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Long-Term Programming Effects of Early Nutrition — Implications for the Preterm Infant

Abstract

The current focus of nutritional science has shifted from meeting needs to determining the biological effects that nutrition has on immediate and lifetime health. Of particular interest is the concept of programming, the idea that “a stimulus or insult during a critical or sensitive period of development can have long-term or lifetime effects on an organism.” Evidence that early nutrition has such “programming” effects in animals is overwhelming. In humans, retrospective observations show a relationship between adult disease and size in early life, though it is difficult to prove nutritional cause from observational associations and therefore difficult to use such data to underpin health policy. However, the results of randomized intervention trials of early nutrition with long-term follow-up are emerging. These experimental studies show that nutrition in early life has a major impact on health into early adulthood, notably on cardiovascular disease risk, bone health and cognitive function. These new findings have major biological, social and medical implications and should increasingly underpin health practices.

INTRODUCTION

Previously, the focus of nutrition in early life was on meeting nutritional needs. Now, a major focus of nutritional science is health. In this regard, there are two key questions: does nutrition matter in terms of the patient's response to disease and does it matter for long-term health and development?

Nutrition and Response to Disease

An illustration of the concept that nutrition influences a patient's response to disease is the relationship between consumption of human breast milk in the NICU and co-morbidities in preterm infants. For instance, consumption of human breast milk, in comparison to formula, may significantly reduce the incidence of necrotizing enterocolitis (NEC) — in one large study in preterm infants <1850 g, from 7.2% in those exclusively fed formula to 1.2% in those exclusively fed human milk.1 The relationship was most dramatic in infants above 30 weeks gestation, where other risk factors become less common. For this subgroup, the breast milk-fed group had an incidence of NEC 1/20 of that seen with formula feeding, and in a further, UK national survey of NEC, a reduced mortality of 5%, compared to 26% in the formula fed group (unpublished).

These findings are cited simply to illustrate an important concept: the benefit of breast milk here was not nutritional, but rather it was due to its biological effects in influencing health outcome. Such biological effects become even more relevant when we examine the impact of nutrition on long-term health and development.

Long-Term Health and Development

The term “programming” refers to the concept that an insult or stimulus applied at a critical or sensitive period may have long-term or lifetime effects on the structure or function of an organism.2 Programming may occur as a result of internal signals or environmental factors, including hormones or drugs.2, 3

McCance was the first to demonstrate, in animals, that early nutrition could also have lifetime “programming” effects.4 Since his studies 40 years ago, numerous studies in animals have shown that nutrition in early life can influence, in adulthood, such outcomes as blood lipids, blood pressure, body fatness, atherosclerosis, behavior, learning and longevity.5, 6, 7, 8 These programming effects have been seen in a number of species, including non-human primates. For example, Lewis7 demonstrated the ability to program obesity in baboons by overfeeding them in infancy. The baboons became temporarily overweight during the overfeeding period, then remained normal weight throughout “childhood,” but became fat in adolescence. This study is important in demonstrating the later emergence of a programmed effect (see later).

Nutritional Programming in Humans

Animal studies are advantageous in that they have a controlled experimental design, but the potential disadvantage is that it is not always possible to compare across species. Therefore, human studies are needed. These may be observational or experimental. Retrospective observations allow a rapid study of major clinical end points in relation to markers of early nutrition.9 However, they cannot be used readily to prove causation or underpin practice. Consequently, there is a need for intervention trials to explore the issue of nutritional programming in humans. Such trials require long-term follow-up, but in return they provide an experimental design, proof of causation and underpinning of practice. Human intervention trials have been used to explore the long-term programming effects on brain development, bone health and risk for cardiovascular disease10, 11

Programming and Brain Development

Numerous studies have investigated the impact of early diet (e.g. breast-feeding12, 13) and malnutrition14, 15 on later cognition. However, these studies tended to be observational and confounded by other differences between the groups. More recently, randomized trials of early nutrition have been conducted. In the early 1980 s, researchers investigated whether early nutrition, at a critical or sensitive stage in the development of the brain, could have lifetime consequences in cognitive functioning for preterm infants.16 The possibility was explored by studies comparing cognitive functioning in preterm infants fed enriched formula to those fed standard formula. The followup showed that at 7.5 to 8 years of age, preterm infants fed standard formula demonstrated neurocognitive impairment with a significant reduction in IQ and a major 13-point reduction in verbal IQ in comparison to the infants fed enriched formula11 (see Figures 1a, b). Unpublished data show that these effects persist when tested in adolescence and early adulthood.

Figure 1
figure1

(a) Preterm infants randomly assigned for on average their first 4 weeks to a standard versus nutrient-enriched preterm formula (1980s; when standard formulas were often used). The data show that in the more vulnerable male, those fed the standard formula had a major reduction in overall IQ and a 12 point reduction in verbal IQ 7 to 8 years later (96% fallow-up rate). (b) Infants randomly assigned to diet as above, at 7 to 8 years (both sexes combined). Those fed the standard formula in the neonatal period had a major increase in ‘neurocognitive impairment’, defined here as either motor impairment or moderate (or worse) impairment of IQ (scores <85).

In addition, scientific tools such as magnetic resonance imaging now make it possible to demonstrate that specific aspects of long-term brain structure are influenced by early dietary insufficiency (unpublished data).

Programming and Bone Health

A large cohort of premature infants was randomly assigned to early diet, and a variety of structural and functional bone indices were studied in later childhood. Results suggest that infants fed a standard formula in the first month had, by late childhood, a major increase in bone formation.17 An increase in bone formation and turnover is one of the features of adult degenerative bone disease, raising the hypothesis that optimal early nutrition is important for reducing the risk of later degenerative bone disease.

PROGRAMMING OF CARDIOVASCULAR DISEASE

For the brain and bones, meeting early nutritional needs and promoting growth appear to have favorable programming effects. For programming the risk of cardiovascular disease, the major cause of mortality in the West, different principles appear to apply. Cardiovascular risk may be programmed both pre- and postnatally — the latter is considered first.

Postnatal Programming

In distilling the evidence for nutritional programming of later cardiovascular disease risk, there appears to be two important influences: breast milk and postnatal growth.

Breast Milk and Later Cardiovascular Health

Breast-fed infants have been shown in observational studies to have lower risk of cardiovascular disease, hypercholesterolemia, obesity, Type II diabetes and high blood pressure.18, 19, 20, 21 These data could be confounded by socio-biological differences between breast-fed and formula-fed groups. However, a causal relationship has been testable in preterm infants.22, 23, 24, 25 Here, it has been possible to take infants whose mothers had elected not to provide breast milk and randomly assign them to human milk from a milk bank (donated by lactating mothers unrelated to the subject) or formula.22, 23, 24, 25

In such trials, those fed human milk, with as little as 1 month (on average) intervention period, had lower blood pressure, LDL cholesterol, “leptin resistance” (possible tendency to later obesity) and insulin resistance.22, 23, 24, 25 These effects were seen at 13 to 16 years post-intervention on prospective follow-up. The effect sizes were large (see below), comparable to or greater than nonpharmacological interventions to affect these risk factors in adulthood.10

As further evidence of causation, exploratory analyses of these trials showed clear dose–response relationships for these outcomes: the greater the breast milk intake in the neonatal period, the lower the risk factor status in adolescence.

Thus, while the observational data may still be challenged as inconclusive, the combination of such evidence with that from formal intervention trials in preterm infants provides compelling overall evidence that breast milk feeding reduces risk of the metabolic syndrome.

Impact of Rapid Postnatal Growth

The trials on preterm infants, cited above, compare infants fed unsupplemented human milk versus enriched (preterm) formula, and also, in parallel, a standard formula versus enriched formula. These studies provide experimental evidence that diets promoting faster neonatal growth increase later cardiovascular risk.22, 23, 24, 25 That is, the infants who were fed growth-promoting enriched diets had greater risk of developing key components of the metabolic syndrome at follow-up.

This finding was not just a feature of prematurity: infants born full term but small for gestation, who were randomly assigned to a growth-promoting formula, had higher diastolic blood pressure 6 to 8 years later than those assigned to standard formula.10

Results of further analyses of these studies on preterm and term infants suggested that it was indeed the growth acceleration that explained the adverse effects of a nutrient-enriched diet on later insulin resistance and blood pressure.22, 24

Postnatal Growth Acceleration Hypothesis

These findings led to a proposed “postnatal growth acceleration hypothesis” as a key to the early programming of cardiovascular disease.10.Consistent with this, later insulin resistance was found greatest in infants born preterm with accelerated growth in the first 2 weeks,24 the period of fastest postnatal growth, and least in those who grew at a rate lower than that normally targeted (the intrauterine growth rate). Such growth was associated with greater endothelial dysfunction (reduced flow-mediated dilatation of the brachial artery) in adolescence.26 Thus, early growth acceleration programmed abnormal vascular biology associated with early atherosclerosis, whereas slower early growth was beneficial (Figure 2).

Figure 2
figure2

Flow-mediated endothelium dependent dilatation of the brachial artery, as an early indication of the atherosclerotic process, in three groups; left and middle: adolescents born preterm (mean gestation 31 weeks) divided into two equal groups: those growing slowest in neonatal period (left) and those growing fastest (middle): right-hand group: healthy adolescents born at term. Those who had the slowest growth in the neonatal period (left) had the best vascular health in adolescence.

These findings are consistent with previous animal data showing that a higher plane of early postnatal nutrition and faster growth program propensity to the metabolic syndrome. Indeed, adverse long-term health effects of early growth acceleration emerge as a fundamental biological phenomenon across animal species.27 Thus, growth acceleration during sensitive windows reduces fat deposition in Atlantic salmon, lowers resistance to starvation in speckled wood butterflies, impairs glucose tolerance and lifespan in rats, and reduces cardiovascular disease risk in non-human primates.

Furthermore, in humans, others have shown that childhood growth acceleration is associated with later insulin resistance, obesity and CVD.28, 29 However, growth acceleration is greatest in early infancy, suggesting that this period may be most critical. Indeed, early growth acceleration is associated with later obesity and dyslipidemia raised concentrations of insulin in infants small for gestation. This hypothesis predicts that a high nutrient intake, which promotes early growth, would adversely program cardiovascular health. Several observations, in addition to the trials cited above, support this prediction. For instance, greater nutrient intake in infancy is associated with raised blood pressure in adults.30

An important public health inference from the postnatal growth hypothesis is that the observed advantages of breast-feeding cited above may be due to the slower early growth of breast-milk-fed infants.10

Fetal Programming

Prenatal programming has less immediate relevance to routine clinical care since it is more difficult to manipulate nutrition in the fetus. While animal studies show sensitivity to programming in fetal life,31, 32 this has been harder to approach in humans, with few randomized trials, though work actively continues in this area. Most evidence is retrospective and observational and often relies on proxy measures for early nutrition, such as size at birth. It is also unclear how the observed relationships between small size at birth and later cardiovascular disease risk9 can be translated into practice recommendations. Moreover, the published evidence on cardiovascular risk suggests that the long-term effects of postnatal nutritional intervention appear of substantially greater magnitude than for, say, birth weight. Nevertheless, the cumulative evidence that the intrauterine environment is important for later outcome is large. Furthermore, programming may be seen as a continuum of influences, with each stage in development having importance for the next. Although not a focus of this article, investment in the study of fetal biology is important for our understanding of early influences on later health and development.

Programming Principles

Against this background, I shall consider three further issues that are important in the context of programming — the timing of the programming window, the timing of the emergence of the programmed effects and, finally, the size of the effect.

(1) Timing of the programming window: Studies on preterm and full-term infants suggest that the effect size of nutrition on cardiovascular risk factors is similar in both term and preterm infants, suggesting that birth, at any gestation, sets the organism for subsequent, postnatal sensitivity to cardiovascular programming.10, 22 In contrast, current evidence suggests that, for the brain, gestation is more critical and that those born more immature are more vulnerable to the neuro-cognitive programming effects of nutrition than those born beyond term.11, 33 The duration of such windows of sensitivity have not yet been defined.

(2) Emergence of the programmed effect: Programmed effects may be detected early. Effects of growth acceleration on increased insulin resistance may be detected within the first year (unpublished). In contrast, and in keeping with studies in baboons,7 above, programmed effects may not emerge until much later. For instance, the benefits of breast milk for later blood pressure were not seen in one study at 7 to 8 years, but were detected in adolescence.22 Moreover, some effects might amplify into adulthood. The potential for late emergence of programmed effects has important implications in terms of the need for long-term follow up, not only to detect efficacy but also the safety of early nutritional intervention.

(3) Size of the effect: How important are the effects of nutritional programming? The effects of early nutrition on subsequent IQ or verbal IQ have been large, in some studies reaching 12 to 15 quotient points, which would have a large population impact.11 The effect on cardiovascular risk factor is sufficient to have a major impact on health of Western populations. The impact of early nutrition in randomized trials on later blood pressure is around 4 mmHg, an effect size which, if applied to the US population as a whole, would be expected to affect the rate of strokes and coronary artery events by around 150,000 cases year.22 A 10% lowering of later LDL cholesterol with breast-feeding would, in adults, reduce cardiovascular disease by around 25% and mortality from it by around 14%.23 Thus, early nutrition emerges as one of the most important factors that can be manipulated in clinical and public health practice.

CONCLUSIONS

Based on 40 years of animal and human research, it is becoming increasingly clear that nutrition in early life has an important impact on long-term health and development. Interestingly, it appears from the evidence above that early programming influences have quite different effects on different systems. Thus, in preterm neonates, while early growth promotion might favor the brain, it appears less advantageous for later cardiovascular risk. Simultaneous risks and benefits exist for many therapeutic interventions in medicine (e.g. drug therapy) and, clearly, in appraising the value of a public health or clinical intervention, a balancing of risks and benefits is needed. Thus, while slow growth (below the intrauterine rate) has some benefit for later cardiovascular outcome, it risks under-nutrition and its adverse consequences, and has a profound adverse effect on later cognition. Currently, the balance of risks favors the brain and preterm infants should be fed with specialized products to support rapid growth (at least at the intrauterine rate). On the other hand, for full-term infants, in whom the brain may be less sensitive, this balance of risks may be different, and it has become a priority to define optimum growth in healthy full-term infants in terms of their later outcome.

This emerging knowledge on the later effects of early nutrition raises a new level of responsibility among those involved in clinical care to consider more broadly the impact of nutritional practices. Products such as specialized and standard infant formulas, which all meet nutritional needs, now have the potential to affect health outcomes differentially, for instance, according to their content of bioactive ingredient such as long-chain polyunsaturated fatty acids or nucleotides. Thus, health-care professionals must now carefully assess efficacy and safety data on products that they use. Counseling of parents on nutrition should also now begin to include information on what we know about the outcome effects. It is clear that nutrition can no longer be considered simply in terms of meeting nutritional needs.

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Correspondence to Alan Lucas MB, MD.

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This research was supported by Farleys, Mead Johnson Nutritionals, Nutricia, Ross Labs, Wyeth Pharmaceuticals.

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Lucas, A. Long-Term Programming Effects of Early Nutrition — Implications for the Preterm Infant. J Perinatol 25, S2–S6 (2005). https://doi.org/10.1038/sj.jp.7211308

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