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

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СКАЧАТЬ of breast milk is significantly lower than previously thought [14], and this is one reason why infant formulas have substantially higher protein content than breast milk.

Thus, as a result of flawed methodology for breast milk compositional analysis, a generation of babies were fed on formulas modeled on EBM composition unphysiologically high in fat, energy, and protein. This constituted in an inadvertent experiment in early overfeeding, and animal studies since the 1960s show early overfeeding increases later cardiovascular risk factors [15].

      The higher nutrient intake of the formula-fed infants is believed to be a major factor in the faster early growth of formula- rather than breastfed infants. So, does it matter that formula-fed babies grow faster? In 2004, based on our nutritional intervention trials and animal evidence, we published our postnatal growth acceleration hypothesis, which proposes that faster early growth increases the risk for later obesity and CVD [15]. In that publication, the known increased risk of obesity and cardiovascular risk markers with formula feeding was proposed to relate to the faster growth rate. Since then, over 60 studies, including randomized trials, have supported the postnatal growth acceleration hypothesis.

      Thus, flaws in research on breast milk composition were indirectly partly responsible for the major modern epidemic of CVD and obesity – a salutary example of the importance of methodology in science. The field has now become a priority for research on both breastfeeding and formula feeding.

      The Benefits of Breastfeeding Revisited

      Arguably, the main platform for the global promotion of breastfeeding is the scientific evidence for its clinical benefits. However, with few exceptions, the comparison of breast- and formula-fed babies has not been based on randomized trials that would prove causation, but rather on observational associations.

Initially, the main outcomes of interest were infection and cognition, but these outcomes are potentially highly confounded by the differences in the populations (statistically) that choose to breastfeed or formula feed. As an example, cognitive benefits in breastfed babies have been described in a number of studies since 1929, but in 2006, Der et al. [16] concluded from a meta-analysis and study of sibling pairs that there was no cognitive benefit due to breastfeeding, and the previous positive findings were explained by the higher maternal IQ in those who chose to breastfeed. This study emphasizes the ever-present potential for confounding in epidemiological studies where there are major demographic differences between the groups compared, though the study by Der et al. [16] was also nonrandomized.

Today, a wide variety of beneficial outcomes has been linked beneficially to breastfeeding [17], including CVD and obesity risk, atopic disease, IQ, brain size, infection, cancer, sudden infant death, celiac disease, and type I and II diabetes – but again these beneficial outcomes have only been epidemiologically associated with breastfeeding and not determined experimentally, leaving uncertainty over causation.

      The challenge then is how better-quality evidence can be obtained, given the constraint that randomized trials, for instance comparing the outcome of breastfeeding versus formula feeding, are generally precluded on ethical grounds.

      The Preterm Infant as a Model

      The area I shall focus on here is the use of the preterm infant as a model. Whilst accepting that the spectrum of diseases and the sensitivity to early nutrition is somewhat different in preterm and term infants, neonatal care is an area where it has been ethically possible to conduct numerous strictly randomized trials of EHM feeding versus exposure to CM. My argument is that if a wide range of important outcomes in preterm human infants are favorably impacted by HM feeding, this would indicate that the weaker observational data on the benefits of breastfeeding in full-term infants are more likely to be causal – especially when the same outcomes (e.g., infection, allergy, cardiovascular risk, or cognitive development) can be studied in both the preterm and term populations.

      Preterm Trials Comparing Exclusive Human Milk Feeding versus Exposure to Cow’s Milk

      There are 3 categories of randomized controlled trials (RCTs) that provide evidence on the benefits of HM or adverse impact of CM.

1. Historical trials [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 СКАЧАТЬ