventing NEC in preterm infants in several RCTs.


OBJECTIVE
Lactoferrin, a mammalian milk glycoprotein involved in innate immune host defences, can reduce the incidence of NEC in animal models, and its action is enhanced by LGG. We tried to assess whether bovine lactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in human infants, something that has not yet been studied.


METHODS
An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010.


METHODS
Thirteen Italian and New Zealand tertiary neonatal intensive care units.


METHODS
743 VLBW neonates were assessed until discharge for development of NEC.


METHODS
Infants were randomly assigned to receive orally either BLF (100 mg/day) alone (group LF; n = 247) or with LGG (at 6×10(9) CFU/day; group BLF + LGG; n = 238), or placebo (Control group; n = 258) from birth until day 30 of life (45 for neonates <1000 g at birth).


METHODS
≥ stage 2 NEC; death-and/or-≥ stage 2 NEC prior to discharge.


RESULTS
Demographics, clinical and management characteristics of the 3 groups were similar, including type of feeding and maternal milk intakes. NEC incidence was significantly lower in groups BLF and BLF + LGG [5/247 (2.0%)] and 0/238 (0%), respectively] than in controls [14/258 (5.4%)] (RR = 0.37; 95% CI: 0.136-1.005; p = 0.055 for BLF vs. control; RR = 0.00; p < 0.001 for BLF + LGG vs. control). The incidence of death-and/or-NEC was significantly lower in both treatment groups (4.0% and 3.8% in BLF and BLF + LGG vs. 10.1% in control; RR = 0.39; 95% CI: 0.19-0.80; p = 0.008. RR = 0.37; 95% CI: 0.18-0.77; p = 0.006, respectively). No adverse effects or intolerances to treatment occurred.


CONCLUSIONS
Compared with placebo, BLF supplementation alone or in combination with LGG reduced the incidence of ≥ stage 2 NEC and of death-and/or ≥ stage 2 NEC in VLBW neonates. BLF might be a promising strategy to prevent NEC in NICU settings. Further data on larger sample sizes are warranted before BLF can be widespreadly used in clinical settings.


BACKGROUND
ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.
Neonatology and NICU, S. Anna Hospital; Torino, Italy. Electronic address: paolomanzoni@hotmail.com.
Paolo
P
Manzoni
Neonatology and NICU, Middlemore Hospital; Auckland, New Zealand.
Michael
M
Meyer
Neonatology and NICU, Policlinico Umberto, Roma, Italy.
Ilaria
I
Stolfi
Neonatology and NICU, Ospedali Riuniti, Foggia, Italy.
Matteo
M
Rinaldi
Neonatology and NICU, University of Modena, Modena, Italy.
Silvia
S
Cattani
NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano; Milano, Italy.
Lorenza
L
Pugni
Neonatology and NICU, Azienda Ospedaliera Universitaria Policlinico, Catania, Italy.
Mario Giovanni
MG
Romeo
Neonatology and NICU, Ospedale Regionale, Bolzano, Italy.
Hubert
H
Messner
Neonatology and NICU, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Lidia
L
Decembrino
Neonatology and NICU, Policlinico University Hospital, Bari, Italy.
Nicola
N
Laforgia
Neonatology and NICU, Arcispedale S.M.Nuova, Reggio Emilia, Italy.
Federica
F
Vagnarelli
Neonatology and NICU, Cà Foncello Hospital, Treviso, Italy.
Luigi
L
Memo
Neonatology and NICU, Cà Foncello Hospital, Treviso, Italy.
Linda
L
Bordignon
Department of Biomedical Sciences and Human Oncology, Cancer Epidemiology Unit, University of Torino, Torino, Italy.
Milena
M
Maule
Neonatology and NICU, S. Anna Hospital; Torino, Italy.
Elena
E
Gallo
Department of Pediatrics, University of Torino, Torino, Italy.
Michael
M
Mostert
Neonatology and NICU, Policlinico University Hospital, Bari, Italy.
Michele
M
Quercia
Neonatology and NICU, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Lina
L
Bollani
Neonatology and NICU, Policlinico Umberto, Roma, Italy.
Roberto
R
Pedicino
Neonatology and NICU, Ospedale Regionale, Bolzano, Italy.
Livia
L
Renzullo
Neonatology and NICU, Azienda Ospedaliera Universitaria Policlinico, Catania, Italy.
Pasqua
P
Betta
Neonatology and NICU, University of Modena, Modena, Italy.
Fabrizio
F
Ferrari
Neonatology and NICU, Middlemore Hospital; Auckland, New Zealand.
Tanith
T
Alexander
Neonatology and NICU, Ospedali Riuniti, Foggia, Italy.
Rosario
R
Magaldi
Neonatology and NICU, S. Anna Hospital; Torino, Italy.
Daniele
D
Farina
NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano; Milano, Italy.
Fabio
F
Mosca
Neonatology and NICU, S. Anna Hospital; Torino, Italy.
Mauro
M
Stronati
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D002417:Cattle; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D007781:Lactoferrin / Q000627:therapeutic use*; D008297:Male
D000890:Anti-Infective Agents; D007781:Lactoferrin
Lactoferrin; Necrotising enterocolitis; Neonate; Preterm; Probiotics; Sepsis