Human Milk: Composition, Clinical Benefits and Future Opportunities. Группа авторов

18] comparing EHM feeding versus CM-based products (used either alone or in combination with HM). In these trials, the HM arm received no CM since this was the era before the development (in the later 1980s) of CM-based breast milk fortifiers. The largest of such trials was by Lucas et al. on over 500 infants but at least 5 other smaller RCTs of this nature were done by other investigators.

2. The historic fortifier trial of Lucas et al. [19] tested the clinical impact of adding CM-based fortifier to breast milk versus no fortification (which was ethical at this time when fortifiers were just being introduced into practice).

3. A third RCT category has a long history, as explained here. In the late 1970s, the first evidence began to emerge that HM protected against necrotizing enterocolitis (NEC) and sepsis. However, extensive research showed that HM alone did not meet the needs of preterm infants for protein and other nutrients needed to fuel the rapid growth of the preterm infant, notably the growth and development of the brain. In response to this, CM-based special preterm infant formulas were devised in the 1970s (CM-based HM fortifiers came later in the 1980s) – but by the late 1970s evidence began to accumulate that CM products had adverse effects. In response to this, Lucas et al. [20] developed the concept of lacto-engineering whereby donor breast milk (DBM) was separated and reconstituted to produce HM-based formulations enriched in HM protein and fat that met nutritional needs of preterm infants and allowed total exclusion of CM. The HIV epidemic in the 1980s closed down HM banks, but with the more recent re-emergence of milk banking the opportunity arose for commercial production of HM-based fortifiers and preterm formulas allowing preterm infants to receive an exclusive HM (EHM)-based diet. In the USA, many level 3 or 4 neonatal intensive care units have used these HM-based products providing a new opportunity to do RCTs and quasi experimental studies comparing current practice using diets containing CM versus feeding an EHM diet with these modern lacto-engineered products.

      Necrotizing Enterocolitis and Systemic Sepsis

In term infants, breastfeeding is associated epidemiologically with significant reduction in infection. In preterm infants, more serious infective/inflammatory conditions – notably NEC and proven systemic sepsis – are common, and RCTs and related studies can be used to test the impact of HM versus CM as a model. At least 7 RCTs including trials from the prefortifier era [18] and 2 trials of lacto-engineered products examined the impact on NEC [21, 22]. In all, 6 trials of HM/CM exposure were included in a Cochrane meta-analysis [18]. Collectively, the RCTs show around a 3-fold increased risk of NEC with CM exposure. Further to this, at least 8 quasi-experimental studies have been done on around 4,000 (published in full [23] or in abstract form) that examine the impact of introducing an EHM diet with lacto-engineered products; the incidence of NEC was on average 3 times higher when infants were exposed to CM compared to those fed the EHM diet. With regard to sepsis, 3 historic RCTs from India showed exposure to CM increased the risk of major infection [24]; and the quasi-experimental study on 1,600 babies before and after introducing an EHM diet using lacto-engineered products showed a major fall in the incidence of late-onset sepsis from 30 to 19% [23]. We conducted 2 further RCTs with NEC or sepsis as a combined outcome – our fortifier trial [19] and an unpublished analysis of our historic trial comparing preterm formula with DBM; in both cases, NEC or sepsis was doubled in the CM limb. The US trials on lacto-engineered products showed NEC, NEC surgery, and sepsis were dose related to the amount of CM in the neonatal diet [25], in accord with our own data from the UK [26].

      Thus, at least 12 RCTs and 8 quasi-experimental studies show that HM has a major protective effect against infective/inflammatory conditions that provide support for a causal role of breastfeeding in protecting against infection in term infants.

The clinical importance of NEC and sepsis is emphasized by the evidence that these are accompanied by an increased risk of cerebral palsy and lower cognitive performance [27].

      Mortality

      The US trials (combined) of lacto-engineered products show that death rate was 4 times higher in those exposed to CM versus an EHM diet comprising modern lacto-engineered products [25].

      Retinopathy of Prematurity

A recent RCT in Canada has been presented in abstract form based on infants with a 100% base diet of HM but randomized to a standard CM-based HM fortifier or a HM-based HM fortifier. The group exposed to the CM fortifier had a significant 6-fold increase in potentially blinding retinopathy of prematurity. In all, at least 7 further studies (5 of them included in a systematic review) showed collectively in around 4,000 subjects a major increase in retinopathy of prematurity with CM exposure compared to EHM [23, 28].

      Cardiorespiratory Impact

In a quasi-experimental 4-center study by Hair et al. [23], comparing CM exposure with an EHM diet, the EHM group had significant reductions in need for ventilation, bronchopulmonary dysplasia, and patent ductus arteriosus. Assad et al. [29] found a 73% increase in bronchopulmonary dysplasia in those exposed to CM rather than an EHM diet.

      Cognitive Development

      In preterm infants, numerous observational studies have shown that use of HM in neonatal care is associated with higher IQ or DQ but, like the studies in full-term infants, such data do not prove causation. However, the opportunity to study this using an experimental design arose with our own RCTs in neonates whose mothers had elected not to provide their own breast milk (thus eliminating the potential confounding relating to mother’ choice to provide breast milk). These two trials compared as sole diets: (i) DBM versus preterm formula (PTF), and (ii) term formula (TF) versus PTF. The first of these trials, DBM versus PTF, compared HM with CM, but the CM arm (PTF) provided much higher protein and energy intakes. Nevertheless, the HM (DBM) group was not disadvantaged in later cognitive scores, suggesting that breast milk had factors that ameliorated the poor nutrient intake. In order to remove the major nutritional difference between these groups, we elected to compare DBM from trial (i) with TF from trial (ii) since these were diets both suitable for term infants. This cross comparison of RCTs was justified since both trials used the same PTF, thus constituting an “internal standard.” The HM (DBM) group had a significant 7-point advantage in the Bayley psychomotor index compared to the TF, providing compelling experimental evidence that HM promoted better cognitive development than seen in the CM (TF) group.

This finding is consistent with a rare RCT done in term infants – the Belarus trial – a cluster RCT done on over 17,000 mother-infant pairs. The intervention in breastfed infants was active breastfeeding promotion compared with no active promotion in the breastfed control group. A significantly longer duration of exclusive breastfeeding was achieved in the intervention