The benefits of human milk for preterm infants

Human milk has a number of benefits for preterm infants, although we do not really know what it is that confers these advantages over cow's milk formula. Milk feeding has three main potential functions in preterm infants (1) immune modulation, (2) mechanical and biochemical priming of the gut and (3) nutrient provision. Human milk probably provides benefits in at least the first two of these functions.1

1. Immune modulation: This is provided by probiotic bacteria, immune molecules including sIgA, lactoferrin, sCD14, lysozyme and leucocytes. The combined effects of caesarean section, separation from the mother, handling by multiple health professionals and the use of broad-spectrum antibiotics (all commonplace in preterm infants) collectively threaten to select pathogenic bacteria and predispose to bacterial translocation and a proinflammatory state in the gut. It is plausible that the earlier human milk is given the more likely it is to overcome these pathological forces.^w1

2. Mechanical and biochemical priming of the gut: There is evidence that human milk is associated with less feed intolerance and earlier attainment of full enteral feeds than formula milk.^w2 Breast milk contains numerous growth factors, some of which have direct effects on the gut, for example, maturation and repair of the mucosa (epidermal growth factor and erythropoietin), the development of the enteral nervous system (neuronal growth factors) and vascular regulation (vascular endothelial growth factor).1

3. Nutrient provision: If intrauterine nutrient accretion and growth are taken as the gold standard, human milk is deficient as the sole feed for preterm infants. Compared to preterm formula, human milk is deficient particularly in energy, protein, sodium, calcium, phosphate and zinc.2

Colostrum, the first milk, produced in low volumes after the baby's birth, has a high concentration of bioactive factors, many of which escape digestion and some of which are absorbed intact. This may have profound effects on the development of the intestinal barrier.^w3 as well as the immune system.^w4

The available evidence suggests reduction in the incidence of several adverse outcomes when human milk, rather than formula, is fed to preterm infants:

1. Necrotising enterocolitis (NEC)3 ,4

2. Late-onset sepsis,5 although a systematic review6 did not substantiate this (the data available was of limited quality).

3. Retinopathy of prematurity7

4. Abnormal brain development (a) improvement in neurodevelopmental outcome8 and (b) altered brain structure on MRI9

5. Features predictive of metabolic syndrome10

6. Hospital admission up to 30 months of age8

Economic modelling suggests that increased human milk feeding would result in large lifetime cost savings.11

It should be noted that some of the evidence above is based on research carried out nearly 25 years ago, when neonatal care was very different.

There appears to be a dose-related change in outcomes with human milk, suggesting a real effect despite potential confounding by social factors in studies in which there was no randomisation of feed.12 It is more difficult to analyse separately the effects of MEBM and DEBM.

The shortfall in nutrients in human milk can be partially made up by adding human milk fortifier (HMF). This has been shown to improve short-term growth, but there is no evidence of any effect on longer term outcome.13 Most HMF is derived from bovine milk. In piglets bovine casein induces inflammatory changes in the gut, and this has lent credence to a role for immune sensitisation to bovine protein in NEC.14 This is one interpretation of the results of a complex feeding trial in which preterm infants were randomised to (i) DEBM or bovine formula to make up any shortfall in MEBM, and (ii) human or bovine-based HMF as nutrient supplement. A secondary analysis showed less NEC in babies who received exclusively human milk-based products. Importantly, however, the interventions resulted in different levels of exposure to both bovine products and human milk (as DEBM), which makes it difficult to draw a clear conclusion from this.

Benefits of mother's own expressed breast milk

Not surprisingly, there have been no randomised controlled trials comparing the use of formula with mother's own expressed breast milk.15 Nevertheless, in light of the cumulative evidence, neonatal professionals are rightly positive about its use in preterm infants.

Fortification with HMF enables provision of good nutritional intake with no clear evidence of risk.13 However, one of the paradoxes about unfortified MEBM is that it is associated with better outcomes than formula feeding in all areas including neurodevelopment despite being associated with poorer growth and markers of ‘undernutrition’, thus indicating its complex bioactive properties.

Obtaining sufficient amounts of MEBM to feed a preterm infant requires a complex process including (a) communication of benefits and of expression techniques to mothers at an emotionally charged time16 (b) provision of space, support and equipment to allow skin-to-skin contact, breast milk expression, and ultimately, breastfeeding17 and (c) consistent focus on this as an important aspect of care from all neonatal staff.18 A recent paper identified 10 potentially better practices whose implementation achieved a sustained improvement in breast milk availability in the space of a few weeks.19

Unknowns about MEBM

Breast milk is not a predictable commodity and, unlike other foods and pharmaceuticals, is not readily amenable to quality assurance.

Breast milk composition varies with stage of lactation (in particular, with a progressive reduction in protein content in the first 4–6 weeks), maternal diet, maternal body habitus and volume of milk produced.

Prescribed medication, alcohol, nicotine and recreational drugs can be transmitted in breast milk20 and are currently thought to justify preventing donation of breast milk, but the benefits are considered sufficient in most cases to encourage feeding MEBM.

Potentially pathogenic bacteria and viruses can be transmitted via MEBM. In the developed world, maternal HIV infection is considered a contraindication to feeding MEBM because of the significant risk of transmission to the infant. Cytomegalovirus (CMV) transmission appears to be most frequently related to reactivation, an almost universal occurrence in previously infected mothers. Lower birth weight and early postnatal transmission are risk factors for symptomatic infection, with nearly half of the preterm infants born to seropositive mothers being affected. Clinical features are a sepsis-like picture with neutropenia and thrombocytopenia, and sometimes also liver dysfunction, pneumonia and enterocolitis. Freeze-thawing milk reduces, but does not abolish, infectivity. In some countries, freezing or pasteurising MEBM is accepted practice. Neonatal CMV infection does not appear to increase the risk of neonatal morbidities related to prematurity or long-term neurodevelopmental or auditory deficits.21 Bacterial transmission can result in neonatal infection, a particular case being Group B streptococcal disease, which may recur through transmission in breast milk in the absence of clinical mastitis.22

Many of the processes involved in handling EBM affect nutrient provision to the baby. This includes standing, refrigeration and freeze-thawing. In addition, continuous tube feeding reduces the delivery of fat compared to intermittent feeding because of losses in the delivery system.2

Banked donor breast milk

What about mothers who are unable to express breast milk for their infant? Compared to formula milk, DEBM might be beneficial in improving feed tolerance, reducing the risk of NEC4 and improving longer term outcomes such as cardiovascular health,10 cognition23 and bone mineral content.24 Extrapolation from data on the costs resulting from NEC suggest that DEBM may be economically as well as clinically effective.25

Interest in DEBM has been increasing since a nadir in the 1980 s, when it was discovered that HIV could be transmitted in breast milk. Its use has been brought into focus since improvement in other preterm morbidities has left infection and gut pathology (including NEC) as the main concerns.26 Many new milk banks have been set up worldwide (w5). In the UK, there are currently 17 milk banks, and most supply surplus milk to neighbouring units. They charge a fee equivalent to a cost of £5–£40 to feed a preterm infant for a day. Currently, a single bank is formally contracted to provide DEBM for all the units in Northern Ireland, and a similar arrangement is being planned in Scotland. It is likely that with active recruitment of donors and additional resources, existing milk banks could provide sufficient DEBM for all units caring for very preterm infants in the UK (Gillian Weaver, personal communication).

Donor milk is collected from mothers of healthy term babies expressing following a breastfeed, mothers of babies in neonatal units who have expressed milk in excess of requirements and (occasionally) from mothers of babies who have died.

Some countries such as Norway use unpasteurised DEBM.27 In most countries, measures are taken to minimise the risk of transmission of bacteria, viruses and emerging pathogens. In the UK, milk donors are screened by lifestyle questionnaire and tested serologically for HIV, Hep B/Hep C, human T-lymphotropic virus I/II and syphilis.28 Milk is then treated by Holter pasteurisation (heating to 62.5°C for 30 min).

The use of DEBM is endorsed by several international bodies, including WHO, United Nations International Children's Emergency Fund (UNICEF), the American Academy of Paediatrics and the World Association of Perinatal Medicine, although there is no agreement on the circumstances in which it should be used. There is general agreement that the use of DEBM should be accompanied by measures to facilitate the expression of MEBM. There is some evidence to suggest that the use of DEBM is in fact associated with higher rates of exclusive breastfeeding on discharge.29

Unknowns about DEBM

Whilst it is probably preferable to use DEBM to formula for some preterm infants, it remains unclear whether DEBM should be used in the same way as MEBM. Most DEBM is from mothers who have term born babies and have established lactation. Milk expressed by mothers delivering preterm infants is more concentrated in most components than term milk (the basis of most DEBM).30 DEBM therefore is often low in nutrient composition (particularly protein) compared to preterm MEBM. There is also known to be variation in the milk produced by different mothers, including a range of 0.6–1.4 g/dL for total protein, 1.8–8.9 g/dL for fat, 6.4–7.6 g/dL for lactose and 50–115 kcal/dL for energy.31 In some countries, including the USA, milk from several donors is mixed in order to avoid extremes of nutrient composition and some milk banks set a minimum composition target.32 In the UK, the practice of not pooling might nutritionally handicap recipients of particular batches, but this issue can be circumvented to an extent by the addition of HMF.

The processes of storage and pasteurisation alter the composition of breast milk. Storage at 4°C alters composition over a few hours, and storage at −20°C (as well as cycles of freezing and thawing) does so in a more extreme way. Pasteurisation also changes the properties of milk, with decreased levels of sIgA, total IgA, lactoferrin, lysozyme, lymphocytes, lipase, alkaline phosphatase, cytokines and some growth factors (IGFs).33 Denaturation of milk components may be less with high-temperature short-time heating (72°C for 15 s), and newer techniques such as ultraviolet light and ultrasound to inactivate viruses and bacteria are being researched (w6).

The use of donor human milk remains highly variable from use not at all, to use in selected infants at highest risk, to use in all very preterm and very low birth infants.34 The literature provides little help as to whether the protective effects of breast milk apply to the whole of a baby's neonatal stay, or predominantly to the period of preterm gut adaptation. There is no consensus on how long to wait for MEBM before giving DEBM, or on the duration for which DEBM should be given if MEBM is not available.

Finally, pretreatment cannot completely negate the risk of transmission of harmful agents in DEBM. While there are no known instances of transmission of infection, there remains a very small uncertainty about emerging pathogens such as Creutzfeld–Jacob agent. Because of this as yet unsubstantiated concern, in the UK, banked milk is not pooled from multiple donors in order to restrict donor exposure.

The way forward

It is clear that there are challenges in providing human milk for preterm infants safely and in a composition similar to that provided to a suckling infant. Despite this, the multiple biological effects of human milk seem to confer significant benefit, justifying its place as the standard for feeding preterm infants. Table 1 summarises what is known and what is unknown about the use of human milk in the preterm infant. It is encouraging that a number of clinical trials looking at various important areas of uncertainty are currently registered on the Clinical Trials website (w7).

It is important that we do not think of one approach to feeding as appropriate for all preterm babies throughout their stay. Thus, it is likely that for immune modulation, fresh MEBM (as colostrum) given early is ideal with DEBM as second best, and for gut priming and advancement to full feeds, a high proportion of human milk is again beneficial. It is not clear how long DEBM should be given in preference to formula milk. It is considered best practice to try to match intrauterine rates of growth by adding fortifier if necessary if human milk is continued.

It seems best to target the use of DEBM, as a limited resource with uncertain benefits, on babies at highest risk of infection and NEC, including those of lowest gestation and those with other risk factors such as antenatal gut hypoxia. Analyses of cost and risk to benefit need to be carried out for DEBM based on data on the UK incidence of infection and NEC. National data on these outcomes (with pragmatic definitions), together with the financial burden of these morbidities, are urgently needed.

Data collected for quality assurance of preterm breast milk feeding are currently often restricted to the crude measures of the number of babies getting any breast milk and the number breastfed at discharge. There is a case to be made for collecting more detailed information, including the timing of the first MEBM feed and the proportion of MEBM in the first 14 days.35

The potential benefits of human milk are so important that we should have a more rigorous approach to quality assurance and use of this variable mixture, as with other bioactive agents used in medicine. There is, otherwise, a danger that we treat all EBM at all times as equally beneficial (w5). Perhaps we should aim towards a “milk kitchen” approach to the use of human milk with greater attention to selective use and individualised nutrient supplementation based on assaying composition as well as testing for microbial contamination and strict hygiene during handling36 (Clinicaltrials.gov trial NCT01609894).

Although the use of mother's breast milk is unlikely ever to be subjected to a randomised controlled trial, on the basis of current evidence neonatal services need to earmark resources to facilitate MEBM feeding for preterm infants and make this a quality improvement priority.

Further research on MEBM is needed to look at the timing of first administration of colostrum and the potential of giving small volumes intraorally for immune protection37 (Clinicaltrials.gov trial no NCT01443091), as well as the concept of critical exposure periods for human milk. An expensive breast milk fortifier made from human milk is marketed in USA (Prolacta Bioscience), and research is under way to see whether an apparent reduction in NEC associated with its use can be replicated.38

There is also ongoing research into how donor breast milk can be used most effectively (Clinicaltrials.gov trial nos. NCT01686477 and NCT01534481). The results of these studies will be important in informing future development of milk banks and the more equitable use of DEBM. A UK probiotic trail (the PiPs trial) is currently under way and a trial of bovine lactoferrin soon to start.39 If these treatments have a significant impact on outcome and become part of neonatal care, further review of the cost-effectiveness of milk banking will be important.