Study design

Design: Systematic review and meta-analysis of 12 studies using multiple electronic data sources including Cochrane Central Register of Controlled Trials, Ovid MEDLINE, Ovid Embase, OVID maternity and infant care database and cumulative index to Nursing and Allied Health Literature as well as Clinicaltrials.gov and WHO’s international trials registry and platform. Randomised or quasi-randomised controlled trials were included.

Study question

Patients: Infants born before 37 weeks gestation or with a birth weight of less than 2500 g. A total of 1879 infants in 12 separate trials (six randomised, six quasi-randomised) were included

Intervention: Enteral feeding with formula versus donor breast milk as the sole diet or supplementary to maternal breast milk

Outcome measures: Growth, neurodevelopment, all-cause mortality, necrotising enterocolitis and invasive infections

Follow-up: Variable; majority of studies used data until discharge from hospital, of the four studies that had longer-term outcome data, follow-up ranged from 15 months corrected age to 7.5–8 years.

Main results

Formula-fed infants had a significantly higher rate of weight gain with subgroup analysis showing the greatest difference in infants receiving preterm formula versus unfortified donor breast milk. Significant differences were also seen in linear growth and head growth favouring formula feeding.

Composite data for severe neurodevelopmental disability was not available. However, in the four trials that measured neurodevelopment using validated assessment tools, no significant differences were found comparing formula to donor milk.

Higher rates of necrotising enterocolitis (NEC) were seen in the formula group, with a number needed to treat for an additional harmful outcome (NNTH) of 33 (95% CI 20 to 100) (Table 1).

Commentary

Maternal breast milk is the feeding method of choice in preterm and low birthweight infants, particularly due to the non-nutritive benefits of maternal breast milk and associated lower rates of necrotising enterocolitis (NEC).1 In cases where maternal milk is not available, common practice is to use donor breast milk, as the current evidence suggests that feeding with donor breast milk, compared with formula is associated with a significantly reduced relative risk of NEC.2 However, the use of donor breast milk comes with its own challenges. There can be significant variability in macronutrient values between different donor samples, in particular the protein content.3 A recent study showed that only 66% of samples of unfortified donor breast milk at 180 mL/kg/day would meet the recommended energy requirements of a preterm infants, and even with the addition of fortifier, only 61% of samples would meet the minimum protein requirements of 3.5g/kg/day.4 In contrast, preterm formula such as Nutriprem 1 at 150 mL/kg/day would exceed the minimum recommended energy and protein requirements for preterm and low birthweight infants. This raises questions on the effects of growth of preterm infants supplemented with donor breast milk compared with formula.

This review shows with moderate certainty that formula feeding is better than donor breast milk for short-term growth, in particular when comparing preterm formula with unfortified donor breast milk. This likely reflects the increased calorie and protein content in formula milk. However, there is not enough direct evidence from these trials to suggest that increased weight gain is associated with long-term improved neurodevelopmental outcome. However, no composite data were available for meta-analysis and the results from the individual studies, with follow-up data, suggest a high level of imprecision as demonstrated by small numbers and wide CIs. It is also worth noting that this review shows with moderate certainty that there is no effect on all-cause mortality when comparing donor milk to preterm formula.

Overall, current evidence clearly indicates that maternal breast milk is safer for preterm and low birthweight babies. This study shows that even when maternal milk is not available, there is little place for the use of unfortified donor breast milk in these babies, as this resulted in the slowest growth patterns. Most of the trials did not include severely growth restricted preterm and sick infants, that is, those most at risk of NEC, so caution must be exercised when applying the results of this study to that group of infants. Therefore, in babies who are at high risk of NEC, supplementation with fortified donor breast milk would probably be the most sensible option. When considering short-term growth in isolation, preterm formula was superior to donor milk, so for infants who have static weight gain on donor breast milk, there is now clear evidence that switching to preterm formula will result in better growth parameters. In practice though, decisions are rarely made based on isolated considerations and we need to balance the benefits of faster growth against the statistically significant increased risks of NEC; although it is worth bearing in mind that the estimate for NNTH for this is anywhere between 20 and 100.