**2. Metabolic aspects**

The maintenance of physiological concentrations of glucose in newborns plays important roles, including protecting the brain from damage caused by insufficient glucose intake and preventing the consequences of hyperosmolarity caused by high glucose concentrations. Although glucose is the preferred energy source of neurons, other sources, such as lactate and ketone bodies [23], seem to exert a neuroprotective effect. However, in hypoketotic states, such as hyperinsulinism or fatty acid oxidation disorders, ketone and lactate concentrations are not high enough to replace glucose, and the risk of a cerebral energy deficit is greater [60, 61].

It is known that, during fasting, several metabolic systems are activated to prevent hypoglycemia, which may be seen as a failure in one of these systems or as an abnormality affecting one or more of the hormones that control these systems [24].

As the brain mass of newborn infants in relation to body size is larger than that of adults, the rate of glucose utilization per kg body weight in newborns is two- to threefold than that of adults (4–6 mg/kg/min) [61].

#### **2.1. Maternal provision of glucose to the fetus**

The first half of pregnancy is characterized by marked anabolism. In early pregnancy, increased caloric intake not only supports fetal development but also facilitates fat deposition in the mother in preparation for the second half of pregnancy, a period of accelerated fetal growth in which maternal stores are mobilized to meet the needs of the fetus. To this end, increased insulin secretion also occurs in early pregnancy, as a way to store energy.

From the midpoint of pregnancy onward, high levels of circulating maternal insulin are also observed, but high levels of anti-insulin factors override this effect, ensuring the provision of nutrients to the fetus during the postprandial period. Thus, in pregnant women with preexisting diabetes, the effects of these anti-insulin factors are potentiated, causing excess provision of glucose and other energy sources to the fetus and thus triggering the abnormalities observed in infants born to diabetic mothers.

In the expectant mother, glucose is found at levels 25–30% higher than in the fetus, and it is transported to the fetus by concentration gradients and simple diffusion and through the action of transporters. In the fetus, the predominant transporter is GLUT-1, which has a high affinity for glucose and facilitates its passage through tissues [28].

Most glucose in the fetus undergoes oxidation to supply its energy needs, while another part contributes significantly to a buildup of glycogen, protein, and fat in triglyceride form. Glucose is the most important source of energy for the fetus and the major substrate for brain metabolism.

#### **2.2. Glucose uptake in the newborn**

Hypoglycemia occurs in 1.3–4.4 per 1000 full-term newborns and 15–55 per 1000 preterm newborns. This suggests that gestational age has enormous influence on its onset; in certain groups, adaptive mechanisms are not adequately developed, which predisposes them to increased risk of hypoglycemia. According to current evidence, the prevalence of hypoglycemia is approximately 10% in full-term neonates [45]; 6.5% in appropriate for gestational age (AGA), 8% in large for gestational age (LGA), and 15% in small for gestational age (SGA)

The maintenance of physiological concentrations of glucose in newborns plays important roles, including protecting the brain from damage caused by insufficient glucose intake and preventing the consequences of hyperosmolarity caused by high glucose concentrations. Although glucose is the preferred energy source of neurons, other sources, such as lactate and ketone bodies [23], seem to exert a neuroprotective effect. However, in hypoketotic states, such as hyperinsulinism or fatty acid oxidation disorders, ketone and lactate concentrations are not high enough to replace glucose, and the risk of a cerebral energy deficit is greater [60, 61].

It is known that, during fasting, several metabolic systems are activated to prevent hypoglycemia, which may be seen as a failure in one of these systems or as an abnormality affecting

As the brain mass of newborn infants in relation to body size is larger than that of adults, the rate of glucose utilization per kg body weight in newborns is two- to threefold than that of

The first half of pregnancy is characterized by marked anabolism. In early pregnancy, increased caloric intake not only supports fetal development but also facilitates fat deposition in the mother in preparation for the second half of pregnancy, a period of accelerated fetal growth in which maternal stores are mobilized to meet the needs of the fetus. To this end,

From the midpoint of pregnancy onward, high levels of circulating maternal insulin are also observed, but high levels of anti-insulin factors override this effect, ensuring the provision of nutrients to the fetus during the postprandial period. Thus, in pregnant women with preexisting diabetes, the effects of these anti-insulin factors are potentiated, causing excess provision of glucose and other energy sources to the fetus and thus triggering the abnormalities

In the expectant mother, glucose is found at levels 25–30% higher than in the fetus, and it is transported to the fetus by concentration gradients and simple diffusion and through the action of transporters. In the fetus, the predominant transporter is GLUT-1, which has a high

increased insulin secretion also occurs in early pregnancy, as a way to store energy.

newborns; and 15.5% in late-preterm infants [7].

one or more of the hormones that control these systems [24].

**2.1. Maternal provision of glucose to the fetus**

observed in infants born to diabetic mothers.

affinity for glucose and facilitates its passage through tissues [28].

**2. Metabolic aspects**

64 Selected Topics in Neonatal Care

adults (4–6 mg/kg/min) [61].

At birth, the fetus becomes dependent on itself to obtain energy and meet the metabolic needs of its vital organs, particularly the central nervous system (CNS). Each mole of oxidized glucose provides 38 moles of adenosine triphosphate (ATP) [54].

Cerebral glucose transport takes place through a facilitated diffusion process, which is dependent on glycemia and is not regulated by insulin. Protection against hypoglycemia is coordinated by the autonomic nervous system by means of hormones that stimulate the production of glucose (through glycogenolysis and gluconeogenesis) and limit peripheral glucose utilization [54].

Glycogen is the only glucose storage medium in the body. Its deposits are found in the liver, striated muscle tissue (including cardiac muscle), kidneys, bowel, brain, and placenta.

The fetal liver contains a complete enzyme system for the synthesis and breakdown of glycogen, levels of which are low in early pregnancy but rise slowly and steadily from gestational weeks 15–20, before peaking in the third trimester. At this time, fat deposition also increases. Thus, part of the energy and substrates used for fetal growth is redirected for storage, which will play an important role in the peripartum and postpartum periods.

Hepatic glycogenolysis is the major mechanism of glucose release in the immediate neonatal period, which leads to depletion of glycogen stores. It is induced by an increase in glucagon and catecholamines and a reduction in insulin. This exhaustion of glycogen stores promotes activation of gluconeogenesis, which occurs largely as a result of free fatty acid oxidation in the liver.

Glucose homeostasis will thus depend on glucose intake; gluconeogenesis; glycogen, protein, and fat stores; and hormonal and neural factors.

Glucose produced from the breakdown of dietary lactose into galactose and glucose, for instance, is not taken up by the liver in the neonatal period; the newborn is thus dependent on hepatic gluconeogenesis to sustain glucose production.

Once glycogen stores are low, gluconeogenesis induced by glucagon, catecholamines, cortisol, and growth hormone mobilizes fat and protein substrates. Insulin, thyroid hormone, cortisol, and glucagon systematically promote induction of specific enzymes, thus adapting the neonate to the abrupt cessation of the supply glucose that was provided continuously before birth.

Upon clamping the umbilical cord, the maternal glucose supply, which was 54 mg/dL during pregnancy, ceases abruptly, and the neonate's blood glucose levels decline rapidly and precipitously—from a concentration similar to that of the mother to approximately 41 mg/dL within the first 6 h of life. Physiologically, glucose concentration decreases to approximately 30 mg/ dL in the first 2 h after birth, subsequently rises, and plateaus at approximately 45 mg/dL 12 h after birth.
