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

INTRODUCTION: The 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 ANALYSIS: A 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 DISSEMINATION: The 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 NUMBER: The study was registered with ClinicalTrials.gov NCT03797157, 9 January 2019.