**3. Definition**

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 represent a red flag for neurological safety.

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

Neonatal Hypoglycemia

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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

Increased levels of glycated hemoglobin in fetal blood appear to precipitate tissue hypoxia, as

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.

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

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

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

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

of the pancreas rather than an increase in the number of pancreatic beta cells.

contributing factors. Levels of cortisol and growth hormone are normal [11].

this form of hemoglobin has high affinity for oxygen molecules.

Severe hypoxemia can ultimately lead to fetal death.

may manifest in the intervening period.

levels within the first few hours of life [32].

*4.1.3. Congenital hyperinsulinemic hypoglycemia*

*4.1.2. Large for gestational age status*

of infants born to women without diabetes.

A plasma glucose level below 30 mg/dL (1.65 mmol/L) in the first 2 h of life or below 45 mg/dL (2.5 mmol/L) after these first 2 h has been considered diagnostic of hypoglycemia [54].

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

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 which treatment should be instituted [61].

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 of diagnostic measures and immediate treatment.
