Hypoglycemia is one of the most common metabolic problems seen in both the newborn nursery and neonatal intensive care unit (NICU). Confirming a diagnosis of clinically significant hypoglycemia requires interpretation of blood glucose values within the clinical context. The definition of hypoglycemia as well as its clinical significance and management remain controversial. Blood glucose levels in the first hours of life are typically lower than normal values of older children or adults. In healthy infants, blood glucose levels can often be maintained in the appropriate range by initiating feeding soon after birth. Most cases of neonatal hypoglycemia are transient, respond readily to treatment, and are associated with an excellent prognosis. Persistent hypoglycemia is more likely to be associated with abnormal endocrine conditions, including hyperinsulinemia, as well as possible neurologic sequelae, but it is not possible to validly quantify the effects of neonatal hypoglycemia on subsequent neurodevelopment.

Hyperglycemia is very rarely seen in the newborn nursery but frequently occurs in very low birth weight (VLBW) infants in the NICU.

I. HYPOGLYCEMIA. Glucose provides approximately 60% to 70% of fetal energy needs. Almost all fetal glucose derives from the maternal circulation by the process of transplacental-facilitated diffusion that maintains fetal glucose levels at
approximately two-thirds of maternal levels. The severing of the umbilical cord at birth abruptly interrupts the source of glucose. Subsequently, the newborn must rapidly respond by glycogenolysis of hepatic stores, inducing gluconeogenesis, and utilizing exogenous nutrients from feeding to maintain adequate glucose levels. During this normal transition, newborn glucose levels fall to a low point in the first 1 to 2 hours of life (to as low as 30 mg/dL) and then increase to >45 mg/dL, stabilizing at mean levels of 65 to 70 mg/dL by 3 to 4 hours of age.

A. Incidence. The incidence of hypoglycemia varies by population and definition used. Furthermore, blood glucose levels change markedly within the first hours of life, and it is necessary to know the infant’s exact age in order to interpret the glucose level and diagnose hypoglycemia. However, a recent prospective New Zealand study of infants at risk for hypoglycemia (defined as a blood glucose <2.6 mOsm [<46.8 mg/dL]) demonstrated that 47% of large for gestational age (LGA) infants, 52% of small for gestational age (SGA) infants, 48% of infants of diabetic mothers (IDMs), and 54% of late preterm infants were found to be hypoglycemic.

B. Definition. In 2011, the American Academy of Pediatrics (AAP) published a clinical report by David Adamkin and the Committee on Fetus and Newborn focused on postnatal glucose homeostasis in late-preterm and term infants. The report provides a practical guideline for screening and management of neonatal hypoglycemia. In the absence of consensus in the literature of exact definitions of hypoglycemia (glucose values or duration), the report guides clinicians to develop hypoglycemia screening protocols to avoid prolonged hypoglycemia in symptomatic infants and asymptomatic at-risk newborns. The Pediatric Endocrine Society also released hypoglycemia guidelines in 2015 which specify that infants >48 hours of age should have higher glucose levels and be evaluated for hypoglycemia with higher thresholds (<60 mg/dL) specifically of plasma glucose which is approximately 15% higher than whole blood glucose. The thresholds for treating hypoglycemia depend on the presence of symptoms, the age of the infant in hours, and the persistence of hypoglycemia.

In the AAP report, the authors recommend measuring blood glucose levels and treatment for the following:

1. Symptomatic infants with blood glucose <40 mg/dL with intravenous (IV) glucose (for symptoms, see section I.D.1)

2. Asymptomatic infants at risk for hypoglycemia defined as late preterm (34 to 36 6/7 weeks of gestation), term SGA, IDM, or LGA

i. Initial screen <25 mg/dL (should be done within first hours after birth), infant should be fed and rechecked, and if the next level, 1 hour later, is <25 mg/dL, treatment with IV glucose should be administered.

ii. If the second check is 25 to 40 mg/dL, feeding may be considered as an alternative to IV glucose.

i. Glucose <35 mg/dL, infants should be fed and glucose rechecked in 1 hour.

ii. If glucose continues to be <35 mg/dL, IV glucose should be administered.

iii. If recheck after initial feeding is 35 to 45 mg/dL, feeding may be attempted.

iv. Recommendation is to target glucose >45 mg/dL.

c. According to the Pediatric Endocrine Society, by 48 to 72 hours of life, glucose control should be similar to that of older children and adults. Plasma glucose levels should be >60 mg/dL. Bedside reagent strips will be within ±10 to 15 mg/dL and less accurate in the hypoglycemic range. Furthermore, typically bedside whole blood glucose measurements are ˜15% lower than plasma levels.

1. Hyperinsulinemic hypoglycemia causes persistent, recurrent hypoglycemia in newborns, and it may be associated with an increased risk of brain injury because it not only decreases serum glucose levels but also prevents the brain from utilizing secondary fuel sources by suppressing fatty acid release and ketone body synthesis. Some cases of hyperinsulinemic hypoglycemia are transient and resolve over the course of several days, whereas others require more aggressive and prolonged treatment.

a. The most common example of hyperinsulinism is the IDM (see Chapter 62). Additionally, LGA infants are at risk for hyperinsulinism. Although women are screened for gestational diabetes during pregnancy, some women either have mild glucose intolerance that is subthreshold for diagnosis or develop late-onset glucose intolerance, and their infants are sometimes LGA and hypoglycemic.

b. Congenital genetic. Hyperinsulinism is seen in mutations of genes encoding the pancreatic beta cell adenosine triphosphate (ATP)-sensitive potassium channel, such as ABCC8 and KCNJ11 which encode for SUR1 and Kir6.2. Elevated insulin levels are also associated with loss of function mutations in HNF4A gene. Additional mutations continue to be identified.

i. Birth asphyxia

ii. Syndromes such as Beckwith-Wiedemann syndrome (macrosomia, mild microcephaly, omphalocele, macroglossia, hypoglycemia, and visceromegaly)

iii. Congenital disorders of glycosylation and other metabolic conditions

iv. Erythroblastosis (hyperplastic islets of Langerhans) (see Chapter 26)

v. Maternal tocolytic therapy with beta-sympathomimetic agents (terbutaline) vi. Malpositioned umbilical artery catheter used to infuse glucose in high concentration into the celiac and superior mesenteric arteries T11-T12, stimulating insulin release from the pancreas vii. Abrupt cessation of high glucose infusion viii. After exchange transfusion with blood containing high glucose concentration

ix. Insulin-producing tumors (nesidioblastosis, islet cell adenoma, or islet cell dysmaturity)

a. Prematurity (Among 193 late preterm infants in a prospective New Zealand study, 54% were hypoglycemic.)

b. Intrauterine growth restriction (IUGR) or SGA. Among 152 SGA infants in New Zealand study, 52% were hypoglycemic.

c. Inadequate caloric intake

d. Delayed onset of feeding

3. Increased utilization and/or decreased production. Any infant with one of the following conditions should be evaluated for hypoglycemia; parenteral glucose may be necessary for the management of these infants.

a. Perinatal stress

i. Sepsis

ii. Shock

iii. Asphyxia

iv. Hypothermia (increased utilization)

v. Respiratory distress

vi. Postresuscitation

b. After exchange transfusion with heparinized blood that has a low glucose level in the absence of a glucose infusion; reactive hypoglycemia after exchange with relatively hyperglycemic citrate-phosphate-dextrose (CPD) blood

c. Defects in carbohydrate metabolism (see Chapter 60)

i. Glycogen storage disease

ii. Fructose intolerance

iii. Galactosemia

d. Endocrine deficiency

i. Adrenal insufficiency

ii. Hypothalamic deficiency

iii. Congenital hypopituitarism

iv. Glucagon deficiency

v. Epinephrine deficiency

e. Defects in amino acid metabolism (see Chapter 60)

i. Maple syrup urine disease

ii. Propionic acidemia

iii. Methylmalonic acidemia

iv. Tyrosinemia

v. Glutaric acidemia type II

vi. Ethylmalonic adipic aciduria

f. Polycythemia. Hypoglycemia may be due to higher glucose utilization by the increased mass of red blood cells. Additionally, decreased amount of serum per drop of blood may cause a reading consistent with hypoglycemia on whole blood measurements but may yield a normal glucose level on laboratory analysis of serum (see Chapter 46).

g. Maternal or infant therapy with beta-blockers (e.g., labetalol or propranolol). Possible mechanisms include the following:

i. Prevention of sympathetic stimulation of glycogenolysis

ii. Prevention of recovery from insulin-induced decreases in free fatty acids and glycerol

iii. Inhibition of epinephrine-induced increases in free fatty acids and lactate after exercise

1. Symptoms that have been attributed to hypoglycemia are nonspecific.

a. Irritability

b. Tremors

c. Jitteriness

d. Exaggerated Moro reflex

e. High-pitched cry

f. Seizures

g. Lethargy

h. Hypotonia

i. Cyanosis

j. Apnea

k. Poor feeding

l. Many infants have no symptoms.

2. Screening. Serial blood glucose levels should be routinely measured in infants who have risk factors for hypoglycemia and in infants who have symptoms that could be due to hypoglycemia (see section I.B).