Nordic study on human milk fortification in extremely preterm infants: a randomised controlled trial—the N-forte trial

Abstract

IntroductionThe mortality rate of extremely low gestational age (ELGA) (born <gestational week 28+0) infants remains high, and severe infections and necrotising enterocolitis (NEC) are common causes of death. Preterm infants receiving human milk have lower incidence of sepsis and NEC than those fed a bovine milk-based preterm formula. Despite this, fully human milk fed ELGA infants most often have a significant intake of cow’s milk protein from bovine-based protein fortifier. The aim of this study is to evaluate whether the supplementation of human milk-based, as compared with bovine-based, nutrient fortifier reduces the prevalence of NEC, sepsis and mortality in ELGA infants exclusively fed with human milk.Methods and analysisA randomised-controlled multicentre trial comparing the effect of a human breast milk-based fortifier with a standard bovine protein-based fortifier in 222–322 ELGA infants fed human breast milk (mother’s own milk and/or donor milk). The infants will be randomised to either fortifier before reaching 100 mL/kg/day in oral feeds. The intervention, stratified by centre, will continue until the target postmenstrual week 34+0. The primary outcome is a composite of NEC, sepsis or death. Infants are characterised with comprehensive clinical and nutritional data collected prospectively from birth until hospital discharge. Stool, urine, blood and breast milk samples are collected for analyses in order to study underlying mechanisms. A follow-up focusing on neurological development and growth will be performed at 2 and 5.5 years of age. Health economic analyses will be made.Ethics and disseminationThe study is conducted according to ICH/GCP guidelines and is approved by the regional ethical review board in Linköping Sweden (Dnr 2018/193-31, Dnr 2018/384-32). Results will be presented at scientific meetings and published in peer-reviewed publications.Trial registration numberThe study was registered with ClinicalTrials.gov NCT03797157, 9 January 2019.

Evidenzbasierte Ernährung von Frühgeborenen

“…< 28 SSW) kann der Verzicht auf die Gabe von bovinem Eiweiß in den ersten 4 Lebenswochen das Risiko für das Auftreten einer NEC reduzieren [39]. Eine kontrolliert randomisierte Studie zum Vergleich der Supplementierung mit bovinem vs. humanem Fortifier wird derzeit in Schweden durchgeführt [40]. Auch für die Supplementierung ist ein standardisiertes Vorgehen von Vorteil.…”

Exclusive Human Milk Diet for Extremely Premature Infants: A Novel Fortification Strategy That Enhances the Bioactive Properties of Fresh, Frozen, and Pasteurized Milk Specimens

“… 40 Recent studies aimed at evaluating the role of MOM and EHMD in modifying gut microbial colonization, and later vascular aging and neurodevelopmental outcomes could possibly reaffirm the uniqueness of HM bioactivity. 5 , 41 , 42 Our study contributes to new information that specific bioactive properties lost or attenuated through the pasteurization of DHM could be reinstated through HMDF, and for MOM, the levels could be augmented offering potential benefits to ELBW infants. An improved understanding of how MOM designs, donates, and modulates the immunochemical components to offspring would be desirable to improve preventative approaches.…”

“…Moreover, cow's milk protein, as present in CMDF, has been established to increase the incidence of NEC. 5 , 12 , 16 , 21 …”

“… 2–4 Even though the guiding tenets of preterm nutrition emphasize early and exclusive HM uptake, adding exogenous cow's milk-derived fortifier (CMDF) remained the standard practice for decades. 5 Recent recognition of nutritional limitations and risks posed by such bovine-origin protein supplementation stimulated a novel enrichment using human milk-derived fortifier (HMDF). 6–9 An exclusive human milk diet (EHMD) for very preterm (VPT, <32 weeks of gestational age) and very low–birthweight (VLBW, <1,500 g birth weight) infant comprises mother's own milk (MOM) or pasteurized banked donor human milk (DHM) fortified with HMDF.…”

Clinical Experience with a New, Non-Acidified Liquid Human Milk Fortifier in Very Low Birth Weight Infants.

“…Currently, there are several commercially available forti ers of human or bovine milk origin in liquid or powder form, which vary in their nutrient composition (8). At present, the evidence does not support better outcomes with human milk-derived forti ers over bovine products (9,19). This notwithstanding, it is very important to examine clinical outcomes, particularly growth, among populations of infants receiving these forti ers.…”