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Three Part Question

In [premature infants (<37weeks)] 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 NICU after an uncomplicated delivery. You have spoken to 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 adequate intake of macro 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 (using PubMed interface) 1966 – 2011:(preterm OR neonate OR infant) AND (human milk OR breast milk OR EBM) AND (fortifier OR fortified OR multicomponent) AND (necrotising enterocolitis OR NEC)]
•Cochrane Library: (preterm infant) AND (milk) AND (fortified OR fortifier)
•SUMSearch2 [(preterm OR very low birth weight) AND milk AND (fortified OR fortifier OR fortification) AND (necrotising enterocolitis OR NEC)

All searches limited to human biology, paediatric population, English language.

Search Outcome

Medline search yielded 25 results, 1 selected
Cochrane search yielded 8 results, 1 selected
Sum search yielded 11 results, 3 selected

Papers which specifically addressed the 3 part question were selected i.e. 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 (primary or secondary) outcome.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kuschel & Harding 2009	Premature infants receiving care within a nursery setting who were enrolled in random or quasi-random allocation to supplementation of human milk with multiple nutrients or no supplementation. Selected from Cochrane Central Register of Controlled Trials and MEDLINE, 2003. 13 studies identified (included more than 600 infants)	Systematic Review (with homogeneity of RCTs) (1a)	Incidence of NEC (secondary outcome)	No significantly increased incidence of NEC in infants receiving fortified human milk (RR 1.33, 95% CI 0.7 – 2.5)
Sullivan et al. 2010 USA	207 infants with birth weight between 500 – 1250g who were fed their own mothers’ milk were randomized to 1 of 3 study groups: Groups HM100 and HM40 received pasteurized donor human milk-based fortifier when the enteral intake was 100 and 40ml/kg/day respectively, and both groups received pasteurized donor human milk if no mother’s milk was available. Group BOV received bovine milk-based human fortifier when the enteral intake was 100ml/kg/day and preterm formula if no mother’s milk was available.	Multicentre Randomised control trial (1b)	Incidence of NEC (secondary outcome)	Significant difference among groups observed for combined outcome of NEC or death in HM100 (6%), HM40 (4.5%) and BOV (20%), p = .02. Significantly higher incidence of NEC in BOV group vs HM100 group (11 vs 3, p = .04), and HM100+HM40 combined group (11 vs 8, p = .02). All cases of surgical NEC occurred in infants who had received bovine milk-based products (7 in BOV group, 2 in HM100/HM40 groups who had received bovine milk-based fortifier in violation of study protocol).	Sample size calculations were based on primary outcome of detecting a difference in total days of parenteral nutrition. Moreover, study failed to detect a difference in any of its primary outcomes. There is a complete lack of blinding in the 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 products.
Lucas et al. 1996	275 preterm infants (birthweight <1850g; mean GA 29.8+/-2.7 wks) from 2 centres, whose mothers chose to provide their own breast milk were randomly assigned to receive either a multinutrient bovine milk based- fortifier or control non-milk fortifier. Preterm formula was used whenever insufficient maternal milk was available in either group.	Multicentre Randomized control trial (1b)	Incidence of NEC (secondary outcome)	No statistically significant difference in incidence of NEC between the two groups.	Confounded by ad hoc use of bovine milk products in both study groups (comprised more than 50% of total enteral intake per group) – authors argue this more accurately reflects clinical practice.
Schanler et al. 2005 USA	243 extremely premature infants (<30 wks) whose mothers intended to breastfeed were randomized to receive either pasteurized donor milk (DM) or preterm formula (PF) if there was insufficient supply of mother’s EBM. A third group of infants who received EBM exclusively (MM) was also included.	Randomised control trial (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 < .02)	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 < .02)
Bhat & Gupta 2003 Oman	100 VLBW infants were assigned to two groups matched for gestation and weight. Control group (n=50; mean birth weight 1239±186g and mean gestation 29.3±2.1wks) was fed human milk only, and in the fortifier group (n=50; mean birth weight 1245±191g and mean gestation 29.5±2.1 wks) human milk was enriched with a fortifier after the babies reached a volume of 140mL/kg/day by the enteral route. Preterm formula was used when mother’s breast milk was insufficient, however those requiring more than 15% caloric intake from formula for more than 2 days were excluded.	Non-randomised control trial (2b)	Incidence of NEC	No significant difference in incidence of NEC between infants receiveing preterm formula vs fortified human milk (p>0.05)	Actual values of NEC incidence in each group not given. Authors state protocol was double-blinded but unclear how EBM was fortified and given in a blinded manner. Groups not randomized; matched for GA and birthweight where possible. Not clear if fortifier was human milk or bovine milk-based. Small sample size, potentially underpowered.

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 (Kramer et al 2004)). 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 of 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 macro- and micronutrient requirements of those infants born before 37 weeks gestation (Schanler et al. 2005). Multinutrient fortifiers which supplement protein, calcium, sodium and phosphate may be added to expressed breast milk (EBM) to bridge this nutritional gap and have been shown to improve bone mineralization as well as short term weight gain, linear growth and head growth (McGuire et al. 2004).

Necrotising enterocolitis (NEC) is the most significant gastrointestinal emergency associated with prematurity (Lin et al. 2006), although the increased risk of NEC in very low birth weight (VLBW) infants may be significantly reduced by a diet of breast milk, rather than premature formula (Schanler et al. 1999). Whilst 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 et al. 1997). 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 RCTs which examined the long and short-term outcomes of preterm infants fed on a diet of fortified EBM and found that, not only was the use of fortifier 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." 3 out of the 4 other relevant papers showed similar results, with no convincing evidence to suggest that the use of EBM fortifiers is associated with an increase in the incidence of NEC.

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 were 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 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 et al. 2009), rather than an actual increased risk due to the use of bovine milk products. These results may point towards a benefit in the use of donor breast milk, in place of premature formula, when maternal supply is insufficient to maximise the proportion of human milk comprising total enteral intake.

In summary, the available evidence suggests that use of EBM fortifiers is safe for use in preterm neonates, and indeed affords significant benefits in terms of optimizing their post-natal growth and nutrition. Arguably the widely reported benefits of the use of EBM fortifiers outweigh any - thus far unfounded - 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.

Editor Comment

AT ADC 24/04/11 KW

Clinical Bottom Line

Multicomponent EBM fortifiers do not appear to increase the risk of NEC in preterm infants but the importance of expressed maternal/donor breast milk rather than use of preterm formula cannot be over-emphasised.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. Kuschel CA, Harding JE Multicomponent fortified human milk for promoting growth in preterm infants Cochrane Database of Systematic Reviews 2004
2. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kiechl-Kohlendorfer U, Chan GM, Blanco CL, Abrams S, Cotten CM, Laroia N, Ehrenkranz RA, Dudell G, Cristofalo EA, Meier P, Lee ML, Rechtman DJ. 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 Journal of Pediatrics 2010 April;156(4):562-U83.
3. Lucas A, Fewtrell MS, Morley R, Lucas PJ, Baker BA, Lister G, Bishop NJ. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. American Journal of Clinical Nutrition 1996 August;64(2):142-51
4. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics 2005 August;116(2):400-6.
5. Bhat BA, Gupta B. Effects of human milk fortification on morbedity factors in very low birth weight infants. Annals of Saudi Medicine 2001 September;21(5-6):292-5.
6. Kramer MS, Kakuma R The optimal duration of exclusive breastfeeding - A systematic review. Protecting Infants Through Human Milk 2004;554:63-77.
7. Schanler RJ, Abrams SA. Postnatal Attainment of Intrauterine Macromineral Accretion Rates in Low-Birth-Weight Infants Fed Fortified Human-Milk. Journal of Pediatrics 1995 March;126(3):441-7.
8. McGuire W, Henderson G, Fowlie PW ABC of preterm birth - Feeding the preterm infant. British Medical Journal 2004 November 20;329(7476):1227-30.
9. Lin PW, Stoll BJ Necrotising enterocolitis. Lancet 006 October 7;368(9543):1271-83.
10. Schanler RJ, Shulman RJ, Lau C Feeding strategies for premature infants: Beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999 June;103(6):1150-7.
11. Gartner LM, Black LS, Eaton AP, Lawrence RA, Naylor AJ, Neifert ME, Ohare D, Schanler RJ, Georgieff M, Piovanetti Y, Queenan J. Breastfeeding and the use of human milk. Pediatrics 1997 December;100(6):1035-9.
12. Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. Journal of Perinatology 2009 January;29(1):57-62.