Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Randomised placebo-controlled trial in very preterm infants born before 32 weeks' gestation and enrolled within 72 hours of birth at 37 neonatal units in the UK. In the active lactoferrin arm, 1099 infants were randomized, 1098 remained after consent withdrawal/unconfirmed consent, and 1093 contributed to the primary modified intention-to-treat analysis.

Bovine lactoferrin was given enterally at 150 mg/kg bodyweight per day, up to a maximum of 300 mg/day, once daily via gastric tube until 34 weeks' postmenstrual age. The investigational product was prepared from 375 mg pots, mixed with sterile water plus expressed breast milk or formula, and placebo was used as the comparator.

Enteral bovine lactoferrin did not reduce late-onset infection or improve major neonatal outcomes in very preterm infants, so routine use is not supported. The primary outcome occurred in 316/1093 (29%) in the lactoferrin group versus 334/1089 (31%) in the control group, with unadjusted RR 0.95 (95% CI 0.86-1.04; p=0.233). There was also no meaningful difference in all-cause mortality (71/1076 [7%] vs 68/1076 [6%]; RR 1.04, 0.69-1.59), NEC (63/1085 [6%] vs 56/1084 [5%]; RR 1.12, 0.71-1.77), severe ROP (64/1080 [6%] vs 72/1080 [7%]; RR 0.89, 0.58-1.35), BPD at 36 weeks' postmenstrual age (358/1023 [35%] vs 355/1027 [35%]; RR 1.01, 0.87-1.18), or the composite of infection, NEC, ROP, BPD, or mortality (525/1092 [48%] vs 521/1094 [48%]; RR 1.01, 0.90-1.13).

The trial was conducted in very preterm infants in UK neonatal units, which may limit generalisability to other settings. Although follow-up for the primary outcome was high, some infants were excluded from analysis because of withdrawn or unconfirmed consent, and several secondary outcomes were exploratory with no clear signal of benefit. Local clinical practices, including feeding approaches and probiotic use, could have introduced site-level variability.