Approximately 60,000 babies are born prematurely (<37 weeks) in the UK each year. While most are born late preterm (34 -37 weeks), around 10,000 babies are born very preterm (<32 weeks’ gestation) (1). Preterm babies often need neonatal intensive care and prolonged hospital stay. While survival rates of extremely preterm (<28 weeks) infants have notably improved over the past two decades, death is still relatively common (2, 3), with late onset sepsis (LOS) and necrotising enterocolitis (NEC) being the most prevalent (4). Preterm infants are at significant risk of long-term complications such as retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD) and cognitive impairment (3). Nutritional management impacts on short and long-term neonatal outcomes (5) but remains challenging as macronutrient intakes can sometimes be hard to meet. (6).
Mother’s own milk
Mother’s own milk (MOM) provides the basis of the optimal diet for preterm babies (7) due to the composition of key proteins and lipids, but also because it provides hormones, enzymes, growth factors and other unique and dyad-specific bioactive nutrients such as human milk oligosaccharides (HMOs) which facilitate early colonisation of the gut and may reduce NEC. Use of MOM is associated with decreased risk of major neonatal morbidities such as NEC, LOS, ROP or BPD (8-11), and this effect is dose-responsive (12). Whilst an exclusive MOM diet has been associated with slower growth in very low birth weight (VLBW) infants compared to growth with PF use (13, 14), cognitive, cardiac and metabolic outcomes are better in the first year (15, 16) and throughout the life-course (17, 18).
Challenges of expressing MOM and breastfeeding in NICU
Despite strong evidence about the benefits of MOM, low breastfeeding rates remain a major health concern. Over 90% of mothers now provide at least some breastmilk after preterm delivery, but breastfeeding rates at discharge for preterm infants vary considerably from 19-70% across Europe (19). In addition to the challenges many women experience when breastfeeding, mothers of preterm babies may also be unwell, they must cope with the stress of having a preterm, often sick infant who is physically separated from them from birth, and they need to maintain breastmilk expression for several weeks. Furthermore, the initiation of lactogenesis is often impaired after preterm birth (20, 21). Delayed initiation, first expression of colostrum more than 6 hours after delivery, is associated with three-fold decrease in milk volumes at 3 weeks postpartum (22).
In view of these challenges, effective support and counselling for mothers who express milk in the NICU is vital. Assessment tools have been developed to identify mothers who are at risk of discontinuing breastfeeding early, but most are only validated for term infants and their reliability varies (23). Despite targeted support, shortfall of MOM is common in neonatal intensive care units ( NICU)s with more than 80% of infants requiring additional milk at some point (1).
Donor Human Milk
The World Health Organisation, American Association for Pediatrics and European Society of Paediatric Gastroenterology, Hepatology and Nutrition recommend the use of donor human milk (DHM) for feeding premature infants as a first alternative when there is a MOM shortfall (7, 24, 25), despite the relatively lack of high-quality RCTs and the heterogeneity of many studies. A recent Cochrane review suggested that DHM may reduce risk of NEC compared to PF, with at least 33 infants needing to receive DHM to prevent one NEC case. The data do not support a reduction in mortality or longer-term neurodevelopmental benefits, and many studies were noted to have been conducted more than 20 years ago. (26). Zipitis et al. demonstrated differences in DHM use amongst UK NICUs (27), with some only providing DHM for the first 10 days of a baby’s life whereas other units use DHM until closer to discharge. Battersby et al. showed that variation between NICUs is not related to the presence of a local milk bank and is most likely linked to uncertainties around DHM use (28).
One key uncertainty is whether DHM affects duration of breastmilk expression or breastfeeding. A systematic review of 10 studies showed that DHM may have a positive impact on any breastfeeding but does not appear to affect rates of exclusive breastfeeding on discharge (29). A large observational study analysing DHM availability in 56 NICUs in the USA showed positive effects on breastfeeding in NICUs where a DHM programme was implemented, along with a decrease in NEC rate (30). A historical cohort comparison study pre- and post-DHM introduction demonstrated increased breastfeeding at discharge and increased consumption of MOM (31). In contrast, another single-centre retrospective study showed that MOM provision decreased over a two-year period following the implementation of a donor milk program where preterm infants consumed less MOM in the first 14 days in the post-DHM cohort. (32). Esquerra-Zwiers et al. showed similarly reduced exclusive MOM use in the first two weeks of life with DHM availability compared to a pre-DHM cohort. However, in these studies enteral feeds were commenced earlier, and infants were exposed to formula later in life in after DHM introduction (33). Tshamala et al. also reported earlier start of enteral feeding and unchanged proportion of infants fed exclusively with maternal breastmilk at discharge after implementation of a DHM programme (34). More recently, Mondkar et al. showed that DHM use in addition to optimising breastfeeding support and kangaroo care led to improved exclusive human milk feeding (35).To date, no RCT has studied the relationship between donor milk availability and breastfeeding at hospital discharge.
Preterm formula
The composition of PF is designed to meet the high nutritional demands of the preterm infant. This has resulted in improved weight gain, linear growth, and head growth of preterm infants (26). However, no RCTs have shown improved long-term growth or neurodevelopmental outcomes compared to use of MOM or DHM (26, 36). PF may provide a more consistent delivery of macro- and micro-nutrients but lacks non-nutritive content, so called bionutrients or immunonutrients, which might be key in reducing disease (e.g. NEC), establishing diverse gut microbiota and improving long-term outcomes (37, 38). The cost of PF (around £5 per litre) is almost 30-fold lower than the cost of DHM (between £125-150 per litre). However, if supplemental DHM feeding prevented NEC, total costs for hospitalisation would favour DHM compared to PF use in case of MOM shortfall (39, 40).
Summary of key issues: donor human milk as a 'complex intervention’
In summary, MOM is the optimal source of nutrition for preterm infants. Despite this evidence, breastfeeding rates in the UK are amongst the lowest in the world (41), and breastfeeding rates in the North East of England are some of the lowest in the UK (42). This is also reflected in breastmilk feeding of premature infants. Currently, around 90-95% of mothers in the North East start expression of breastmilk for their preterm baby, but only 35% are still providing breastmilk at discharge compared to the national average of 60% (42). Improving availability of MOM in NICUs is crucial to reducing key neonatal morbidities. The use of DHM is increasing in most UK neonatal units and is recommended by ESPGHAN when there is a shortfall of mother’s own milk, largely because meta-analysis suggests a lower rate of NEC (26). However, because DHM also affects growth, which may in turn be associated with longer term brain and metabolic outcomes, the optimal strategy for improving lifelong health remains uncertain. Observational data show that availability of DHM impacts on breastmilk expression and breastfeeding duration demonstrating that DHM affects beliefs and behaviours of mothers, healthcare staff or perhaps both, and DHM is therefore a ‘complex intervention’. Complex interventions in healthcare impact on biology (i.e. health and disease), behaviour and belief (e.g., breastfeeding rates). They may have multiple relevant outcomes and mechanistic causal pathways; and may be affected by context e.g. NICUs with differing background rates of NEC or breastfeeding. There is often long lag time between intervention and outcome (metabolic and cognitive outcomes in adulthood) (43).
Provision of DHM may be the best example of a complex intervention in neonatal medicine, and uncertainties around the optimal strategy are unlikely to be resolved with a single RCT. However, this trial could lay foundation for further trials to investigate the optimal implementation and use of DHM (Figure 1).