Normal fetal nutrition is a useful guide for understanding postnatal nutrition of infants born very preterm. Fetal lipid uptake gradually increases towards term and is primarily used to produce fat in adipose tissue, with essential fatty acid uptake providing necessary structural and functional elements in membranes of cells in the central nervous system. Fetal glucose uptake and utilization rates are nearly twice as high at 23–26 weeks gestation as they are at term, contributing primarily to energy production and glycogen formation. Amino-acid uptake by the fetus is two-to threefold greater at 23–26 weeks gestation than at term and is required to meet the very high fractional protein synthesis and growth rates at this gestational period; amino acids also contribute significantly to fetal energy production. In contrast, after birth most of the very preterm infants are fed more lipid and glucose and less amino acids and protein than they need. Not surprisingly, therefore, very preterm infants accumulate fat but remain relatively growth restricted at term gestational age compared to those infants who grew normally in utero, and this postnatal growth restriction has long-term adverse growth, development, and health consequences. More thorough understanding of the unique nutritional, metabolic, and growth requirements of the normally growing fetus and the very preterm infant, once born, are needed to determine optimal nutritional strategies to improve the outcome of preterm infants.
The current standard for postnatal nutrition of very preterm infants is one that meets the unique nutritional requirements of the growing human fetus and duplicates normal in utero human fetal growth and development.1 Normal fetal nutrition, therefore, may be a useful guide for designing postnatal nutritional strategies in very preterm infants who need to grow and develop outside the uterus.2 At 50–60% of gestation there is little fetal lipid uptake, which indicates that energy metabolism is not dependent on fat early in the third trimester and only gradually increases towards term. Essential lipid uptake involves the essential fatty acids, which are necessary for membrane development, particularly in cells in the central nervous system and in red blood cells. Glucose delivery to the fetus is determined by the maternal glucose concentration and occurs at a rate that reflects fetal glucose utilization for energy production. Glucose utilization also occurs at relatively low plasma insulin concentrations. Amino-acid uptake by the fetus exceeds that needed for protein accretion requirements; the excess amino acids are oxidized, contributing significantly to fetal energy production. A summary of these issues is presented in Table 1. In contrast, in the very preterm infant, lipid commonly is provided as an energy source but in amounts that exceed in utero delivery rates; glucose is administered at higher rates than the fetus receives in utero; and amino acids are delivered at low rates that are significantly less than fetal accretion rates (Table 2). Thus, there is a contrast between the nutrient supply that the normally growing fetus receives (high amino acid, sufficient glucose and lipid) and what the very preterm infant is commonly fed (high energy intakes of lipid and glucose, low amino-acid and/or protein intakes). Nutritional practices in preterm infants vary considerably and there are no definitive regimens that have been shown to safely optimize nutrition, growth, and development of these infants. Not surprisingly, therefore, very preterm infants still are relatively growth restricted at term gestational age compared to those infants who grew normally in utero,3 they continue to have short stature into childhood and adolescence,4 and they have less than normal intellectual and developmental outcomes that have been shown to be owing in part to nutritional deficiencies.5 More thorough understanding of the unique nutritional, metabolic, and growth requirements of the normally growing fetus and the very preterm infant once born are needed to determine optimal nutritional strategies for immediate metabolic needs, short-term growth, and long-term growth and developmental outcome of preterm infants.
Nutritional requirements of the very preterm infant
Normal fetal nutrition requires certain ‘nutrients’ in optimal amounts together with certain growth promoting hormones that increase in response to nutrient supply that in combination support optimal fetal nutritional metabolism, growth, and development.
Although oxygen usually is not thought of as a nutrient, insufficient oxygen does lead to growth failure by decreasing protein synthesis more than breakdown, producing a deficit in net protein balance and growth.6, 7 Preterm infants with chronic lung disease (as a general diagnosis or specifically as bronchopulmonary dysplasia) also do not grow well when chronically deficient in oxygen,8 and past studies have documented clearly that progressively more severe anemia in preterm infants leads to slower rates of growth.9 Several recent studies and reports indicate that various forms of oxygen toxicity in preterm infants might be prevented by maintaining blood oxygen concentrations in lower ranges than are customarily used, for example, PaO2 of 45–65 Torr and SaO2 (or SpO2) of 80–90%.10 These lower levels of PaO2 and SaO2 will magnify the deficit in blood oxygen content that occurs with anemia of prematurity and its potential to produce decreased rates of growth.11 New research is necessary to determine whether such lower oxygen levels, or in fact, whether the normal fluctuations in oxygen levels into the lower portion (80–90%) of the conventional SaO2 range that occur in all infants, especially those born preterm and suffering respiratory distress syndrome and chronic lung disease, affect metabolism sufficiently to limit the synthesis of amino acids into protein and thus the rate of growth of these vulnerable infants.
The very preterm infant has relatively high energy requirements, because of the relatively large body proportions of metabolically active organs, including the heart, liver, kidney, and especially the brain that are present at this early stage of development.12, 13 Thus, the very preterm infant requires a large and continuous supply of glucose for energy metabolism. Because glycogen content is relatively limited in the very preterm infant, unless glucose is supplied directly, glucose deficiency and hypoglycemia commonly develop in these infants.
Minimal glucose intakes
The minimal glucose requirement has been measured directly in fetal sheep – about 7–9 mg/min/kg at the start of the third trimester.14 Similar rates of glucose utilization have been estimated from endogenous glucose production rates in the stable very preterm infant with sufficient glycogen stores.15 Glucose needed to support protein deposition adds an additional requirement of ∼2–3 mg/min/kg.16 If there is no endogenous glucose production, the appropriate starting intravenous glucose infusion rates into preterm infants, therefore, would vary from as high as 9–10 mg/min/kg at 24–25 weeks gestation to 6–7 mg/min/kg in infants at 27–32 weeks gestation, to 3–5 mg/min/kg at term. These rates should be adjusted downward (e.g., to 5–7 mg/min/kg in the very preterm infant) in response to the frequent complication of hyperglycemia in relatively unstable infants who have large rates of hepatic glucose production (see below); they also should be adjusted downward as enteral nutrition increases. In both cases, frequent measurement of plasma glucose concentration is necessary to guide glucose infusion rate.
Appropriate glucose concentrations
Normal fetal glucose concentrations are not less than about 3 mM (∼54 mg/dl) over the second half of gestation.17 Thus, it is reasonable to assume that to grow a normal very preterm infant to normal size and with normal metabolism and development, the infant should have a glucose concentration above 3 mM (∼54 mg/dl) most of the time. This assumption has not been tested, but needs to be, as a retrospective study by Lucas et al. indicated that neurodevelopment was progressively impaired in preterm infants with an increasing number of days in which they had recurrent low glucose concentrations (<2.6 mmol/l [47 mg/dl]).18 The upper limit of the normal glucose concentration has not been defined in preterm infants, although most references use the value of 120 mg/dl (6.7 mmol/l). Hyperglycemia is relatively common among very preterm infants, particularly those who are either small for gestational age (from intrauterine growth restriction) or stressed at birth. Such hyperglycemia appears to result primarily from high glucose infusion rates coupled with endogenous glucose production in response to stress-reactive hormones, especially epinephrine, norepinephrine, and glucagon, as well as cortisol somewhat later in their course. Catecholamines inhibit insulin secretion and diminish insulin's action to promote glucose utilization in peripheral tissues. Along with glucagon and cortisol, they also increase rates of glycogen breakdown and promote proteolysis and the release of amino acids that then are available for increased rates of gluconeogenesis. Catecholamines also promote lipolysis; free fatty acids, produced either from such lipolysis or from intravenous lipid infusion, have been shown to enhance glucose production by inhibiting insulin's normal suppression of hepatic glucose production as well as by providing cofactors from their own metabolism in the liver (NADPH, NADH, ATP) that are essential for promoting gluconeogenesis. Fatty acids also contribute to hyperglycemia by providing their own carbon for tissue oxidation, thus limiting glucose carbon oxidation. Glucagon also activates phosphoenolpyruvate carboxykinase (PEPCK), the rate limiting step for gluconeogenesis. Cortisol activates the activity of glucose-6-phosphatase, the enzyme that releases glucose from the liver into the circulation. Whereas such natural mechanisms appear to have a positive value in providing glucose to the brain and heart immediately after birth when glucose supply from the placenta stops, their persistence is inappropriately enhanced by persistent stress and exogenous catecholamine and hydrocortisone treatments of cardiac failure and lung inflammation, respectively. Whereas there has been considerable discussion about possible adverse effects of hyperglycemia, definitive conclusions have not been rigorously determined. Most cases of hyperglycemia are successfully treated by reducing the aggressive intravenous glucose infusion rates and exogenous catecholamine infusions these infants commonly receive and providing good supportive care including early intravenous amino-acid supply to promote insulin secretion.
Adaptation to low and chronically high glucose concentrations
Animal studies indicate that chronic hypoglycemia leads to increased concentrations of glucose transporters, especially in the brain, which are associated with upregulated glucose utilization capacity; similar changes in skeletal muscle, adipose tissue, and liver occur.19 Preliminary studies in animal models indicate increased insulin action in such conditions (Limesand et al., 2005, unpublished data), but future studies are needed to determine whether they are associated with sustained increased insulin sensitivity and glucose uptake capacity. Whereas sustained hypoglycemia leads to growth failure and enhanced glucose production rates, sustained hyperglycemia may diminish insulin production (in contrast to intermittent hyperglycemia which promotes insulin production and secretion) and limit insulin action.20, 21 Mechanisms responsible for the regulation of insulin production and secretion in preterm infants, especially in response to chronic changes in nutrient and hormone supply, are poorly understood, as are mechanisms responsible for variations in insulin action. Of particular interest is the recent observation that mitochondrial number and function in pancreatic β-cells, myocytes, and adipocytes can be impaired in fetal and early neonatal life and might contribute to mitochondrial failure later in life, leading ultimately to increased propensity to develop type II diabetes.22 Furthermore, many preterm infants are growth restricted at birth (perhaps indicating that the processes that led to growth failure also led to preterm delivery) and nearly all develop growth restriction during the neonatal period. Studies in a variety of animal models have shown that IUGR from nutrient insufficiency results in decreased pancreatic growth and development with decreased numbers of islets and insulin-producing β-cells and thus the capacity for insulin secretion.23 Persistence of such mechanisms also might contribute to failure of insulin secretion later in life when the pancreas is overstressed by a rich diet to provide increased insulin in response to developing insulin resistance that also is common in later life in such infants.
The most remarkable aspect of lipid development during late fetal life in humans is the deposition of large amounts of body fat, up to 12–18% of body weight.13 The value of this adiposity is not known, nor are the mechanisms that produce it or whether this developmental growth pattern should be recapitulated in preterm infants. Because such infants traditionally have been fed diets high in carbohydrate and lipids, they usually meet or exceed normal rates of intrauterine fat deposition in adipose tissue.24, 25
Although fatty acids are not readily oxidized in the fetus, fat oxidation does develop after birth, even in very preterm infants. Failure to provide sufficient non-protein energy will lead to increased rates of lipolysis and fatty acid oxidation, and this applies to the essential fatty acids as readily as the non-essential variety. This could lead to deleterious alterations in the amount and structure of critical membranes of cells of the developing central nervous system and potentially to abnormal neurological outcome.26 The roles of, requirements for, and appropriate balance of the ω-3 and the ω-6 essential polyunsaturated fatty acids series remain to be determined, although there is increasing evidence that increased supply of ω-3 end products, particular docosahexaenoic acid, has beneficial effects on selected aspects of development.27
Many unique lipid and fatty acid entry rates and fetal plasma concentrations are present in the normal fetus and likely contribute to important aspects of fetal metabolic development, but there has been little study of which of these are truly essential for normal development.28 Furthermore, to date, no intravenous lipid mix or dietary lipid source has been studied specifically to determine whether or not such unique plasma lipid and fatty acid concentrations should be mimicked in the preterm infant.
Amino-acid requirements are high in the fetus and very preterm infant, necessary to provide for the exceptionally high fractional protein synthetic and growth rates at this early developmental age.29 Amino-acid and protein insufficiency has produced growth failure of the whole fetus and preterm infant.30, 31 Protein deficits adversely affecting the kidney32 and the pancreas33 are also common with IUGR and appear to last into adulthood, leading to hypertension and diabetes, respectively; mechanisms have not been determined. Current research has not defined optimal amino-acid intakes in such infants, or whether higher amino-acid intakes will produce better growth, body composition, and developmental outcome. There also is uncertain knowledge about protein-energy relationships. The relationship between energy supply and protein accretion appears to be curvilinear with most of the effect of energy on protein gain taking place at less than 50–60 kcal/kg/day.34 In contrast, increasing protein intake leads to increased protein accretion at nearly all energy intakes above 30–50 kcal/kg/day.35
Many unique amino-acid entry rates and plasma concentrations are present in the normal fetus and likely contribute to important aspects of fetal metabolic development.36 As with the essential fatty acids, whereas many of the individual amino acids have been shown to have specific roles in various aspects of fetal metabolism and growth, there has been little study of which of these are truly essential for normal development. Furthermore, to date, no amino-acid mix or dietary protein source has been studied specifically to determine whether or not such unique plasma amino-acid concentrations should be mimicked in the preterm infant. Currently used intravenous amino-acid mixtures designed for normal infants have been shown to promote nitrogen and protein balance more favorably than mixtures more commonly used in adults,37 but they still do not provide normal fetal concentrations of all of the essential amino acids38 leaving considerable room for development of more optimal formulations specifically designed for the unique needs of the very preterm infant.
Effect of illnesses, pathophysiological conditions, and drugs
Little is known about the effects of the many different illnesses, pathophysiological conditions, or drugs that preterm infants receive on their nutrient metabolism.39, 40, 41, 42 Hormones appear to be important, but their direct effects still need further study, particularly those such as the catecholamines that directly promote glucose production, inhibit protein synthesis, and promote protein breakdown.43 Dexamethasone clearly produces protein breakdown and, more disturbingly, arrests brain growth and development.44 Also, insulin appears to act quickly to increase glucose utilization, but regulation of this process following acute and chronic changes in glucose, lipid, and amino-acid supplies and concentrations are poorly defined. Furthermore, insulin-induced enhanced rates of glucose and lipid uptake has resulted in fatty infiltrations of various tissues, which may not contribute to normal function and development. The independent effect of insulin on amino-acid utilization for protein synthesis, net protein accretion, and oxidation also remains to be determined.45
Caution about overly aggressive nutrition of the very preterm newborn infant
Nutrient deprivation early in life, before normal growth trajectories are established, leads to permanent growth failure.46 This is relevant to human preterm infants, who have the potential for normal growth but who often are undernourished during early postnatal life. As a result, most preterm infants fail to grow normally after birth and end up growth restricted by term gestational age.47 Also, recent epidemiological evidence indicates that obesity, insulin resistance, glucose intolerance, diabetes, lipid metabolic disorders and cardiovascular disease are more common among adults (human and animal models) who were smaller than normal at birth secondary to intrauterine growth restriction.48
In response to such observations, there has been a recent surge in interest in promoting earlier, more aggressive nutrition of preterm infants. This approach probably is appropriate for those infants who are simply born preterm, especially when focused on providing adequate amino acids for protein synthesis into protein accretion and growth, as well as neuronal development, and probably also applies to provision of important amino acids and essential fatty acids that have necessary roles in vital aspects of brain development. However, there also is concern that aggressive feeding producing catch-up growth, or rapid positive crossing of weight-for-length centiles with advancing age, might be equally deleterious as the primary nutritional deficiency and growth failure. Recent observations indicate that such rapid overgrowth specifically is associated with subsequent development of obesity, insulin resistance, and diabetes in later life, a phenomenon called the ‘Catch-up Growth’ hypothesis.49
In addition to these observations, it has been shown many times now among a variety of experimental and human conditions, that slower and leaner rates of growth, and maintenance of leaner body mass, is associated with less adult morbidity and with longer life spans. Perhaps, therefore, whereas more aggressive supply of essential amino acids and fatty acids after birth is important for selected aspects of development, the slower growth rate of preterm infants who are fed their own mothers' milk, like their term counterparts, might produce a more favorable developmental outcome.50 Very clearly there is considerable need for more research to define optimal nutrient regimens for the very preterm infant. A suggested starting regimen, emphasizing intravenous nutrition in the immediate postnatal period, is shown in Table 3.
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This work was supported by grants from the National Institutes of Health: M01RR00069 (WWH, Associate Director); RO1 HD42815 (WWH, PI); RO1 HD28794 (WWH, PI); RO1 DK52138 (WWH, PI); T32 HD07186 (WWH, PI).
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Hay, W. Early postnatal nutritional requirements of the very preterm infant based on a presentation at the NICHD-AAP workshop on research in neonatology. J Perinatol 26, S13–S18 (2006). https://doi.org/10.1038/sj.jp.7211426
- nutritional requirements
- preterm infant
- fetal nutrition
- postnatal nutrition
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