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Three Part Question

In [premature infants (<37 weeks)] does [supplementation of expressed breast milk with multicomponent fortifier] increase [the risk of necrotising enterocolitis]?

Clinical Scenario

A premature infant (30 weeks) weighing 1050g was recently admitted to the neonatal intensive care unit after an uncomplicated delivery. You have spoken to the mother regarding the benefits of expressed breast milk (EBM) compared to premature formula milk, including the decreased risk of necrotising enterocolitis (NEC), and this is being administered via a nasogastric tube. At the ward round the consultant suggests the addition of EBM fortifier to ensure the baby has an adequate intake of macronutrients and micronutrients and to maximise extra-uterine growth. You wonder if the addition of a cow's milk-based fortifier to EBM will confer an increased risk of NEC and decide to find out more.

Search Strategy

MEDLINE (1966–2011) was searched using the search terms: (preterm OR neonate OR infant) AND (human milk OR breast milk OR EBM) AND (fortifier OR fortified OR multicomponent) AND (necrotising enterocolitis OR NEC). The Cochrane Library was searched using the search terms: (preterm infant) AND (milk) AND (fortified OR fortifier). SUMSearch2 was searched using the search terms: (preterm OR very low birth weight) AND milk AND (fortified OR fortifier OR fortification) AND (necrotising enterocolitis OR NEC).
All searches were limited to human biology, paediatric population and English language. The MEDLINE search yielded 25 results, one of which was selected, while the Cochrane Library search yielded eight results, one of which was selected. The SUMSearch2 search yielded 11 results, three of which were selected.

Search Outcome

The three papers which specifically addressed the question were selected, that is, where there was direct comparison of fortified (either bovine milk-based or human milk-based) with non-fortified EBM and incidence of NEC was examined as the (primary or secondary) outcome

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Schanler et al, 1995	243 extremely premature infants (<30 weeks) whose mothers intended to breastfeed were randomised to receive either pasteurised donor milk (DM) or PF if there was insufficient supply of mother's expressed breast milk (EBM). A third group of infants who received EBM exclusively (MM) was also included.	RCT (1b)	Incidence of late onset sepsis (LOS) and NEC	No difference in incidence of LOS or NEC between the DM and PF groups. Incidence of NEC correlated negatively with cumulative intake of MM (r=(−0.1 to −0.2), p<0.02)
Kuschel and Harding, 2004	Premature infants receiving care in a nursery setting who were randomly or quasi-randomly allocated to supplementation of human milk with multiple nutrients or no supplementation. 13 studies selected from the Cochrane Central Register of Controlled Trials and MEDLINE (2003) were reviewed.	Systematic review (with homogeneity of randomised controlled trials (RCTs)) (1a)	ncidence of necrotising enterocolitis (NEC) in infants receiving fortified human milk (secondary outcome)	Data available from 7 studies which collectively included 640 infants. Pooled RR 1.33 (95% CI 0.7 to 2.5)	I2=2.1% indicating homogeneity of trials, and supports use of fixed effects analysis
Sullivan et al, 2010	207 infants with birth weight between 500 and 1250 g who were fed their own mothers' milk were randomised to 1 of 3 study groups: groups HM100 and HM40 received pasteurised donor human milk-based fortifier when enteral intake was 100 and 40 ml/kg/day, respectively, and both groups received pasteurised donor human milk if no mother's milk was available. Group BOV received bovine milk-based human fortifier when the enteral intake was 100 ml/kg/day and preterm formula (PF) if no mother's milk was available.	Multicentre RCT (1b)	Incidence of NEC (secondary outcome)	Incidence of NEC significantly different between the three groups (p=0.05) HM100 (3/69) vs BOV (11/69), p=0.04 HM40 (5/69) vs BOV (11), p=NS HM100+40 (8/138) vs BOV (11/69), p=0.02	Non-blinded study design and also some evidence of violation from the study protocol in which some infants in the HM100/40 groups erroneously received bovine milk. All cases of surgical NEC occurred in infants who had received bovine milk-based products

Comment(s)

The WHO recommends that all term infants should be exclusively breastfed for the first 6 months of life, a recommendation supported by an abundance of high-quality evidence. Breast milk may be thought of as the optimum biological fluid to support the nutritional demands of the rapidly growing infant, as well as meeting its requirements for micronutrients, immunoglobulins and hormones. Advances in neonatal care have led to improved viability and survival in preterm infants. Due to their reduced nutrient stores and relatively rapid growth compared to term babies, however, maternal breast milk as the sole nutritive substance may be insufficient to provide the increased macronutrient and micronutrient requirements of those infants born before 37 weeks gestation (Schanler). Multinutrient fortifiers which supplement protein, calcium, sodium and phosphate may be added to EBM to bridge this nutritional gap and have been shown to improve bone mineralisation as well as short term weight gain, linear growth and head growth (McGuire).

NEC is the most significant gastrointestinal emergency associated with prematurity (Lin)although the increased risk of NEC in very low birthweight (VLBW) infants may be significantly reduced by a diet of breast milk rather than premature formula (Schanler). While the biological mechanisms underlying this benefit are not completely understood, the use of human breast milk is recommended over bovine milk products for all preterm infants(Gartner).EBM fortifiers, however, are often bovine milk-based and thus the question is raised whether their use may confer an increased risk of NEC in VLBW infants who receive fortified EBM.

The Cochrane review by Kuschel and Harding presents the result of 13 randomised controlled trials which examined the long and short-term outcomes of preterm infants fed on a diet of fortified EBM and not only found that the use of fortifier was associated with improved weight gain, linear growth and head growth, but also did not detect any significant increase in adverse outcomes, including NEC. While admitting that “the abstractable data from the published studies is limited”, the authors state that “there does not appear to be any increase in clinically significant adverse effects in supplemented infants”.

The 2010 study by Sullivan et al did find a significantly higher incidence of NEC in infants receiving bovine milk-based fortifier rather than human milk-based fortifier, and was the only trial in which the control group was restricted to an exclusively human milk diet (with any supplementary milk being from human donors rather than preterm formula). The clinical significance of this result, however, is uncertain as the actual difference in the frequency of infants who developed NEC is small between groups. Moreover, it may be a result of the apparent dose-related association of increased EBM feeding with a reduced risk of NEC (Meinzen-Derr).

In summary, the available evidence suggests that the use of EBM fortifiers is safe for use in preterm neonates, and indeed affords significant benefits in terms of optimising their postnatal growth and nutrition. Arguably, the widely reported benefits of the use of EBM fortifiers outweigh any uncertain suggestions of an increase in adverse outcomes such as NEC. Further study is warranted to examine these outcomes with greater statistical power, and also to fully evaluate the use of human milk-based fortifiers.

Clinical Bottom Line

Multicomponent expressed breast milk fortifiers do not appear to increase the risk of necrotising enterocolitis in preterm infants. (Grade C)

References

1. Kramer MS, Kakuma R . The optimal duration of exclusive breastfeeding: a systematic review. Adv Exp Med Biol 2004;554:63–77.
2. Schanler RJ, Abrams SA . Postnatal attainment of intrauterine macromineral accretion rates in low birth weight infants fed fortified human milk. J Pediatr 1995;126:441–7.
3. McGuire W, Henderson G, Fowlie PW . Feeding the preterm infant. BMJ 2004;329:1227–30.
4. Lin PW, Stoll BJ . Necrotising enterocolitis. Lancet 2006;368:1271–83.
5. Schanler RJ, Shulman RJ, Lau C . Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999;103:1150–7.
6. Gartner LM, Black LS, Eaton AP, et al . Breastfeeding and the use of human milk. Pediatrics 1997;100:1035–9.
7. Kuschel CA, Harding JE . Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2004;1:CD000343.
8. Sullivan S, Schanler RJ, Kim JH, et al . An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156:562–7.e1.
9. Meinzen-Derr J, Poindexter B, Wrage L, et al . Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol 2009;29:57–62.
10. Schanler RJ, Lau C, Hurst, et al . Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics 2005;116:400–6.