That events during critical or sensitive periods of development may "program" long-term or life-time structure or function of the organism is well recognized. Evidence for programming by nutrition is established in animals, in whom brief pre- or postnatal nutritional manipulations may program adult size, metabolism, blood lipids, diabetes, blood pressure, obesity, atherosclerosis, learning, behavior and life span. Human epidemiological data link potential markers of early nutrition (size at birth or in infancy) to cardiovascular disease and its risk factors in adulthood. However, these retrospective data cannot prove nutritional cause or underpin health policies. After 16 y, however, of ethical, randomized intervention studies of early nutrition in humans with long-term follow-up to test experimentally the nutritional programming hypothesis, we find that humans, like other species, have sensitive windows for nutrition in terms of later outcomes; for instance, perinatal diet influences neurodevelopment and bone mineralization into mid-childhood. Possible biological mechanisms for storing throughout life the "memory" of early nutritional experience and its expression in adulthood include adaptive changes in gene expression, preferential clonal selection of adapted cells in programmed tissues and programmed differential proliferation of tissue cell types. Animal and human evidence supporting nutritional programming has major potential biological and medical significance.

Programming by Early Nutrition: An Experimental Approach

https://www.perinatology.theclinics.com/article/S0095-5108(02)00011-8/pdf

Vulnerability of the developing brain. Neuronal mechanisms.

Neonatal nutrition has a pivotal role in normal child development and is of even greater importance in the sick or premature neonate. This 2006 edition includes a comprehensive account of the basic science, metabolism and nutritional requirements of the neonate, and a greatly expanded number of chapters dealing in depth with clinical issues ranging from IUGR, intravenous feeding, nutritional therapies for inborn errors of metabolism, and care of the neonatal surgical patient. Evolving from these scientific and clinical aspects, the volume highlights the important long-term effects of fetal and neonatal growth on health in later life. In addition, there are very practical chapters on methods and techniques for assessing nutritional status, body composition, and evaluating metabolic function.

Neonatal Nutrition and Metabolism

Objectives: To test whether nutrition early in20infants9 development programmes later blood pressure and whether the reported relation between low birth weight and later high blood pressure is due to poor nutrition or growth before full term. Design: Prospective randomisation of preterm infants to early diets differing greatly in nutrient content in four parallel multicentre trials, with blinded follow up 7.5-8 years later. Setting: Neonatal units at Cambridge, Ipswich, King9s Lynn, Norwich, and Sheffield. Subjects: 758 children weighing under 1850 g at birth. Main outcome measure: Blood pressure at age of 7.5-8 years. Results: There were major differences in nutrient intake from randomised diets (preterm formula v standard formula and preterm formula v donor breast milk; in each case with or without mother9s milk), but follow up showed no differences in later blood pressure. Individual subjects showed large variation in protein and energy intakes and in growth performance, including degrees of growth failure seldom seen in utero, but these factors were also unrelated to later blood pressure. Conclusion: Extremes of nutritional intake and growth performance in preterm infants do not programme later blood pressure at 7.5-8 years of age. These findings do not support the hypothesis that high blood pressure has early nutritional origins. We suggest that the long term rise in blood pressure reported in individuals who had low birthweight (at full term) is not, as previously speculated, due to poor fetal nutrition or growth as such.

/pdf/does-early-nutrition-in-infants-born-before-term-programme-2sailc3hee.pdf

Does early nutrition in infants born before term programme later blood pressure

Background
Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly variable, and inadequate to support rapid infant growth. This is a 2018 update of a Cochrane Review first published in 1999.

Objectives
To determine whether protein-supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes, without significant adverse effects.

Search methods
We used the standard search strategy of Cochrane Neonatal to search CENTRAL, MEDLINE via PubMed, Embase, and CINAHL (February 2018). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials.

Selection criteria
Published and unpublished RCTs were eligible if they used random or quasi-random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation.

Data collection and analysis
Two review authors independently abstracted data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta-analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed-effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses.

Main results
We included six RCTs, involving 204 preterm infants. Low-quality evidence showed that protein supplementation of human milk increased in-hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). There was no evidence of a clear difference in rate of growth of skin fold thickness between the supplemented and unsupplemented groups (triceps MD 0.06 mm/wk, 95% CI –0.09 to 0.21; one RCT, 20 infants; or subscapular MD 0.00 mm/wk, 95% CI –0.17 to 0.17; one RCT, 20 infants). Protein supplementation led to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low-quality evidence), and higher blood urea nitrogen concentrations compared to the unsupplemented group (MD 0.95 mmol/L, 95% CI 0.81 to 1.09; four RCTs, 81 infants; I² = 56%). Very low-quality evidence did not show that protein supplementation clearly increased the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants), or clearly altered serum albumin concentrations (MD 2.5 g/L, 95% CI –5.66 to 10.66; one RCT, 11 infants), compared with the unsupplemented groups. No data were available about the effects of protein supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes.

Authors' conclusions
Low-quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short-term growth. However, the small sample sizes, low precision, and very low-quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low-resource settings, as none of the included studies were conducted in these settings.

Since protein supplementation of human milk is now usually done as a component of multi-nutrient fortifiers, future studies should compare different amounts of protein in multi-component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long-term growth, body composition, cardio-metabolic, and neurodevelopmental outcomes.

Fat supplementation of human milk for promoting growth in preterm infants

The effects of two extremes of dietary intake on protein accretion in preterm infants.

After several decades of intensive research into feeding preterm infants, it is important to question why there is persisting uncertainty over their dietary management. The evolution of scientific investigation in this field is compared with that in other areas of clinical science, where a three-phase pattern emerges: phase 1, reports of anecdotal observation and clinical experience; phase 2, epidemiological observation and physiological experiment; and phase 3, controlled prospective trials of specific interventions on clinical outcome. It is argued that research into feeding preterm infants has not evolved beyond physiological experiment (phase 2) and that the absence of clinical outcome data (phase 3 research) explains major uncertainties in clinical practice. Data from a large randomized multicentre outcome study of preterm nutrition are used to demonstrate how the wealth of previous and current 'physiological' information cannot be used satisfactorily to predict desirable clinical outcome responses to early diet.

Does Diet in Preterm Infants Influence Clinical Outcome

The multiplicity of dietary regimes available for low birthweight infants is a measure of clinical uncertainty in this field. The reasons for this persisting uncertainty are analysed: few studies have examined whether early diet matters in terms of clinical outcome; instead, management decisions have been based on short-term ‘physiological’ studies on nutrient accretion, growth and metabolism. Data from this Unit's multicentre outcome trials on nearly 1000 preterm infants, randomly assigned to early diet, are used to demonstrate that whilst diet influences many aspects of the infants ‘physiology’ in the short term, such physiological responses have limited value in predicting clinical outcome. Preliminary data from the early follow-up of this cohort to 18 months post-term suggest that the diet used in the neonatal period may have persisting consequences in terms of motor and mental development and growth. The longer-term significance of these findings is being investigated.

Alan Lucas

Papers

The effects of two extremes of dietary intake on protein accretion in preterm infants.

Does Diet in Preterm Infants Influence Clinical Outcome

Does it matter how we feed premature babies