Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants

Background Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. Objectives To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive‐pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later. Search methods We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi‐randomized trials. Selection criteria In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. Data collection and analysis We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. Main results Meta‐analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased suspected or confirmed late‐onset sepsis (typical RR 0.80, 95% CI 0.72 to 0.89; typical RD ‐0.05, 95% CI, ‐0.07 to ‐0.02; NNTB 20, 95% CI 14 to 50; 12 studies, 5425 participants, low‐certainty evidence) and decreased length of hospital stay (MD ‐2.38 to 95% CI, ‐4.67 to ‐0.09; 3 studies, 1079 participants, low‐certainty evidence). A subgroup analysis including data of infants with confirmed sepsis demonstrates a decrease in confirmed late‐onset sepsis (typical RR 0.83, 95% CI 0.73 to 0.94; typical RD ‐0.03, 95% CI, ‐0.04 to ‐0.01; NNTB 33, 95% CI 25 to 100; 12 studies, 5425 participants, low‐certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late‐onset sepsis (both suspected and confirmed) with enteral lactoferrin supplementation (typical RR 0.82, 95% CI, 0.74 to 0.91; typical RD ‐0.04, 95% CI, ‐0.06 to ‐0.02; NNTB 20, 95% CI 14 to 50; 9 studies, 4702 participants, low‐certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86 to 1.41; typical RD ‐0.00, 95% CI, ‐0.02 to 0.01; 7 studies, 4874 participants; low‐certainty evidence) or 'all‐cause mortality' (typical RR 0.90, 95% CI 0.69 to 1.17; typical RD ‐0.00, 95% CI, ‐0.01 to 0.01; 11 studies, 5510 participants; moderate‐certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low‐certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late‐onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD ‐0.13, 95% CI ‐0.18 to ‐0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low‐certainty evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD ‐0.05, 95% CI ‐0.08 to ‐0.03; NNTB 20, 95% CI 12.5 to 33.3; 1 study, 496 participants; very low‐certainty evidence), but not 'all‐cause mortality' (very low‐certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low‐certainty evidence). Investigators reported no adverse effects in the included studies. Authors' conclusions We found low‐certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late‐onset sepsis (both suspected and confirmed, and confirmed only) but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low‐ to very low‐certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late‐onset sepsis (data from confirmed sepsis only) and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.