Am J Perinatol 2019; 36(S 02): S120-S125
DOI: 10.1055/s-0039-1691807
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Is Lactoferrin More Effective in Reducing Late-Onset Sepsis in Preterm Neonates Fed Formula Than in Those Receiving Mother's Own Milk? Secondary Analyses of Two Multicenter Randomized Controlled Trials

Paolo Manzoni*
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Maria Angela Militello
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
Stefano Rizzollo
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
Elena Tavella
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Alessandro Messina
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Marta Pieretto
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Elena Boano
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Martina Carlino
2  Neonatology and NICU, Sant'Anna Hospital, AOU Città della Salute e della Scienza, Torino, Italy
,
Eleonora Tognato
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
Roberta Spola
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
Anna Perona
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
Milena Maria Maule
3  Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Torino, Italy
,
Ruben García Sánchez
4  Department of Neonatology and NICU, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
,
Mike Meyer
5  Department of Neonatology and NICU, Middlemore Hospital, Auckland, New Zealand
,
Ilaria Stolfi
6  Department of Neonatology, Azienda Ospedaliera Universitaria Policlinico Umberto I, Roma, Italy
,
Lorenza Pugni
7  Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
,
Hubert Messner
8  Department of Neonatology and NICU, Ospedale Regionale, Bolzano/Bozen, Italy
,
Silvia Cattani
9  NICU, University of Modena and Reggio Emilia, Modena, Italy
,
Pasqua Maria Betta
10  NICU, Azienda Ospedaliera Universitaria Policlinico di Catania, Catania, Italy
,
Luigi Memo
11  U.O.C. di Pediatria e Patologia Neonatale, Ospedale San Martino, Belluno, Italy
,
Lidia Decembrino
12  UOC Neonatologia e Terapia Intensiva, IRCCS Policlinico San Matteo, Pavia, Italy
,
Lina Bollani
12  UOC Neonatologia e Terapia Intensiva, IRCCS Policlinico San Matteo, Pavia, Italy
,
Matteo Rinaldi
13  Department of Neonatology, Ospedali Riuniti, Foggia, Italy
,
Maria Fioretti
14  Terapia Intensiva Neonatale, Ospedale Monaldi-Azienda Ospedaliera dei Colli, Napoli, Italy
,
Michele Quercia
15  Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy
,
Chryssoula Tzialla
12  UOC Neonatologia e Terapia Intensiva, IRCCS Policlinico San Matteo, Pavia, Italy
,
Nicola Laforgia
14  Terapia Intensiva Neonatale, Ospedale Monaldi-Azienda Ospedaliera dei Colli, Napoli, Italy
,
Fabio Mosca
7  Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, NICU, Milan, Italy
16  Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
,
Rosario Magaldi
13  Department of Neonatology, Ospedali Riuniti, Foggia, Italy
,
Michael Mostert
17  Department of Pediatrics, University of Turin, Torino, Italy
,
Daniele Farina
1  Division of Pediatrics and Neonatology, Department of Maternal, Neonatal, and Infant Medicine, Nuovo Ospedale Degli Infermi, Biella, Italy
,
William Tarnow-Mordi
18  NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
,
on behalf of the Italian Task Force for the Study Prevention of Neonatal Fungal Infections; the Italian Society of Neonatology› Author Affiliations
Funding None.
Further Information

Publication History

Publication Date:
25 June 2019 (online)

Abstract

Background Lactoferrin is the major antimicrobial protein in human milk. In our randomized controlled trial (RCT) of bovine lactoferrin (BLF) supplementation in preterm neonates, BLF reduced late-onset sepsis (LOS). Mother's own milk (MM) contains higher concentrations of lactoferrin than donor milk or formula, but whether BLF is more effective in infants who receive formula or donor milk is uncertain.

Aim To evaluate the incidence of LOS in preterm infants fed MM and in those fed formula and/or donor milk.

Study Design This is a (A) post hoc subgroup analysis, in our RCT of BLF, of its effects in preterm infants fed MM, with or without formula, versus those fed formula and/or donor milk (no-MM) and (B) post hoc meta-analysis, in our RCT of BLF and in the ELFIN (Enteral Lactoferrin in Neonates) RCT, of the effect of BLF in subgroups not exclusively fed MM.

Results (A) Of 472 infants in our RCT, 168 were randomized to placebo and 304 were randomized to BLF. Among MM infants, LOS occurred in 22/133 (16.5%) infants randomized to placebo and in 14/250 (5.6%) randomized to BLF (relative risk or risk ratio (RR): 0.34; relative risk reduction (RRR): 0.66; 95% confidence interval (95% CI) for RR: 0.18–0.64; p < 0.0008). Among no-MM infants, LOS occurred in 7/35 (20.0%) randomized to placebo and in 2/54 (3.7%) randomized to BLF (RR: 0.19; RRR: 0.81; 95% CI for RR: 0.16–0.96; p = 0.026). In multivariable logistic regression analysis, there was no interaction between BLF treatment effect and type of feeding (p = 0.628). (B) In 1,891 infants not exclusively fed MM in our RCT of BLF and in the ELFIN RCT, BLF reduced the RR of LOS by 18% (RR: 0.82; 95% CI: 0.71–0.96; p = 0.01).

Conclusion Adequately powered studies should address the hypothesis that BLF is more effective in infants fed formula or donor milk than those fed MM. Such studies should evaluate whether a specific threshold of total lactoferrin intake can be identified to protect such patients from LOS.

* Paolo Manzoni wrote the first draft of the manuscript.