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

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СКАЧАТЬ 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 We conducted 2 further RCTs with NEC or sepsis as a combined outcome – our fortifier trial [19] and an unpublished analysis of our historic trial comparing preterm formula with DBM; in both cases, NEC or sepsis was doubled in the CM limb.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 group, which showed a 7.5-point advantage in verbal IQ at 6.5 years [30].

      These two pieces of experimental evidence give weight to the view that studies that show an association between breastfeeding and superior cognitive outcome are causal.

      Cardiovascular Risk Factors

Many epidemiological studies link breastfeeding to CVD risk factors. In our large historic RCT of EHM versus CM exposure in preterm neonates, we found at the 16-year follow-up that the EHM group had favorably reduced the LDL:HDL cholesterol ratio, diastolic blood pressure, insulin resistance, and metabolic tendency to fatness (leptin resistance) [31–33]. Thus, early HM feeding in a strictly randomized trial reduced 4 key risk factors for CVD. The effect size was large; for instance, the impact of early HM feeding on later cholesterol alone would be expected in adults to reduce CVD by 25% and death by 13–14%. These data add weight to the causal nature of a protective role of breastfeeding for future obesity and CVD.

      Atopic Disease

The relationship between breastfeeding and later atopy has been observational and uncertain. In our historic RCT comparing EHM with CM exposure, those with a family history of atopy fed an EHM diet had a major reduction in eczema, food and drug reactions, and wheezing at the 18-month follow-up [34]. Thus, strict experimental evidence confirms that HM, at least in those with a family history of atopy, is protective against future development of atopic phenomena.

      Conclusion

      Clearly, the HM-fed preterm infant is not a perfect model for the breastfed term infant, and some outcomes considered above would not occur in term infants. Nevertheless, it is a very useful model and conceptually, experimental studies in preterm infants add much weight to the view that breast milk is likely to have broad and important causal effects on short- and long-term outcomes in healthy full-term infants.

      Further Models

      Given the difficulty in providing an evidence-based underpinning for the impact of breastfeeding on clinical outcome, it is important to explore creatively further opportunities for experimental studies. In this paper, I have considered the value of RCTs in preterm infants and noted the inventive Belarus study on breast milk and cognitive development in term infants. One potentially promising area is the use of RCTs to study the impact on outcome of individual components of breast milk, for instance, HM oligosaccharides.

      Overview

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