Emma A Amissah, Julie Brown, Jane E Harding

As preterm infants do not experience the nutrient accretion and rapid growth phase of the third trimester of pregnancy, they are vulnerable to postnatal nutritional deficits, including of fat. Consequently, they require higher fat intakes compared to their full term counterparts to achieve adequate growth and development. Human milk fat provides the major energy needs of the preterm infant and also contributes to several metabolic and physiological functions. Although human milk has many benefits for this population, its fat content is highly variable and may be inadequate for their optimum growth and development. This is a 2018 update of a Cochrane Review last published in 2000. To determine whether supplementation of human milk with fat compared with unsupplemented human milk fed to preterm infants improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes without significant adverse effects. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 1), MEDLINE via PubMed (1966 to 08 February 2018), Embase (1980 to 08 February 2018), and CINAHL (1982 to 08 February 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Published and unpublished randomised controlled trials were eligible if they used random or quasi-random methods to allocate preterm infants fed human milk in hospital to supplementation or no supplementation with additional fat. No new randomised controlled trials matching the selection criteria were found but we extracted data from the previously included trial due to changes in review outcomes from when the protocol was first published. Two reviewers independently abstracted data, assessed trial quality, and the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. We planned to perform meta-analyses using risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We planned to use a fixed-effect model and to explore potential causes of heterogeneity via sensitivity analyses. One randomised trial involving 14 preterm infants was included. There was no evidence of a clear difference between the fat-supplemented and unsupplemented groups in in-hospital rates of growth in weight (MD 0.6 g/kg/day, 95% CI -2.4 to 3.6; 1 RCT, n = 14 infants, very low-quality evidence), length (MD 0.1 cm/week, 95% CI -0.08 to 0.3; 1 RCT, n = 14 infants, very low-quality evidence) and head circumference (MD 0.2 cm/week, 95% CI -0.07 to 0.4; 1 RCT n = 14 infants, very low-quality evidence). There was no clear evidence that fat supplementation increased the risk of feeding intolerance (RR 3.0, 95% CI 0.1 to 64.3; 1 RCT, n = 16 infants, very low-quality evidence). No data were available regarding the effects of fat supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes. The one included trial suggests no evidence of an effect of fat supplementation of human milk on short-term growth and feeding intolerance in preterm infants. However, the very low-quality evidence, small sample size, few events, and low precision diminishes our confidence that these results reflect the true effect of fat supplementation of human milk in preterm infants, and no long-term outcomes were reported. Further high-quality research should evaluate the effect on short and long-term growth, neurodevelopmental and cardio-metabolic outcomes in the context of the development of multicomponent fortifiers. Optimal dosage, adverse effects, and delivery practices should also be evaluated.