Paolo Manzoni1, Michael Meyer2, Ilaria Stolfi3, Matteo Rinaldi4, Silvia Cattani5, Lorenza Pugni6, Mario Giovanni Romeo7, Hubert Messner8, Lidia Decembrino9, Nicola Laforgia10, Federica Vagnarelli11, Luigi Memo12, Linda Bordignon12, Milena Maule13, Elena Gallo14, Michael Mostert15, Michele Quercia10, Lina Bollani9, Roberto Pedicino3, Livia Renzullo8, Pasqua Betta7, Fabrizio Ferrari5, Tanith Alexander2, Rosario Magaldi4, Daniele Farina14, Fabio Mosca6, Mauro Stronati14. 1. Neonatology and NICU, S. Anna Hospital; Torino, Italy. Electronic address: paolomanzoni@hotmail.com. 2. Neonatology and NICU, Middlemore Hospital; Auckland, New Zealand. 3. Neonatology and NICU, Policlinico Umberto, Roma, Italy. 4. Neonatology and NICU, Ospedali Riuniti, Foggia, Italy. 5. Neonatology and NICU, University of Modena, Modena, Italy. 6. NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano; Milano, Italy. 7. Neonatology and NICU, Azienda Ospedaliera Universitaria Policlinico, Catania, Italy. 8. Neonatology and NICU, Ospedale Regionale, Bolzano, Italy. 9. Neonatology and NICU, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 10. Neonatology and NICU, Policlinico University Hospital, Bari, Italy. 11. Neonatology and NICU, Arcispedale S.M.Nuova, Reggio Emilia, Italy. 12. Neonatology and NICU, Cà Foncello Hospital, Treviso, Italy. 13. Department of Biomedical Sciences and Human Oncology, Cancer Epidemiology Unit, University of Torino, Torino, Italy. 14. Neonatology and NICU, S. Anna Hospital; Torino, Italy. 15. Department of Pediatrics, University of Torino, Torino, Italy.
Abstract
IMPORTANCE: 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. DESIGN: An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010. SETTING:Thirteen Italian and New Zealand tertiary neonatal intensive care units. PARTICIPANTS: 743 VLBW neonates were assessed until discharge for development of NEC. INTERVENTION: 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). MAIN OUTCOME MEASURES: ≥ 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 AND RELEVANCE: 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. TRIAL REGISTRATION: ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.
RCT Entities:
IMPORTANCE: 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 bovinelactoferrin (BLF), alone or with the probiotic LGG, has a similar effect in humaninfants, something that has not yet been studied. DESIGN: An international, multicenter, randomized, double-blind, placebo-controlled trial conducted from October 1st, 2007 through July 31st, 2010. SETTING: Thirteen Italian and New Zealand tertiary neonatal intensive care units. PARTICIPANTS: 743 VLBW neonates were assessed until discharge for development of NEC. INTERVENTION: 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). MAIN OUTCOME MEASURES: ≥ 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 AND RELEVANCE: 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. TRIAL REGISTRATION: ISRCTN53107700-http://www.controlled-_trials.com/ISRCTN53107700.
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