Metabolic adaptation at birth

Seminars in Fetal & Neonatal Medicine (2005) 10, 341e350

www.elsevierhealth.com/journals/siny

Metabolic adaptation at birth Martin Ward Platt a,*, Sanjeev Deshpande b a

Newcastle Neonatal Services, Royal Victoria Infirmary, Department of Child Health, Queen Victoria Road, Newcastle upon Tyne NE1 4 LP, UK b Royal Shrewsbury Hospital, Mytton Oak Road, Shrewsbury SY2 6SP, UK

KEYWORDS Neonatal metabolic adaptation; Glucose; Insulin; Neonate; Preterm; Intrauterine growth restriction; Fetal metabolism

Summary After birth, the neonate must make a transition from the assured continuous transplacental supply of glucose to a variable fat-based fuel economy. The normal infant born at term accomplishes this transition through a series of well-coordinated metabolic and hormonal adaptive changes. The patterns of adaptation in the preterm infant and the baby born after intrauterine growth restriction are, however, different to that of a full-term neonate, with the risk for former groups that there will be impaired counter-regulatory ketogenesis. There is much less precise linkage of neonatal insulin secretion to prevailing blood glucose concentrations. These patterns of metabolic adaptation are further influenced by feeding practices. ª 2005 Elsevier Ltd. All rights reserved.

Introduction Birth poses major metabolic challenges for the emerging neonate. With the severance of the umbilical cord, the assured continuous transplacental supply of glucose is abruptly disrupted, and the neonate must now switch on the endogenous production of glucose until exogenous nutritional intake becomes established. The neonate then has to adjust to alternating periods of feeding and fasting. These challenges are met through wellorchestrated metabolic and hormonal adaptive * Corresponding author. Tel.: C44 191 282 5197; fax: C44 191 282 5038. E-mail address: [email protected] (M. Ward Platt).

changes that ensure a continuing supply of energy fuels and constitute the neonatal metabolic adaptation. Although not as dramatic as adaptive changes in the cardiorespiratory system, this adaptation is equally complex and essential for survival in the extrauterine environment.

Fetal metabolism Before birth, the fetus is entirely dependent on continuous transplacental nutrient transfer from the maternal circulation, and no significant production of glucose by the fetus has been demonstrated. Glucose crosses the placenta along a concentration gradient between maternal and fetal

1744-165X/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2005.04.001

342 plasma, facilitated by specific placental glucose transporters. Measurements of circulating fuels in fetal blood samples obtained at midgestation (18e21 weeks) by fetoscopy and cordocentesis show that the fetal blood glucose concentrations are lower than e but very close to e those of mother.1,2 The fetal glucose pool is thus in equilibrium with the maternal glucose pool. Although the enzymes necessary for gluconeogenesis are well developed by 2 months of gestational age in the human fetus, gluconeogenesis is not expressed in utero under physiological conditions.3 Only 40e50% of the maternal glucose taken up by the placenta is transferred to the fetus, and this cannot account for its total oxidative metabolism. About 60% of the glucose utilized by the placenta is converted to lactate and is released into the fetal and maternal circulation in a ratio of 1:3. Fetal lactate uptake is about half of the fetal glucose uptake and provides a major substrate for both oxidative and non-oxidative (such as glycogen synthesis) fetal metabolism. Additionally, amino acids are actively transported to the fetus against a transplacental gradient, and the human placenta is also permeable to small amounts of triglycerides, fatty acids, glycerol, and keto acids. In the third trimester, glucose converts to fat in adipose tissue in preparation for changes at birth. Glucose, however, remains the principal energy substrate for the human fetus under physiological conditions. The fetal endocrine milieu is characterized by insulin dominance. Human liver contains the full complement of glycogenic enzymes as early as 8 weeks of gestation, and glycogen deposition begins in early pregnancy. Hepatic glycogen content increases from only 3.4 mg/g at 8 weeks of age to 50 mg/g by term.4e6 Apart from glucose, three-carbon products such as lactate, pyruvate and alanine probably serve as indirect precursors of fetal glycogen.

Changes at birth The cascade of events in successful adaptation to extrauterine life has unique characteristics in the biology of the human life cycle. In essence, these changes consist of an endocrine stress response, in which the roles of insulin and glucagon differ significantly from those in the adult, driving metabolic changes such as hepatic glycogenolysis, lipolysis, fatty acid b-oxidation with generation of ketone bodies, and proteolysis that generates lactate and other substrates for gluconeogenesis. Ketone bodies and lactate serve as alternative fuels with glucose-sparing effects, and are

M. Ward Platt, S. Deshpande especially important in maintaining cerebral energy supplies. Having ensured an adequate supply of fuels in the immediate newborn period, the infant now has to adapt to enteral feeding and assimilation of nutrients (of which more than half is fat) for a continuing supply of substrates in the ensuing period. Thus, successful adaptation to extrauterine life entails not only an immediate catabolic cascade but also adaptation to enteral feeding.

Metabolic fuels for the newborn infant Endogenous glucose production has been estimated to be 4e5 mg kg/min in the first few hours after birth,7,8 and is two- to three-fold greater per unit body weight in 1-day-old newborns than older subjects.9 There is a linear relationship between glucose production and estimated brain weight, with a particularly high cerebral glucose consumption in the neonate due to its greater brain mass (10e12% of total body weight).9 Although many other tissues (e.g. astrocytes) store glucose in the perinatal period, hepatic glucose output through glycogenolysis and gluconeogenesis provides the only source of this fuel until feeding is established. Glucose enters the brain by facilitated diffusion mediated by specific glucose transporters, GLUT1 and GLUT3, which have been demonstrated in the brains of both preterm and term infants.10 Measured rates of glucose oxidation in the fasted human neonate can only supply w70% of the estimated energy needs of the brain,11 emphasizing the need for alternative energy substrates such as ketone bodies and lactate during fasting. Newborn brain is capable of extracting and utilizing ketone bodies at a rate that is about five- to 40-fold greater than that of infant or adult brain.12 Studies of metabolic fuels and tracer studies with deuterium-labelled b-hydroxybutyrate confirm that ketogenesis and ketone body consumption are active even in regularly fed newborn infants, providing as much as 12% of the cerebral oxygen consumption in neonates after a 6-h fast.13e15 Lactate appears to be an important energy substrate for the infant in the immediate newborn period.16 It is utilized through oxidation by lactate dehydrogenase in the brain and thus has a glucosesparing effect. Although the lactate pool is small (2.4 mM), it is possibly generated through proteolysis17,18 and the concentrations tend to be higher in the crucial first 2e3 postnatal hours. The presence of abundant lactate at this time probably accounts for the observed paradox that even as blood glucose values transiently fall to

Metabolic adaptation at birth very low levels, babies remain in good health and show no symptoms which suggest cerebral fuel deficiency. In the first few hours energy needs are met by glucose derived from glycogenolysis and gluconeogenesis, and to a lesser extent from lactate. In the space of few hours, fat utilization becomes more prominent. These biochemical changes are reflected by a change in the respiratory quotient from 0.9e1.0 to 0.7 during this period.

Immediate postnatal changes At birth, the blood glucose concentration in the umbilical venous blood is 80e90% of that in the maternal venous blood.19 Blood glucose concentration falls rapidly after birth, reaching a nadir by 1 h of age and then rising to stabilize by 3 h of age even in the absence of any exogenous nutritional intake (Fig. 1).19,20 During this period, plasma insulin levels fall and there is a marked surge in plasma immunoreactive glucagon levels.21,22 Mechanisms other than hypoglycaemia seem to be responsible for these changes in the pancreatic hormone secretion and are attributed to the stress of the birth process mediated through the catecholamine surge.23 Although growth hormone concentration increases markedly after birth, it has no known role in metabolic adaptation. This initial glucagon surge with its resultant low insulin/glucagon molar ratio is the key hormonal adaptation in the newborn infant, leading to mobilization of glycogen. The liver glycogen stores are limited, however, and are depleted to a tenth of their size within 12 h of birth.6 Maintenance of normoglycaemia in the newborn infant is then dependent upon the exogenous glucose provided by the hydrolysis of milk lactose, or endogenous production through gluconeogenesis.

Figure 1 Profile of blood glucose concentrations in the immediate postnatal period. Adapted from Ref. 20 with kind permission.

343

Patterns of metabolic adaptation The pattern of subsequent changes in the metabolic and hormonal milieu differs according to the gestational maturity, intrauterine growth characteristics and postnatal feeding practices. In contrast to the wealth of information available about the changes in blood glucose concentration immediately after birth, there is a paucity of data on the concentrations and interactions of metabolic substrates in subsequent neonatal metabolic adaptation. Such research is limited by ethical considerations and sampling volume restrictions in the human neonate. Recent methodological advances e including the development of microassay techniques for intermediary metabolites and hormonal estimations, kinetic studies using stable isotopic tracers, and continuous measurements by means of subcutaneously placed microdialysis probes e have allowed evaluation of various aspects of this metabolic adaptation in the human neonate.

Term infants A number of studies have described the normal pattern of blood glucose concentrations in healthy, appropriately grown term infants during the first few postnatal hours or days.15,19,20,24e26 However, variations in the feeding schedules, methods of glucose measurement and timing of blood sampling make comparison between studies rather difficult. In line with findings in other mammalian species, all studies show that blood glucose concentration falls rapidly immediately after birth, reaching a nadir 30e90 min after birth.20,24,25 The blood glucose concentrations rise and stabilize between 2.4 and 5 mmol/L by 12e24 h of age, even in the absence of feeding.15,19,20,27 Subsequent concentrations of circulating glucose depend upon the feeding practices. This is reflected in the higher blood glucose profiles in term infants reported by Srinivasan et al.20 (infants being fed by 4 h of age) compared to those reported by Cornblath et al.24 (when the infants were routinely starved). Some studies show that the interval between feeds is the major determinant of blood glucose concentration,15 whilst others have not found such an association.26 Nevertheless, excessively low blood glucose concentrations are exceedingly uncommon among breast-fed term infants with modern feeding practices, even with prolonged intervals between feeds.15,25 There is a positive relationship between postnatal age and blood glucose concentrations, with the lowest values usually found on day 1.15,25

344 Using kinetic studies, the rate of glucose production in the human neonate during the first few postnatal days is estimated to be 4e6 mg kg/ min.7,9,11 Glycogenolysis has been estimated to account for only a third of the glucose production, and nearly 80% of the liver glycogen stores would be dissipated within 10 h of birth.5,6,28 Gluconeogenesis then assumes an important role in ensuring continued glucose supply. Under non-stressed conditions, fetal gluconeogenic capacity is limited due to low activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK).29 There is a marked increase in the activity of this rate-limiting enzyme after birth, modulated by the fall in the plasma insulin/glucagon molar ratio. The concentrations of gluconeogenic precursors such as alanine and lactate are higher in term neonates than in older children or adults.15,30,31 These observations may reflect the slow postnatal maturation of PEPCK enzyme,32,33 or may simply reflect the catabolic status of the neonate at this time. Accurate measurement of gluconeogenesis and hence its contribution to overall glucose production is difficult owing to the involvement of various intermediates. Nevertheless, tracer studies suggest that gluconeogenesis is active as early as 2 h after birth in the term human neonate,8 and that gluconeogenesis through glucose carbon recycling (mostly through lactate), alanine and glycerol contributes to 30%, 5e10% and 5e7%, respectively, of endogenous glucose production in the human neonate on the first day.11,18,34e36 However, the overall rate of glucose oxidation can only meet 70% of the neuronal energy needs, which emphasizes the importance of ketones and lactate to spare glucose requirements. Mammalian animal studies show that long-chain fatty acids are required for the postnatal induction of enzymes of mitochondrial fatty acid b-oxidation.37 Long-chain fatty acids play a major role in the post-transcriptional regulation of the ratelimiting carnitine palmitoyltransferase system, and it has been speculated that augmented ketogenesis in breast-fed infants (see below) may be due to the activation of this pathway by some factor in breast milk, although direct evidence for this is lacking.38 During the first 8 h after birth, newborn infants have been shown to have rather low plasma ketone body concentrations despite adequate levels of precursor free fatty acids (FFAs), reflecting limited capacity for hepatic ketogenesis.30 Thereafter, from 12 h of age, healthy term infants show high ketone body turnover rates (12e 22 mmol kg/min) approaching those found in adults after several days of fasting,14 and during

M. Ward Platt, S. Deshpande days 2 and 3 after birth they exhibit high ketone body concentrations quantitatively similar to those observed after an overnight fast in older children (Fig. 2).15 Such ketone body concentrations may account for as much as 25% of the neonate’s basal energy requirements during this time. Thus vigorous ketogenesis appears to be an integral part of extrauterine metabolic adaptation in the term human neonate. Role of pancreatic insulin and glucagon Plasma insulin concentrations remain low by adult standards for several days after birth,22 but in comparison to those in older infants and children they are relatively high when related to the simultaneous blood glucose concentrations.39 The plasma immunoreactive insulin levels are also variable in term infants and are incompletely suppressed at low blood glucose concentrations. In adults, endogenous glucose production is suppressed by exogenous glucose infusion through stimulation of insulin, attesting to the latter’s regulatory effect on glucoregulation. In the term human neonate such glucose infusions achieve a variable suppression of endogenous glucose production,40,41 indicating a looser link between glucose concentrations and insulin secretion. After the immediate postnatal surge, plasma glucagon levels show another peak between 1 and 3 days of age, corresponding to the period of maximal gluconeogenic activity. Glucagon levels remain high during the first postnatal week. Effect of feeding Enteral feeding triggers a cascade of developmental changes affecting gut structure, function and growth through the secretion of gut regulatory peptides. These changes are closely linked to the metabolic adaptation beyond the immediate newborn period. Modern nursery practices incorporating early enteral feeding are reflected in higher plasma glucose concentrations and fewer hypoglycaemic episodes in healthy term infants. Breast-fed infants demonstrate lower blood glucose concentrations than their formula-fed counterparts, probably reflecting the low energy content of breast milk in the first few days.15 However, these lower blood glucose concentrations in breast-fed infants are accompanied by substantial ketone body concentrations, ensuring a supply of alternative fuel. By the 6th postnatal day, although breast-fed and formula-fed babies have the same pattern of glucose response to feed, the former show significantly higher ketone body concentrations and lower insulin responses.42 These findings

Metabolic adaptation at birth

345 blood glucose concentrations and indeed had some of the highest ketone body concentrations in the study by Hawdon et al.15 This is particularly reassuring in the light of current feeding practices which encourage exclusivity of breast feeding when this is the mother’s preference.

Preterm infants

Figure 2 Relationship between blood glucose and ketone body concentrations in (a) children aged from 1 month to 10 years after an overnight fast, and (b) term infants and (c) preterm infants during the first postnatal week. Reproduced from Ref. 15 with kind permission.

do not simply reflect an active ketogenic response to lower blood glucose concentrations found in breast-fed infants, but suggest a direct ketogenic effect of breast milk e for example by virtue of its lipase content allowing improved delivery of fatty acids to the liver. The findings may also reflect the suppressive effect of the unphysiological protein, fat and energy load provided to the formula-fed infant in the first few days after birth. Of note, breast-fed infants with prolonged between-feed intervals of up to 8 h did not show excessively low

It has been a long-held view that blood glucose values during the first 3 days are generally lower in preterm infants than in term neonates, and that they are better tolerated by the former.24 This misconception arises from the definition of lower ‘normal’ blood glucose concentrations in preterm infants measured in the decades when these infants were routinely starved in the first few days. More recent work suggests that it is now unusual to find such low blood glucose values in preterm infants.15 This is certainly attributable to current policies of early enteral feeding together with recourse to intravenous glucose infusions in those infants unable to tolerate enteral feeds. Within the first few hours of birth there is a significantly greater fall in blood glucose concentration in preterm infants than in term infants, suggesting that they are less able to adapt to the cessation of intrauterine nutrition.15 Circulating levels of gluconeogenic substrates have been noted to be rather high in preterm infants,15 and the activity of microsomal glucose-6-phosphatase (the final enzyme of glycogenolysis and gluconeogenesis) in preterm infants has been reported to be at the extreme low end of that found in term infants.43 In a study of five preterm infants of %32 weeks’ gestation, administration of alanine (an important gluconeogenic precursor) did not result in an increased glucose production rate despite high serum alanine levels.44 These findings suggest that the gluconeogenic ability is limited in preterm infants, possibly due to immaturity of the enzymatic pathways. On the other hand, in a series of kinetic studies using tracer dilution techniques, Sunehag et al. showed that preterm infants born as early as 25e26 weeks’ gestation have a capacity to produce glucose on their first day of life at rates close to those of term infants, and that they are capable of converting part of the parenteral glycerol into glucose.45e47 Similarly, enhanced gluconeogenesis from pyruvate was reported in 15 5-day-old preterm infants of 26e31 weeks’ gestation in another investigation.17 These discrepant findings remain unexplained. Preterm infants, however, differ from their term counterparts in some important aspects.

346 Their metabolic profiles indicate an inability to mount mature counter-regulatory ketogenic responses to falling blood glucose levels in the first week after birth.15 These low ketone body concentrations are less closely linked with plasma FFA concentrations, indicating that the low ketone body concentrations in these infants may be due to a combined failure of lipolysis and ketogenesis. In contrast to term infants, preterm infants demonstrated a positive relationship between blood ketone body concentrations and the volume of enteral feed.15 It may be that the enteral feeding induces enzymes of ketogenesis. In a subsequent longitudinal study of metabolic counter-regulation in preterm infants, we and others have shown a persistent immaturity of counter-regulatory ketogenesis during the first 8 postnatal weeks, persisting in some even at 2e6 months beyond their expected term equivalence.48,49 Although preterm neonates do not seem to mobilize their fat stores and produce ketone bodies during fasting, they do so under conditions of operative stress.50 However, operative stress cannot be equated with starvation stress, and under the latter conditions preterm infants seem unable to mobilize adequate quantities of alternative fuels. Basal insulin secretion (reflected by plasma immunoreactive insulin concentrations at low blood glucose values) is higher in preterm infants than in term infants or children.39 While basal insulin concentrations showed a decreasing trend with increasing maturity in a cross-sectional study, they remained persistently high in the longitudinal evaluation of metabolic counter-regulation in preterm infants.48 Effect of feeding In preterm infants, unlike term infants, no demonstrable change occurs in the concentration of any metabolite or gut hormone after the first feed, but multiple gut hormonal surges occur following regular bolus milk feeds, with a three- to four-fold rise over values at birth by the 6th day.51 These changes are elicited by a volume of milk as small as 15 mL kg/day. Thus milk acts not only as a nutrient but also as a pharmacological agent to maintain the stimulus to gut development. Although there are no significant differences in the concentrations of intermediary metabolites e including glucose e between the human milk-fed and formula-fed preterm infants, the profiles of plasma amino acids and gut polypeptides differ significantly between these groups.52 Apart from the composition of the feed, the method of feeding also modulates the pattern of metabolic adaptation in preterm infants. Preterm infants

M. Ward Platt, S. Deshpande who are given regular boluses of enteral milk experience marked cyclical surges in anabolic hormones e including insulin e which are not seen in infants receiving the same volume of milk delivered continuously through a nasogastric tube.53

The baby born after intrauterine growth restriction Intrauterine growth restriction has long been recognized as a cause of failure of metabolic adaptation in neonates. The compromising factors include depletion of hepatic glycogen reserves, increased metabolic demands due to a relatively larger brain size, decreased PEPCK activity, limited mobilization and subsequent oxidation of fatty acids, and functional hyperinsulinism. Additionally, perinatal complications might impair the processes of normal metabolic adaptation in such infants. Some growth-restricted infants demonstrate metabolic evidence of antenatal stress in the form of raised concentrations of FFAs, total gluconeogenic substrates and lactate in the cord blood, with severe fetal nutritional compromise reflected in the low cord blood glucose concentrations.54e56 Recent studies have shown little difference in the mean blood glucose concentrations in intrauterine growth-restricted (IUGR) and appropriatefor-gestational-age (AGA) infants,19,57 or in the frequency of blood glucose concentrations !2.6 mmol/L.57 This is in contrast to previous reports of lower blood glucose concentrations and increased frequency of hypoglycaemia in IUGR infants,58,59 and may be the result of closer attention to the nutritional management of such infants in recent years. Despite these normal blood glucose concentrations, IUGR infants show metabolic profiles substantially different from those of AGA infants. Compared to AGA babies, IUGR infants show higher concentrations of gluconeogenic precursors such as lactate and alanine57,59,60 and a poor glycaemic response to oral alanine administration.61 These findings have been attributed to the presumed delayed activation of PEPCK in IUGR infants.59 On the other hand, similar glucose production rates e and the fractional as well as quantitative contribution of glycerol to glucose e between IUGR and well-grown term infants in kinetic studies,18,62 and the IUGR infant’s ability to incorporate alanine into glucose soon after birth,34 suggest that endogenous glucose production and gluconeogenesis are normal in the IUGR infant.63 FFA and ketone body concentrations are reported to be lower in IUGR than AGA infants, with the degree of growth retardation being the

Metabolic adaptation at birth most important determinant of the failure of ketogenesis, but these findings are not invariable.38,57,59,64 Reduced ketogenic capacity may be secondary to an inability to mobilize FFAs from adipose tissue, or the impairment of b-oxidation of FFAs, or a combination of the two. Hormonal abnormalities are not responsible for these metabolic profiles. Insulin and glucagon secretion in IUGR infants is normal under basal conditions, and does not differ significantly from that in AGA infants after administration of glucose and amino acids.61,65 Previous reports have suggested hyperinsulinism as a pathogenetic mechanism of disordered glucose metabolism in these infants.66,67 However, this can be disputed on the basis that insulineglucose relationships in these groups do not differ from those in healthy AGA infants.57 Variations in findings between studies of babies thought to have intrauterine growth restriction may be explained by differences in feeding practices, inclusion of ‘small normals’, or the confounding effects of perinatal hypoxiae ischaemia. Effect of feeding Among 164 term infants with birth weight below the 5th centile who were fed 60 mL kg/day of milk, only nine developed hypoglycaemia.68 In a study of 65 IUGR infants, no significant differences in blood glucose concentrations were found between infants who were exclusively breast-fed and those who were wholly or partially formula-fed.38 However, feeding of IUGR infants exclusively with breast milk was associated with significantly higher ketone body concentrations compared to those in formula-fed babies, independent of the blood glucose levels. In summary, enteral feeding, particularly with breast milk, appears to promote normal metabolic adaptation in these vulnerable infants.

Infants of diabetic mothers Low blood glucose levels are found relatively frequently in infants of diabetic mothers (IDMs), and the risk is particularly high among macrosomic and growth-restricted infants (see Chapters 1 and 6). The pathogenesis of this increased risk of hypoglycaemia in IDM is multifactorial. It has long been thought that maternal hyperglycaemia results in unchecked fetal hyperglycaemia leading to overstimulation of fetal pancreatic b-cells and fetal hyperinsulinism.69 Cessation of maternal glucose supply at birth with continuing fetal hyperinsulinism results in an exaggerated, or

347 more prolonged, postnatal fall in blood glucose concentration. Hypoglycaemia, however, still occurs with increased frequency even among babies of women with ‘tightly controlled’ diabetes as judged by HbA1c values.70 It has been suggested that intermittent hyperglycaemia during pregnancy that will not be picked up by the average HbA1c levels,71 and hyperglycaemia during labour,70,72 may underlie this increased propensity for hypoglycaemia in IDM. Defective hormonal counter-regulation has also been implicated in the pathogenesis of hypoglycaemia in IDM. Plasma glucagon concentrations 2 h after birth in IDM were found to be less than half of those of normal term infants, indicating a blunted glucagon response.21 Chronic hyperglycaemic stress in utero due to poorly controlled maternal diabetes is thought to result in fetal sympathoadrenal exhaustion, increasing the risk of hypoglycaemia in IDM. In support of this hypothesis, increased plasma73 and low urinary74 catecholamine levels have been found in IDM, with normalization of plasma glucose and FFAs with infusion of epinephrine.75 Kinetic studies have shown conflicting results concerning the rate of endogenous glucose production in IDM, with methodological variations accounting for some of the reported differences. Kalhan et al.76 reported lower endogenous glucose production rates in IDM suggestive of impaired glycogenolysis and/or gluconeogenesis. However, others have reported near-normal rates of glucose production in IDM.77e79 A recent evaluation showed higher insulin concentrations and attenuated hepatic glucose production but unaffected lipolysis in infants born to women with tightly controlled diabetes.80 This was thought to be due either to high concentrations of lipolytic hormones or lack of sensitivity of adipose tissue to insulin. Thus, although there does not appear to be a single unique pathogenetic mechanism for the increased incidence of hypoglycaemia in IDM, there is some evidence that tighter metabolic control during pregnancy and labour may reduce the frequency of this complication.81

Conclusion It is through an understanding of the physiology of metabolic adaptation that rational approaches to nutrition and the identification and management of hypoglycaemia can be developed. Yet there is still much unknown and unexplored: the physiology of human neonatal adaptation has too often been

348

M. Ward Platt, S. Deshpande

studied in the baby alone rather than as a component of the mothereinfant dyad, and many of the mysteries of the properties of human breast milk in relation to adaptation remain unsolved.

Practice points  Postnatal metabolic adaptation in fullterm neonate is characterized by vigorous ketogenesis  Preterm and IUGR infants may demonstrate impairment of counter-regulatory ketogenesis  Feeding e particularly with breast milk e augments ketogenic ability

Research directions  Brain function in relation to a comprehensive portfolio of neural fuels (glucose, ketone bodies and lactate), adaptive changes in cerebral microcirculation and local (e.g. astrocytes) factors  The mechanism of the ability of breast milk to enhance ketogenesis  Precise definition of most vulnerable IUGR infants for impaired metabolic adaptation

References 1. Aynsley-Green A, Soltesz G, Jenkins PA, Mackenzie IZ. The metabolic and endocrine millieu of the human fetus at 18e21 weeks of gestation: II. Blood glucose, lactate, pyruvate and ketone body concentrations. Biol Neonate 1985;47:19e25. 2. Bozzetti P, Ferrari MM, Marconi AM, Ferrazzi E, Pardi G, Makowski EL, et al. The relationship of maternal and fetal blood glucose concentrations in the human from midgestation until term. Metabolism 1988;37:358e63. 3. Kalhan SC, D’Angelo LJ, Savin SM, Adam PAJ. Glucose production in pregnant women at term gestation. Sources of glucose for the human fetus. J Clin Invest 1979;63:388e94. 4. Capkova A, Jirasek JE. Glycogen reserves in organs of human fetuses in the first half of pregnancy. Biol Neonate 1968;13:129e42. 5. Shelly HJ, Neligan GA. Neonatal hypoglycaemia. Br Med Bull 1966;22:34e9. 6. Shelly HJ. Glycogen reserves and their changes at birth and in anoxia. BMJ 1961;17:137e43. 7. Kalhan SC, Savin SM, Adam PAJ. Measurement of glucose turnover in the human newborn with glucose-1-13C. J Clin Endocrinol Metab 1976;43:704e7. 8. Kalhan SC, Bier DM, Savin SM, Adam PAJ. Estimation of glucose turnover and 13C recycling in the human newborn by simultaneous [1-13C] glucose and [6-6-2H2] glucose tracers. J Clin Endocrinol Metab 1980;50:456e60.

9. Bier DM, Leake RD, Haymond MW, Arnold KJ, Gruenke LD, Sperling MA. Measurement of ‘true’ glucose production rates in infancy and childhood with 6,6-dideuteroglucose. Diabetes 1977;26:1016e23. 10. Mantych GJ, Sotelo-Avila C, Devasker SU. The bloodebrain glucose transporter is conserved in preterm and term newborn infants. J Clin Endocrinol Metab 1993;77:46e9. 11. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986;251:E71e7. 12. Persson B, Settergren G, Dahlquist G. Cerebral arteriovenous differences of acetoacetate and D-b-hydroxybutyrate in children. Acta Paediatr Scand 1972;61:273e8. 13. Kraus H, Schlenker S, Schwedsky D. Developmental changes of cerebral ketone body utilization in human infants. Hoppe Seylers Z Physiol Chem 1974;355:164e70. 14. Bougneres PF, Zemmel C, Ferre P, Bier DM. Ketone body transport in the human neonate and infant. J Clin Invest 1986;77:42e8. 15. Hawdon J, Ward Platt M, Aynsley-Green A. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child 1992;67:357e65. 16. Medina JM, Tabernero A, Tovar JA, Martin-Barrientos J. Metabolic fuel utilization and pyruvate oxidation during the postnatal period. J Inherit Metab Dis 1996;19:432e42. 17. Keshen T, Miller R, Jahoor F, Jaksic T, Reeds PJ. Glucose production and gluconeogenesis are negatively related to body weight in mechanically ventilated, very low birth weight neonates. Pediatr Res 1997;41:132e8. 18. Kalhan SC, Parimi P, Beek RV, Gilfillan C, Saker F, Gruca L, et al. Estimation of gluconeogenesis in newborn infants. Am J Physiol Endocrinol Metab 2001;281:E991e7. 19. Heck LJ, Erenberg A. Serum glucose levels in term neonates during the first 48 hours of life. J Pediatr 1987;110:119e22. 20. Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lillen LD. Plasma glucose values in normal neonates: a new look. J Pediatr 1986;109:114e7. 21. Bloom SR, Johnston DI. Failure of glucagon release in infants of diabetic mothers. BMJ 1972;4:453e4. 22. Sperling MA, DeLamater PV, Phelps D, Fiser RH, Oh W, Fisher DA. Spontaneous and amino acid stimulated glucagon secretion in the immediate post-natal period: relation to glucose and insulin. J Clin Invest 1974;53:1159e66. 23. Padbury JF, Roberman B, Oddie TH, Hobel CJ, Fisher DA. Fetal catecholamine release in response to labour and delivery. Obstet Gynecol 1982;60:607e11. 24. Cornblath M, Reisner SH. Blood glucose in the neonate and its clinical significance. N Engl J Med 1965;273:378e81. 25. Hoseth E, Joergensen A, Ebbesen F, Moeller M. Blood glucose levels in a population of healthy, breast fed, term infants of appropriate size for gestational age. Arch Dis Child Fetal Neonatal Ed 2000;83:F117e9. 26. Diwakar KK, Sasidhar MV. Plasma glucose levels in term infants who are appropriate size for gestation and exclusively breast fed. Arch Dis Child Fetal Neonatal Ed 2002;87: F46e8. 27. Swenne I, Ewald U, Gustafsson J, Sandberg E, Ostenson C-G. Inter-relationship between serum concentrations of glucose, glucagon and insulin during the first two days of life in healthy newborns. Acta Paediatr Scand 1994;83:915e9. 28. Bougneres PF. Stable isotope tracers and the determination of fuel fluxes in newborn infants. Biol Neonate 1987; 52:87e96. 29. Girald J. Gluconeogenesis in late fetal and early neonatal life. Biol Neonate 1986;50:237e58. 30. Stanley CA, Anday EK, Baker L, Delivoria-Papadopolous M. Metabolic fuel and hormone responses to fasting in newborn infants. Pediatrics 1979;64:613e9.

Metabolic adaptation at birth 31. Haymond MW, Karl IR, Pagliara AS. Ketotic hypoglycaemia: an amino acid substrate limited disorder. J Clin Endocrinol Metab 1974;35:521e30. 32. Robinson BH. Development of gluconeogenic enzymes in the newborn guinea pig. Biol Neonate 1976;29:48e55. 33. Marsac C, Saudubray JM, Moncion A, Leroux JP. Development of gluconeogenic enzymes in the liver of human newborns. Biol Neonate 1976;28:317e25. 34. Fraser TE, Karl IE, Hillman LS, Bier DM. Direct measurement of gluconeogenesis from [2,3-13C2] alanine in the human neonate. Am J Physiol Endocrinol Metab 1981;240: E615e21. 35. Patel DG, Kalhan SC. Glycerol metabolism in the newborn. Pediatr Res 1988;23:489A [abstract]. 36. Sunehag A, Gustafsson J, Ewald U. Glycerol carbon contributes to hepatic glucose production during the first eight hours in healthy term infants. Acta Paediatr 1996;85: 1339e43. 37. Pegorier JP, Chatelain F, Thumelin S, Girard J. Role of longchain fatty acids in the postnatal induction of genes coding for liver mitochondrial beta-oxidative enzymes. Biochem Soc Trans 1998;26:113e20. 38. de Rooy L, Hawdon JM. Nutritional factors that affect the postnatal metabolic adaptation of full-term small- and large-for-gestational-age infants. Pediatrics 2002;109:e42. 39. Hawdon JM, Aynsley-Green A, Alberti KGMM, Ward Platt MP. The role of pancreatic insulin secretion in neonatal glucoregulation. I. Healthy term and preterm infants. Arch Dis Child 1993;68:274e9. 40. Kalhan SC, Oliver A, King KC, Lucero C. Role of glucose in the regulation of endogenous glucose production in the human newborn. Pediatr Res 1986;20:49e52. 41. Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the human neonate. J Clin Invest 1983;71:467e75. 42. Lucas A, Boyes S, Bloom SR, Aynsley-Green A. Metabolic and endocrine responses to a milk feed in 6 day old term infants: differences between breast and cow’s milk formula feeding. Acta Paediatr Scand 1981;70:195e200. 43. Hume R, Burchell A. Abnormal expression of glucose-6phosphatase in preterm infants. Arch Dis Child 1993;68: 202e4. 44. van Kempen AA, Romijn JA, Ruiter AF, Endert E, Weverling GJ, Kok JH, et al. Alanine administration does not stimulate gluconeogenesis in preterm infants. Metabolism 2003;52:945e9. 45. Sunehag A, Ewald U, Larsson A, Gustafsson J. Glucose production rate in extremely immature neonates (!28 weeks) studied by use of deuterated glucose. Pediatr Res 1993;33:97e100. 46. Sunehag A, Ewald U, Gustafsson J. Extremely preterm infants (!28 weeks) are capable of gluconeogenesis from glycerol on their first day of life. Pediatr Res 1996;40:553e7. 47. Sunehag A. Parenteral glycerol enhances gluconeogenesis in very premature infants. Pediatr Res 2003;53:635e41. 48. Deshpande S, Hawdon JM, Ward Platt MP, Aynsley-Green A. Metabolic adaptation to extrauterine life. In: Rodeck CH, Whittle MJ, editors. Fetal medicine: basic science and clinical practice. London: Churchill Livingstone; 1999. p. 1059e69. 49. Hume R, McGeechan A, Burchell A. Failure to detect preterm infants at risk of hypoglycaemia before discharge. J Pediatr 1999;134:499e502. 50. Anand KJS, Brown MJ, Causon RC, Christofides ND, Bloom SR, Aynsley-Green A. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg 1985;20:41e8.

349 51. Lucas A, Bloom SR, Aynsley-Green A. Development of gut hormone responses to feeding in neonates. Arch Dis Child 1980;55:678e82. 52. Calvert SA, Soltesz G, Jenkins PA, Harris D, Newman C, Adrian TE, et al. Feeding premature infants with human milk or preterm milk formula. Effects on postnatal growth and on circulating concentrations of intermediary metabolites, amino acids, and regulatory peptides. Biol Neonate 1985;47:189e98. 53. Aynsley-Green A, Adrian TE, Bloom SR. Feeding and the development of enteroinsular hormone secretion in the preterm infants: effects of continuous gastric infusions of human milk compared with intermittent boluses. Acta Paediatr Scand 1982;71:379e83. 54. Hawdon JM, Ward Platt MP, McPhail S, Cameron H, Walkinshaw SA. Prediction of impaired metabolic adaptation by antenatal Doppler studies in small for gestational age fetuses. Arch Dis Child 1992;67:789e92. 55. Economides DL, Nicolaides KH. Blood glucose and oxygen tension levels in small for gestational age fetuses. Am J Obstet Gynecol 1989;160:385e9. 56. Soothill PW, Nicolaides KH, Campbell S. Prenatal asphyxia, hyperlacticaemia, hypoglycaemia, and erythroblastosis in growth retarded fetuses. BMJ 1987;294:1051e3. 57. Hawdon JM, Ward Platt MP. Metabolic adaptation in small for gestational age infants. Arch Dis Child 1993;68:262e8. 58. Lubchenco LO, Bard H. Incidence of hypoglycaemia in newborn infants classified by birth weight and gestational age. Pediatrics 1971;47:831e8. 59. Haymond MW, Karl IE, Pagliara AS. Increased gluconeogenic substrate in the small for gestational age infant. N Engl J Med 1974;291:322e8. 60. Mestyan J, Soltesz G, Schultz K, Horvath M. Hyperaminoacidaemia due to the accumulation of gluconeogenic amino acid precursors in hypoglycaemic small for gestational age infants. J Pediatr 1975;87:409e14. 61. Williams PR, Fiser RH, Sperling MA, Oh W. Effects of oral alanine feeding on blood glucose, plasma glucagon and insulin concentrations in small-for-gestational-age infants. N Engl J Med 1975;292:612e3. 62. Patel D, Kalhan S. Glycerol metabolism and triglyceride fatty acid cycling in the newborn: effect of maternal diabetes and intrauterine growth retardation. Pediatr Res 1992;31:52e8. 63. Kalhan S, Alur P. Glucose and small for gestational age infants. Indian Pediatr 1999;36:1262e4. 64. Sabel KG, Olegard R, Mellander M, Hildingsson K. Interrelation between fatty acid oxidation and control of gluconeogenic substrates in small for gestational age (SGA) infants with hypoglycaemia and normoglycaemia. Acta Paediatr Scand 1982;71:53e61. 65. Salle BL, Ruiton-Ugliengo A. Effects of oral glucose and protein load on plasma glucagon and insulin concentrations in small for gestational age infants. Pediatr Res 1977;11: 108e12. 66. Collins JV, Leonard JV, Teale D, Marks V, Williams DM, Kennedy CR, et al. Hyperinsulinaemic hypoglycaemia in small for dates babies. Arch Dis Child 1990;65:1118e20. 67. Bhowmick SK, Lewandowski G. Prolonged hyperinsulinism and hypoglycaemia. In an asphyxiated, small for gestation infant. Case management and literature review. Clin Pediatr 1989;28:575e8. 68. Whitby C, deCates CR, Roberton NRC. Infants weighing 1.8e 2.5 kg: should they be cared for in neonatal units or on postnatal wards? Lancet 1982;1:322e5. 69. Pedersen J. The pregnant diabetic and her newborn. 2nd ed. Baltimore: Williams & Wilkins; 1977.

350 70. Taylor R, Lee C, Kyne-grzebalski D, Marshall SM, Davison JM. Clinical outcomes of pregnancy in women with type 1 diabetes. Obstet Gynecol 2002;99:537e41. 71. Kyne-Grzebalski D, Wood L, Marshall SM, Taylor R. Episodic hyperglycaemia in well controlled type 1 diabetic women in pregnancy: a potential cause of macrosomia. Diabet Med 1999;16:702e4. 72. Andersen O, Hertel J, Schmilker L, Kuhl C. Influence of maternal plasma glucose on the risk of hypoglycaemia in infants of insulin dependent diabetic mothers. Acta Paediatr Scand 1985;74:268e73. 73. Young JB, Cohen WR, Rappaport EB, Landsberg L. High plasma norepinephrine concentrations at birth in infants of diabetic mothers. Diabetes 1979;28:697e9. 74. Stern L, Ramos A, Leduc J. Urinary catecholamine excretion in infants of diabetic mothers. Pediatrics 1968;42: 598e605. 75. Keenan WJ, Light IJ, Sutherland JM. Effects of exogenous epinephrine on glucose and insulin levels in infants of diabetic mothers. Biol Neonate 1972;21:44e53.

M. Ward Platt, S. Deshpande 76. Kalhan SC, Savin SM, Adam PAJ. Atteunated glucose production rate in newborn infants of insulin dependent diabetic mothers. N Engl J Med 1977;296:375e6. 77. King KC, Tserng KY, Kalhan SC. Regulation of glucose production in newborn infants of diabetic mothers. Pediatr Res 1982;16:608e12. 78. Cowett RM, Susa JB, Giletti B, Oh W, Schwartz R. Glucose kinetics in infants of diabetic mothers. Am J Obstet Gynecol 1983;146:781e6. 79. Baarsma R, Reijngoud D-J, van Asselt WA, van Doormaal JJ, Berger R, Okken A. Postnatal glucose kinetics in newborns of tightly controlled insulin-dependent diabetic mothers. Pediatr Res 1993;34:443e7. 80. Sunehag A, Ewald U, Larsson A, Gustafsson J. Attenuated hepatic glucose production but unimpaired lipolysis in newborn infants of mothers with diabetes. Pediatr Res 1997;42:492e7. 81. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ 1999;39:1223e7.