**4. Etiology and pathogenesis**

Overall, neonatal hypoglycemia is caused by one of the three main mechanisms: situations associated with hyperinsulinemia, situations associated with low or depleted glycogen stores, and situations associated with excessive glucose consumption. These mechanisms may also be compounded by the effects of certain drugs used in pregnancy.

#### **4.1. Situations associated with hyperinsulinemia**

#### *4.1.1. Infant born to a mother with diabetes*

Offspring of diabetic mothers may be abnormally large at birth (LGA), even when the mother was able to keep blood glucose within normal or near-normal range throughout pregnancy. The risk of birth defects is two to four times higher in fetuses of pregnant women with diabetes, particularly when the disorder is poorly controlled during the period of fetal organ development (i.e., gestational weeks 6–7), and the neonatal mortality rate is fivefold than that of infants born to women without diabetes.

Intermittent maternal hyperglycemia causes fetal hyperglycemia, which, in turn, stimulates excess insulin production by the fetal pancreas. On the one hand, this increased fetal insulin synthesis stimulates excess organ growth (except of the brain and liver, which are not dependent on insulin supply for growth), thus causing fetal macrosomia. On the other hand, it is associated with a high incidence of neonatal hypoglycemia and marked lipolysis during the first few hours after birth. Hyperinsulinism and hyperglycemia may also cause fetal acidosis, which results in an increased rate of stillbirths. Although hyperinsulinemia is probably the leading cause of hypoglycemia, reduced epinephrine and glucagon responses can also be contributing factors. Levels of cortisol and growth hormone are normal [11].

Increased levels of glycated hemoglobin in fetal blood appear to precipitate tissue hypoxia, as this form of hemoglobin has high affinity for oxygen molecules.

Furthermore, chronic fetal hyperinsulinemia increases metabolic rates, thus increasing oxygen consumption and inducing relative hypoxemia; this, in turn, boosts red blood cell production, causing polycythemia and, consequently, hemolysis and neonatal hyperbilirubinemia. Severe hypoxemia can ultimately lead to fetal death.

After birth, the supply of glucose to the fetus is cut off, but hyperinsulinemia persists, speeding both exogenous glucose utilization and endogenous glucose production; this phenomenon may last approximately 3 days, until normal insulin secretion is established. Hypoglycemia may manifest in the intervening period.

#### *4.1.2. Large for gestational age status*

**3. Definition**

66 Selected Topics in Neonatal Care

represent a red flag for neurological safety.

which treatment should be instituted [61].

**4. Etiology and pathogenesis**

of diagnostic measures and immediate treatment.

**4.1. Situations associated with hyperinsulinemia**

*4.1.1. Infant born to a mother with diabetes*

be compounded by the effects of certain drugs used in pregnancy.

Current evidence is still unable to define a specific glucose concentration that is safe to prevent acute neurological damage or chronic, irreversible neurological injury in the neonate. Weight and gestational age, as well as the age at onset, severity, duration, and number of episodes of hypoglycemia, are all determinants of the blood glucose level most appropriate for protection of the neonatal brain [54]; thus, doubts persist as to whether any single level may

A plasma glucose level below 30 mg/dL (1.65 mmol/L) in the first 2 h of life or below 45 mg/dL

Various situations can influence the appropriateness of a blood glucose level for use as a cutoff point for treatment initiation, including nutritional timing and the presence and absence of symptoms [64]. Thus, in 2011, the American Academy of Pediatrics proposed that neonatal hypoglycemia be defined as a blood glucose level of 2.5 mmol/L before routine feeding [1, 20]. Other studies suggest a limit of 2 mmol/L in asymptomatic newborns and 2.5 mmol/L in symptomatic neonates [42]. Although cutoff values below 2.6 mmol/L have been cited in various studies as defining of neonatal hypoglycemia, there is no guarantee that such a concentration is the most appropriate choice for establishing a diagnosis of this disorder and prompting initiation of treatment. An important finding reported by McKinlay et al. [34] has encouraged neonatologists to consider a glucose concentration >47 mg/dL as the level at which no impair-

These proposed levels serve to provide a margin of safety until additional data are available to support a more accurate definition. However, the potential risk of neurologic sequelae has led many authors to consider blood glucose values <50 mg/dL in infants as the limit beyond

In practice, blood glucose levels below 50 mg/dL as measured by a glucometer should warrant careful monitoring, and plasma glucose levels below 45 mg/dL should prompt initiation

Overall, neonatal hypoglycemia is caused by one of the three main mechanisms: situations associated with hyperinsulinemia, situations associated with low or depleted glycogen stores, and situations associated with excessive glucose consumption. These mechanisms may also

Offspring of diabetic mothers may be abnormally large at birth (LGA), even when the mother was able to keep blood glucose within normal or near-normal range throughout pregnancy.

(2.5 mmol/L) after these first 2 h has been considered diagnostic of hypoglycemia [54].

ment of appropriate neurological development was observed at age 2 years.

LGA neonates may also develop hypoglycemia [44], through the same mechanism observed in infants born to diabetic mothers; however, in these infants, blood glucose reaches normal levels within the first few hours of life [32].

#### *4.1.3. Congenital hyperinsulinemic hypoglycemia*

Hypoglycemia associated with congenital hyperinsulinism (CHH), also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is the result of inappropriate insulin secretion or hyperinsulinism. In infants with this disease, hypoglycemia is triggered by fasting and is always accompanied by an increase in plasma insulin concentrations, which are usually inappropriately high for the concomitant low blood glucose concentration. The disease appears to be more closely related to an increase in global endocrine functional activity of the pancreas rather than an increase in the number of pancreatic beta cells.

CHH is an important etiology that should be considered in cases of persistent and difficultto-control hypoglycemia. It is a medical emergency that requires precise etiological diagnosis and represents a serious therapeutic challenge. The term PHHI was first proposed by Glaser in 1989 [19] and has since come to replace the now-outdated terms nesidioblastosis and islet-cell dysmaturity syndrome to describe pancreatic abnormalities associated with hypoglycemia and hyperinsulinism.

ion channels. In the third type, onset is delayed and severity is mild, as these patients have

Neonatal Hypoglycemia

69

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A diagnosis of CHH is usually considered when hypoglycemia develops shortly after birth and requires glucose infusion at high rates, usually exceeding 10 mg/kg/min and occasionally up to 15–20 mg/kg/min. Typically, these infants have high blood levels of insulin, sometimes exceeding 10 μU/mL, and the insulin (μU/mL)-to-glucose (mg/dL) ratio is 1:4 or higher.

Beta-cell adenomas are characterized by marked, early onset hyperinsulinemia. These tumors require surgical removal or partial pancreatectomy. They are uncommon in the neonatal period. Definitive diagnosis can only be established through histopathology, and immuno-

Beckwith-Wiedemann syndrome is one of the most common overgrowth disorders and can be identified in more than 75% of neonates above the 90th percentile for weight and length. It is estimated to occur in 1 in 13,700 births, but mild cases may lead to underestimation of its true frequency [31]. There is no gender predominance. The syndrome is characterized by gigantism, omphalocele, and macroglossia, a triad that occurs in over 80% of cases. Other abnormalities that occur less frequently include earlobe creases and posterior helical ear pits, microcephaly, wide fontanels, a prominent occipital protuberance, facial nevus flammeus, nonspecific cardiac defects, abdominal wall defects (umbilical hernia, diastasis recti), visceromegaly, and hyperplasia of the kidneys, pancreas, adrenal cortices, gonadal interstitial cells, and pituitary [50].

Neonatal hypoglycemia occurs in at least 50% of cases of Beckwith-Wiedemann syndrome. It is generally serious and may be associated with future mental retardation. Thus, early diagnosis is important for proper treatment of low serum glucose levels, to prevent neurological damage. It is believed that hypoglycemia in this syndrome is secondary to hyperinsulinism caused by beta-cell hyperplasia and hypertrophy, but glucagon deficiency and a reduction in

There is a clear evidence of genomic influence in the development of Beckwith-Wiedemann syndrome. A mutation in 11p15.5, a region that encompasses multiple gene loci, has been

CHH has been described in other diseases and syndromes, including congenital hypothyroidism [29], Sotos syndrome [4], Costello syndrome [21], Donohue syndrome [63], and Kabuki

Prematurity and intrauterine growth restriction are among the situations that can influence

somatostatin-producing delta cells have also been documented.

*4.1.3.2. Congenital hyperinsulinemic hypoglycemia and other syndromes*

**4.2. Situations associated with low or depleted glycogen stores**

functional KATPs and respond to clinical treatment.

histochemical study may be required.

*4.1.3.1. Beckwith-Wiedemann syndrome*

implicated [37].

syndrome [62].

neonatal blood glucose levels [35].

Most cases of CHH are sporadic (1:40,000–50,000 live births), but a higher prevalence has been described in communities with a high degree of consanguinity. This familial form associated with inbreeding may occur in up to 1:2500 live births. Thus, an autosomal recessive inheritance pattern has been posited to explain it. There is no evidence of sex predominance, and the maternal history is generally negative; however, a careful history may reveal prior neonatal deaths or unexplained seizures or mental retardation in other siblings.

Patients with CHH are mostly LGA, as a consequence of hyperinsulinism, but without significant hepatomegaly. They exhibit persistent symptoms of hypoglycemia, including hypotonia, cyanosis, apnea, and difficult-to-control seizures, as early as the neonatal period. Sudden infant death is also seen in patients with CHH. Although the condition is rare, the high frequency of brain damage and developmental delay as a result of severe, treatment-refractory hypoglycemia in these patients justifies the need for early etiologic diagnosis and immediate treatment.

Currently, the most accepted etiogenic hypothesis for the dysfunction of CHH is inappropriate insulin secretion by pancreatic beta cells. The molecular basis of congenital hyperinsulinism involves defects in key genes that regulate the complex mechanism of insulin secretion control [12]. Nine genes have been identified and classified within the potassium channelopathies (ABCC8, KCNJ11) and metabolic disorders (GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2, HADH) [47, 52]. Genetic defect mutations involving the ABCC8/KCNJ11 genes, which encode the SUR1/Kir 6.2 components of the ATP-sensitive potassium channels (KATP) in pancreatic beta cells, are the most common [13, 27]. In normal cells, the KATP channels remain open or closed in response to variation in blood glucose levels, which leads to changes in the action potential of the cell membrane. An increase in blood glucose raises the rate of glucose metabolism in beta cells, resulting in increased adenosine triphosphate (ATP) and decreased adenosine diphosphate (ADP) within the cell, triggering closure of KATP channels and subsequent depolarization of the beta-cell membrane. This change in potential opens voltage-dependent calcium channels and leads to calcium influx. The subsequent increase in the cytosolic calcium concentration stimulates exostosis of insulin secretory granules; thus, insulin is released continuously.

The potassium channel is a complex of two proteins: SUR1, a receptor with high affinity for sulfonylureas, and Kir 6.2, which forms the inner pore of the channel and maintains its alignment [39, 58, 59]. The regulatory genes of the sulfonylurea receptor and potassium channels were recently mapped to region 11p15.1 of chromosome 11. Individually; none of these proteins has the ability to act as a potassium channel. Depending on the type of mutation affecting the genes that regulate these proteins, CHH may manifest with three distinct phenotypes. The first represents the familial form, with truncation of SUR1 and the absence of KATP. These patients have the most severe form of CHH and, in most cases, respond poorly or not at all to clinical treatment. In the second type, which accounts for sporadic cases, there is loss of KATP function but partial response to clinical treatment, due to formation of new potassium ion channels. In the third type, onset is delayed and severity is mild, as these patients have functional KATPs and respond to clinical treatment.

A diagnosis of CHH is usually considered when hypoglycemia develops shortly after birth and requires glucose infusion at high rates, usually exceeding 10 mg/kg/min and occasionally up to 15–20 mg/kg/min. Typically, these infants have high blood levels of insulin, sometimes exceeding 10 μU/mL, and the insulin (μU/mL)-to-glucose (mg/dL) ratio is 1:4 or higher.

Beta-cell adenomas are characterized by marked, early onset hyperinsulinemia. These tumors require surgical removal or partial pancreatectomy. They are uncommon in the neonatal period. Definitive diagnosis can only be established through histopathology, and immunohistochemical study may be required.

#### *4.1.3.1. Beckwith-Wiedemann syndrome*

dysmaturity syndrome to describe pancreatic abnormalities associated with hypoglycemia

Most cases of CHH are sporadic (1:40,000–50,000 live births), but a higher prevalence has been described in communities with a high degree of consanguinity. This familial form associated with inbreeding may occur in up to 1:2500 live births. Thus, an autosomal recessive inheritance pattern has been posited to explain it. There is no evidence of sex predominance, and the maternal history is generally negative; however, a careful history may reveal prior neonatal

Patients with CHH are mostly LGA, as a consequence of hyperinsulinism, but without significant hepatomegaly. They exhibit persistent symptoms of hypoglycemia, including hypotonia, cyanosis, apnea, and difficult-to-control seizures, as early as the neonatal period. Sudden infant death is also seen in patients with CHH. Although the condition is rare, the high frequency of brain damage and developmental delay as a result of severe, treatment-refractory hypoglycemia in these patients justifies the need for early etiologic diagnosis and immediate

Currently, the most accepted etiogenic hypothesis for the dysfunction of CHH is inappropriate insulin secretion by pancreatic beta cells. The molecular basis of congenital hyperinsulinism involves defects in key genes that regulate the complex mechanism of insulin secretion control [12]. Nine genes have been identified and classified within the potassium channelopathies (ABCC8, KCNJ11) and metabolic disorders (GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2, HADH) [47, 52]. Genetic defect mutations involving the ABCC8/KCNJ11 genes, which encode the SUR1/Kir 6.2 components of the ATP-sensitive potassium channels (KATP) in pancreatic beta cells, are the most common [13, 27]. In normal cells, the KATP channels remain open or closed in response to variation in blood glucose levels, which leads to changes in the action potential of the cell membrane. An increase in blood glucose raises the rate of glucose metabolism in beta cells, resulting in increased adenosine triphosphate (ATP) and decreased adenosine diphosphate (ADP) within the cell, triggering closure of KATP channels and subsequent depolarization of the beta-cell membrane. This change in potential opens voltage-dependent calcium channels and leads to calcium influx. The subsequent increase in the cytosolic calcium concentration stimulates exostosis of insulin secretory granules; thus, insulin is released

The potassium channel is a complex of two proteins: SUR1, a receptor with high affinity for sulfonylureas, and Kir 6.2, which forms the inner pore of the channel and maintains its alignment [39, 58, 59]. The regulatory genes of the sulfonylurea receptor and potassium channels were recently mapped to region 11p15.1 of chromosome 11. Individually; none of these proteins has the ability to act as a potassium channel. Depending on the type of mutation affecting the genes that regulate these proteins, CHH may manifest with three distinct phenotypes. The first represents the familial form, with truncation of SUR1 and the absence of KATP. These patients have the most severe form of CHH and, in most cases, respond poorly or not at all to clinical treatment. In the second type, which accounts for sporadic cases, there is loss of KATP function but partial response to clinical treatment, due to formation of new potassium

deaths or unexplained seizures or mental retardation in other siblings.

and hyperinsulinism.

68 Selected Topics in Neonatal Care

treatment.

continuously.

Beckwith-Wiedemann syndrome is one of the most common overgrowth disorders and can be identified in more than 75% of neonates above the 90th percentile for weight and length. It is estimated to occur in 1 in 13,700 births, but mild cases may lead to underestimation of its true frequency [31]. There is no gender predominance. The syndrome is characterized by gigantism, omphalocele, and macroglossia, a triad that occurs in over 80% of cases. Other abnormalities that occur less frequently include earlobe creases and posterior helical ear pits, microcephaly, wide fontanels, a prominent occipital protuberance, facial nevus flammeus, nonspecific cardiac defects, abdominal wall defects (umbilical hernia, diastasis recti), visceromegaly, and hyperplasia of the kidneys, pancreas, adrenal cortices, gonadal interstitial cells, and pituitary [50].

Neonatal hypoglycemia occurs in at least 50% of cases of Beckwith-Wiedemann syndrome. It is generally serious and may be associated with future mental retardation. Thus, early diagnosis is important for proper treatment of low serum glucose levels, to prevent neurological damage. It is believed that hypoglycemia in this syndrome is secondary to hyperinsulinism caused by beta-cell hyperplasia and hypertrophy, but glucagon deficiency and a reduction in somatostatin-producing delta cells have also been documented.

There is a clear evidence of genomic influence in the development of Beckwith-Wiedemann syndrome. A mutation in 11p15.5, a region that encompasses multiple gene loci, has been implicated [37].

#### *4.1.3.2. Congenital hyperinsulinemic hypoglycemia and other syndromes*

CHH has been described in other diseases and syndromes, including congenital hypothyroidism [29], Sotos syndrome [4], Costello syndrome [21], Donohue syndrome [63], and Kabuki syndrome [62].

#### **4.2. Situations associated with low or depleted glycogen stores**

Prematurity and intrauterine growth restriction are among the situations that can influence neonatal blood glucose levels [35].

#### *4.2.1. Prematurity*

As very low-birth-weight preterm infants have limited glycogen stores, gluconeogenesis is their main source of glucose production. Gluconeogenesis is induced by decreased glucose intake, as well as by high cortisol, catecholamine, and glucagon levels.

The association of severe respiratory distress, from various causes, and hypoglycemia caused

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Neonatal sepsis is defined as a clinical syndrome characterized by systemic signs of infection and bacteremia (detected by positive blood cultures) during the first month of life. It is becoming increasingly important due to the reduction of neonatal mortality among the most

Decreased glycogen stores, impaired gluconeogenesis, and increased peripheral glucose utilization appear to be the factors responsible for hypoglycemia associated with sepsis, although the usual response to sepsis observed in animal models has been an increase in the rates of glucose *turnover* and gluconeogenesis, as the result of a counter-regulatory hormonal response [33]. Blunting of this process is observed only during the final stage of illness and serves as a

Drugs such as beta-adrenergic agonists [57], corticosteroids, thiazide diuretics, oral antidiabetics, propranolol, labetalol [3], valproic acid [10], antidepressants (SSRIs) [40], phenytoin,

B. Zhu et al. (2016) [67] reported an association between metformin use by diabetic patients during pregnancy and a reduction in incidence of neonatal hypoglycemia when compared to mothers who used insulin. Metformin has proven an effective alternative for use in this

In most cases, infants—even those at risk—are asymptomatic. Nevertheless, an infant who is apathetic and refusing feeds and has a feeble cry should heighten suspicion of hypoglycemia. In high-risk infants, major findings include fine tremors, acrocyanosis, seizures, and apnea; if

After birth, neonates born to mothers with diabetes develop complications related to their hyperinsulinemic state. In the first 3 days of life, these infants may exhibit episodes of irritability, tremor, and hyperexcitability or may present with hypotonia, lethargy, and weak suckling—manifestations consistent with early development of hypoglycemia and late onset of hypocalcemia. However, one must bear in mind that these infants are sometimes asymp-

The presence of tachypnea in the first days of life may be a transient manifestation of hypoglycemia, hypothermia, polycythemia, heart failure, cerebral edema secondary to traumatic delivery (particularly in macrosomic infants), or asphyxiation. The incidence of respiratory distress syndrome is high in these infants, since hyperinsulinemia may alter fetal lung maturation, inhibiting the development of enzymes required for the synthesis of pulmonary surfactant.

tomatic and the absence of symptoms should not delay testing for hypoglycemia.

and terbutaline [55], among others, can cause hypoglycemia in infants.

patient population, although it can cross the placenta.

**5. Manifestations and clinical diagnosis**

left untreated, coma and death may follow.

premature newborns and to the prolonged care of these infants in neonatal units.

by increased glucose consumption has often been described.

marker of fulminant sepsis [38].

**4.4. Drugs used in pregnancy**

Increased neurologic morbidity is particularly common in children with severe, recurrent hypoglycemia. Experimental observations have stressed the resistance of the immature brain to damage caused by hypoglycemia. This resistance is a consequence of compensatory increase in blood flow to the brain, reduced energy needs, increased endogenous carbohydrate stores, and ability to take up and consume alternative organic substrates while saving glucose for energy production [36].

#### *4.2.2. Intrauterine growth restriction*

As a result of intrauterine growth restriction, SGA neonates may exhibit several abnormalities shortly after birth, including increased susceptibility to infections, pulmonary hemorrhage, hyperbilirubinemia, and hypoglycemia. The widely varying incidence of the latter may reflect the different etiologies of intrauterine growth restriction (e.g., poor maternal nutrition, mothers with advanced age, uteroplacental insufficiency, derangements in maternal metabolism, or fetal infection). Furthermore, polycythemia and fetal and neonatal hypoxemia, which are often seen in SGA infants, can themselves contribute to development of hypoglycemia [49].

SGA infants are most at risk of hypoglycemia. Of those who do develop it, 65% are premature and 25% are post-term. Hypoglycemia can be asymptomatic or symptomatic and is generally observed in the first 24 h of life.

The factors contributing to low blood glucose levels include inadequate hepatic glycogen stores due to the high brain-to-body-mass ratio of SGA infants, the glucose-dependent nature of cerebral oxidative metabolism, and high overall metabolic rates. Furthermore, a reduction in rates of gluconeogenesis is probably responsible for 1% of episodes of prolonged hypoglycemia in SGA infants, as these infants exhibit high concentrations of gluconeogenesis precursors (such as alanine); this suggests an inability to convert these exogenous precursors into glucose.

Hypoglycemia combined with asphyxia is more damaging to the immature brain than either condition alone.

#### **4.3. Situations associated with increased glucose consumption**

Various situations can increase glucose consumption in the neonate. These include severe birth asphyxia [9], severe respiratory distress, and sepsis.

Perinatal asphyxia may initially feature hyperglycemia secondary to cortisol and catecholamine release; this is followed by hypoglycemia secondary to depletion of hepatic glycogen stores, mobilized in response to this excess glucose consumption. The association of hypoglycemia with transient hyperinsulinism has been described [18].

The association of severe respiratory distress, from various causes, and hypoglycemia caused by increased glucose consumption has often been described.

Neonatal sepsis is defined as a clinical syndrome characterized by systemic signs of infection and bacteremia (detected by positive blood cultures) during the first month of life. It is becoming increasingly important due to the reduction of neonatal mortality among the most premature newborns and to the prolonged care of these infants in neonatal units.

Decreased glycogen stores, impaired gluconeogenesis, and increased peripheral glucose utilization appear to be the factors responsible for hypoglycemia associated with sepsis, although the usual response to sepsis observed in animal models has been an increase in the rates of glucose *turnover* and gluconeogenesis, as the result of a counter-regulatory hormonal response [33]. Blunting of this process is observed only during the final stage of illness and serves as a marker of fulminant sepsis [38].

#### **4.4. Drugs used in pregnancy**

*4.2.1. Prematurity*

70 Selected Topics in Neonatal Care

glucose for energy production [36].

*4.2.2. Intrauterine growth restriction*

hypoglycemia [49].

condition alone.

observed in the first 24 h of life.

As very low-birth-weight preterm infants have limited glycogen stores, gluconeogenesis is their main source of glucose production. Gluconeogenesis is induced by decreased glucose

Increased neurologic morbidity is particularly common in children with severe, recurrent hypoglycemia. Experimental observations have stressed the resistance of the immature brain to damage caused by hypoglycemia. This resistance is a consequence of compensatory increase in blood flow to the brain, reduced energy needs, increased endogenous carbohydrate stores, and ability to take up and consume alternative organic substrates while saving

As a result of intrauterine growth restriction, SGA neonates may exhibit several abnormalities shortly after birth, including increased susceptibility to infections, pulmonary hemorrhage, hyperbilirubinemia, and hypoglycemia. The widely varying incidence of the latter may reflect the different etiologies of intrauterine growth restriction (e.g., poor maternal nutrition, mothers with advanced age, uteroplacental insufficiency, derangements in maternal metabolism, or fetal infection). Furthermore, polycythemia and fetal and neonatal hypoxemia, which are often seen in SGA infants, can themselves contribute to development of

SGA infants are most at risk of hypoglycemia. Of those who do develop it, 65% are premature and 25% are post-term. Hypoglycemia can be asymptomatic or symptomatic and is generally

The factors contributing to low blood glucose levels include inadequate hepatic glycogen stores due to the high brain-to-body-mass ratio of SGA infants, the glucose-dependent nature of cerebral oxidative metabolism, and high overall metabolic rates. Furthermore, a reduction in rates of gluconeogenesis is probably responsible for 1% of episodes of prolonged hypoglycemia in SGA infants, as these infants exhibit high concentrations of gluconeogenesis precursors (such as alanine); this suggests an inability to convert these exogenous precursors into glucose. Hypoglycemia combined with asphyxia is more damaging to the immature brain than either

Various situations can increase glucose consumption in the neonate. These include severe

Perinatal asphyxia may initially feature hyperglycemia secondary to cortisol and catecholamine release; this is followed by hypoglycemia secondary to depletion of hepatic glycogen stores, mobilized in response to this excess glucose consumption. The association of hypogly-

**4.3. Situations associated with increased glucose consumption**

birth asphyxia [9], severe respiratory distress, and sepsis.

cemia with transient hyperinsulinism has been described [18].

intake, as well as by high cortisol, catecholamine, and glucagon levels.

Drugs such as beta-adrenergic agonists [57], corticosteroids, thiazide diuretics, oral antidiabetics, propranolol, labetalol [3], valproic acid [10], antidepressants (SSRIs) [40], phenytoin, and terbutaline [55], among others, can cause hypoglycemia in infants.

B. Zhu et al. (2016) [67] reported an association between metformin use by diabetic patients during pregnancy and a reduction in incidence of neonatal hypoglycemia when compared to mothers who used insulin. Metformin has proven an effective alternative for use in this patient population, although it can cross the placenta.
