Randomized Controlled Trial of Bovine Lactoferrin for Prevention of Sepsis and Neurodevelopment Impairment in Infants Weighing Less Than 2000 Grams

Abstract

Objectives: To determine the effect of bovine lactoferrin on prevention of late-onset sepsis (LOS) and neurodevelopment delay.

Study design: Randomized, double-blind, controlled trial in neonates with a birth weight of 500-2000 g in 3 neonatal units in Lima, Peru, comparing bovine lactoferrin 200 mg/kg/day with placebo administered for 8 weeks. The primary outcome was the first episode of culture-proven LOS or sepsis-associated death. Neurodevelopment delay was assessed by the Mullen Scales at 24 months corrected age.

Results: Of the 414 infants enrolled, 209 received bovine lactoferrin and 205 received placebo. LOS or sepsis-associated death occurred in 22 infants (10.5%) in the bovine lactoferrin group vs 30 (14.6%) in the placebo group; there was no difference after adjusting for hospital and birth weight; hazard ratio 0.73 (95% CI, 0.42-1.26). For infants with birth weights of <1500 g the hazard ratio was 0.69 (95% CI, 0.39-1.25). The mean age-adjusted normalized Mullen composite score at 24 months was 83.3 ± 13.6 in the bovine lactoferrin group vs 82.6 ± 13.1 in the placebo group. Growth outcomes and rehospitalization rates during the 2-year follow-up were similar in both groups, except for significantly less bronchiolitis in the bovine lactoferrin group (rate ratio, 0.34; 95% CI, 0.14-0.86).

Conclusions: Supplementation with bovine lactoferrin did not decrease the incidence of sepsis in infants with birth weights of <2000 g. Growth and neurodevelopment outcomes at 24 months of age were similar. Neonatal bovine lactoferrin supplementation had no adverse effects.

Trial registration: ClinicalTrials.gov: NCT01525316.

Keywords: infection; milk; mortality; neonate; premature.

Figure 1.

Consort diagram Lactoferrin vs Placebo. ^a Infants that died during the first 72 hours of life (n=75), were discharged (n=17), or whose parents were not available for enrollment during that period (n=103). ^b Infants of single mothers (n=8), adolescent mothers (n=13), mothers in the UCI (n=10), father outside the city (n=5), father absent (n=10), father participating in the trial (n=1). ^c This analysis includes a patient that was diagnosed after randomization with esophageal atresia, a condition that prevented oral intake, an exclusion criterion.

Figure 2.

Mullen Scores at 12, 18 and 24 months corrected age among infants supplemented with lactoferrin (L) or placebo (P) in the neonatal period. A total of 299 tests were performed at 12 months, 299 at 18 months and 301 at 24 months corrected age; 438 in the lactoferrin group and 461 in the placebo.

Figure 3.

Comparison of growth measurements from 40 weeks to 24 months corrected age. A. Weight-for-age Z-scores (mean); B. Length-for-age Z scores (mean); C. Weight-for-length Z-scores (mean); D. Head circumference Z-scores (mean).