Multi-nutrient fortification of breast milk for preterm infants

Review question: Do preterm infants (babies born early) grow and develop better when they are fed breast milk supplemented with extra protein and calories ("fortified")?

Background: Breast milk alone might not be enough to support preterm infants to grow and develop optimally. Extra nutrients, such as protein and energy (calories) from carbohydrates or fat, can be added to breast milk to make it about 10% to 20% more nutritious. These additional nutrients are called "fortifiers". Feeding preterm infants, especially very preterm infants (born before 32 weeks), fortified breast milk may mean that they take in more nutrients, grow faster, and develop better.

Study characteristics: We included 18 trials; most were small (involving 1456 infants in total) and had some design weaknesses that might bias their findings. The search is up-to-date as of September 2019.

Key results: Preterm infants who were fed fortified breast milk put on weight and grew in length and head size a little more quickly while they were in-hospital. The trials we included did not report a lot of information about the effects fortified breast milk might have on development and growth later in the baby's life. The data we have available do not suggest an effect of feeding fortified breast milk on outcomes when the child is older. The included trials provide no consistent evidence of other potential benefits or harms of fortified breast milk, including any effects on feeding or bowel problems.

Conclusion: Trial data show that multi-nutrient fortification increases growth rates of preterm infants during their first hospital admission but do not provide enough evidence to show any effects on longer-term growth or development. New trials are needed to discover more about this issue.

Certainty of evidence: We assessed this evidence for effects on growth as being of "low or moderate certainty" because the included trials were small, had methodological weaknesses, and reported findings that were inconsistent with each other. This means that further research is very likely to have an important impact on the estimates of effect and on our confidence in study findings.

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.

Read the full abstract...

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.


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 strategy: 

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).