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They also reported that lactoferrin supplementation can reduce the risk of these infants' hospital-acquired infection and infection-related mortality.
Researchers at Chongqing Medical University, the China International Science and Technology Cooperation Base of Child Development and Critical Disorders, and Chongqing Key Laboratory of Paediatrics conducted a systematic review to determine if lactoferrin intake was safe and effective for pre-term infants, especially against NEC and LOS.
They searched databases such as Medline, The Cochrane Library, and Ovid-Embase for English- and Chinese-language RCTs on lactoferrin use to prevent LOS and NEC in premature infants, settling on nine RCTs involving 1,834 patients.
According to pooled analysis, prophylactic lactoferrin was found to have markedly lowered the incidence of all-culture proven LOS by up to 15.3%, compared to 6.5% in the control groups. It was also reported to have reduced the incidence of NEC by up to 5.6%, compared to 2% in the control groups.
NEC was the primary outcome of interest in five of the nine studies reviewed, with the incidence of NEC at 2% in the treatment groups as opposed to 5.6% in the control groups after lactoferrin supplementation.
Sub-group analysis of the pathogen type of sepsis suggested that lactoferrin's beneficial effects were applicable to not only LOS, but all kinds of sepsis.
The researchers wrote: "Although the distribution of pathogens by type was not significantly different in the treated and control groups, lactoferrin tends to have better prevention efficacy in fungal sepsis compared to bacterial sepsis."
Lactoferrin was also linked to a significant decrease in hospital-acquired infection by 25% (11.5% in control groups), and infection-related mortality by 4.9% (0.8% in the control groups).
Additionally, it was found to be able to shorten the time needed to reach full enteral feeding, and contributed to a declining trend of the duration of hospitalisation.
At the same time, lactoferrin was also found to particularly benefit infants with very low birth weight (below 1.5kg), more so than infants with low birth weight (between 1.5kg and 2.5kg), for whom the efficacy of lactoferrin was not statistically significant.
However, the researchers also reported that lactoferrin supplementation "did not have a significant effect on all-cause mortality" (5.4% in the treatment groups versus 3.5% in the control groups), though none of the RCTs reviewed reported any adverse effects brought on by lactoferrin or probiotic supplementation.
A question of quality
Several potential limitations were highlighted for consideration when interpreting the results, including the RCTs having been conducted in different regions, among both developing and developed countries.
This meant that lower detection rates of culture-proven sepsis and higher sepsis risk in lower-income countries could lead to high heterogeneity in data. However, the researchers noted low heterogeneity when analysing lactoferrin's effects against LOS, NEC, and infection-related mortality.
The initial time of intervention was also different among the studies, an important detail due to lactoferrin concentration being high in colostrum and relatively low in mature milk.
Lactoferrin interacts with gut cells differently, depending on its concentration: in high concentration, the interaction manifests as lactoferrin-driven gut cell proliferation and maturation, while in low concentration, it manifests merely as intestinal differentiation.
To mimic the property of lactoferrin in colostrum, the initial supplementation time in pre-term infants should be within their very first days of life; some of the studies only began supplementation after four days of life.
The researchers also wrote that for exclusively breastfed infants, lactoferrin's benefits were still significant, with the incidence of LOS in untreated infants similar between those who were breastfed and those who were fed formula.
This suggested that breastmilk alone did not confer the benefits of lactoferrin intake, and as such, that pre-term infants needed additional lactoferrin, "specifically to prevent LOS".
Furthermore, despite colostrum containing the highest lactoferrin content, supplementing premature infants with additional lactoferrin is still important.
This is because it can take two to three weeks for infants with very low birth weight to receive full-volume enteral feedings, as well as full amounts of the protective components in human milk.
The researchers concluded: "The nine included trials indicated that lactoferrin supplementation in pre-term neonates is safe, without obvious adverse effects. The results of our meta-analysis demonstrated that prophylactic supplementation of lactoferrin could significantly reduce the incidence of NEC, LOS, and hospital-acquired infection in pre-term neonates.
"It also detects a trend of decreased infection-related mortality, with statistical significance. Our study also revealed that lactoferrin could slightly reduce the time to achieve full enteral feeding and duration of hospitalisation of preterm infants, with statistical significance.
"In addition, lactoferrin with LGG (Lactobacillus rhamnosus) seems to have greater benefits in the prevention of NEC and LOS (very low evidence). However, there are not enough high-quality trials to determine whether the beneficial effects of lactoferrin could be enhanced by combining it with probiotics.
"The efficacy of lactoferrin for preventing LOS and NEC still needs more high-quality RCTs to demonstrate. The long-term effects of lactoferrin also need follow-up, (as) current evidence is under-powered to detect (these effects).
"Future studies should focus on the optimal duration, dosage, type, and long-term effects of lactoferrin."
"Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis"
Authors: Yi He, et al.