Multi-nutrient fortification of human milk for preterm infants

Background: Human breast milk-fed preterm infants can accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with multi-nutrient fortified human milk could increase nutrient accretion and growth rates and improve neurodevelopmental outcomes. Concern exists, however, that multi-nutrient fortifiers are associated with adverse events such as feed intolerance and necrotising enterocolitis. Objectives: To determine whether multi-nutrient fortified human milk, compared with unfortified human milk, affects important outcomes (including growth rate and neurodevelopment) of preterm infants without increasing the risk of adverse effects (such as feed intolerance and necrotising enterocolitis). Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 26 September 2019), Embase (1980 to 26 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 26 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Selection criteria: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with multi-nutrient (protein and energy plus minerals, vitamins, or other nutrients) fortified human breast milk versus unfortified (no added protein or energy) breast milk. Data collection and analysis: We used the standard methods of Cochrane Neonatal. Two review authors separately evaluated trial quality, extracted data, and synthesised effect estimates using risk ratios (RRs), risk differences, and mean differences (MDs). We assessed the certainty of the body of evidence at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods. Main results: We identified 18 trials in which a total of 1456 preterm infants participated. These trials were generally small and methodologically weak. Meta-analyses provided low- to moderate-certainty evidence showing that multi-nutrient fortification of human milk increases in-hospital rate of weight gain (MD 1.76 g/kg/d, 95% confidence interval (CI) 1.30 to 2.22), body length (MD 0.11 cm/week, 95% CI 0.08 to 0.15), or head circumference (MD 0.06 cm/week, 95% CI 0.03 to 0.08) among preterm infants. Few data on growth and developmental outcomes assessed beyond infancy are available, and these do not show effects of multi-nutrient fortification. The data do not suggest other benefits or harms and provide low-certainty evidence suggesting effects of multi-nutrient fortification on the risk of necrotising enterocolitis in preterm infants (typical RR 1.37, 95% CI 0.72 to 2.63; 13 studies, 1110 infants). Authors' conclusions: Feeding preterm infants with multi-nutrient fortified human breast milk compared with unfortified human breast milk is associated with modest increases in in-hospital growth rates. Evidence is insufficient to show whether multi-nutrient fortification has any effect on long-term growth or neurodevelopment.