Hypoglycemia and Hyperglycemia
Richard E. Wilker
Hypoglycemia is historically one of the most common metabolic problems seen in both the newborn nursery and neonatal intensive care unit (NICU), but confirming a diagnosis of clinically significant hypoglycemia requires that one interpret the blood glucose value 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 babies, the blood glucose level 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.
Persistent hyperglycemia is very rarely seen in the newborn nursery, but frequently occurs in very low birth weight (VLBW) babies in the NICU.
I. HYPOGLYCEMIA.
Glucose provides the fetus with approximately 60% to 70% of its 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, and to maintain adequate glucose levels, the newborn must rapidly respond by glycogenolysis of hepatic stores, inducing gluconeogenesis, and utilizing exogenous nutrients from feeding. During this normal transition, newborn glucose levels fall to a low point in the first 1 to 2 hours of life, and then increase and stabilize at mean levels of 65 to 70 mg/dL by the age of 3 to 4 hours.
Incidence. The reported incidence of hypoglycemia varies with its definition, but it has been estimated to occur in up to 16% of large-for-gestational-age (LGA) infants and 15% of small-for-gestational-age (SGA) infants. Since blood glucose levels change markedly within the first hours of life, it is necessary to know the baby’s exact age in order to interpret the glucose level.
Definition. The continued lack of a rational evidence-based definition of neonatal hypoglycemia has hampered the discussion of its incidence, effects, and treatment goals.
Historical Definitions
Previous epidemiologic definitions that resulted in the acceptance of repeated glucose levels in the range of 20 to 30 mg/dL are no longer considered valid.
Using a clinical definition (Whipple’s triad) that required demonstrating symptoms in association with low glucose levels and resolution when the levels were restored to the normal range is also problematic since the development of clinical signs or symptoms may be a late manifestation of hypoglycemia. One of the goals of current management is to anticipate and attempt to prevent symptomatic hypoglycemia rather than react to it.
Operational threshold. In 2000, Cornblath recommended the use of an “operational threshold” for blood sugar management in newborn infants. The operational threshold is an indication for action and is not diagnostic of disease or abnormality.
Cornblath’s description of operational thresholds suggested glucose levels at which intervention should be considered based on clinical experience and analysis of the available evidence. Some important features of operational thresholds are listed subsequently:
Lower than therapeutic goal
Dependent on clinical state and age
Do not define normal or abnormal
Provide margin of safety
Operational thresholds as suggested by Cornblath et al.
Healthy full-term infant
<24 hours of age—30 to 35 mg/dL may be acceptable at one time, but threshold is raised to 45 mg/dL if it persists after feeding or if it recurs in first 24 hours.
After 24 hours, threshold should be increased to 45 to 50 mg/dL.
Infant with abnormal signs or symptoms—45 mg/dL.
Asymptomatic infants with riskfactors for low blood sugar—36 mg/dL. Close surveillance is required and intervention is needed if plasma glucose remains below this level, does not increase after feeding, or if abnormal clinical signs are seen.
For any baby, if glucose levels are <20 to 25 mg/dL, IV glucose is needed to raise the plasma glucose to >45 mg/dL.
The significance of a given glucose level depends on the method of measurement, the infant’s gestational age, chronological age, and other risk factors.
The absence of overt symptoms at low glucose levels does not rule out central nervous system (CNS) injury. There is no evidence indicating that the premature or young infant is protected from the effects of inadequate glucose delivery to the CNS.
There is no single value below which brain injury definitely occurs.
Within the first hours of life, normal asymptomatic babies may have a transient glucose level in the 30s (mg/dL) that will increase either spontaneously or in response to feeding. These babies have an excellent prognosis.
A glucose level less than 40 mg/dL at any time in any newborn requires a prompt follow-up glucose measurement to document normal values. If the value has not increased, an intervention is needed.
On the basis of developmental, neuroanatomic, metabolic, and clinical studies, our goal is to maintain the glucose value above 45 mg/dL in the first day, and more than 50 mg/dL thereafter.
Knowledge gaps. A report from the Eunice Kennedy Shriver National Institute of Child Health and Human Development workshop on neonatal hypoglycemia in 2009 identified the following knowledge gaps:
The complex nature and maturational features of global and regional brain energy use remain to be studied in human neonates.
There is no evidence-based study to identify any specific plasma glucose concentration (or range of glucose values) to define pathologic “hypoglycemia.” Research studies are needed to fulfill this basic gap in knowledge and to help demonstrate the relationship between plasma glucose concentrations during the neonatal period and later neurologic outcomes.
There is great inconsistency in the sources and sampling methods of blood (capillary, venous, arterial) and the methods used for subsequent analysis, including processing techniques, thus affecting “normal” values on the basis of existing literature.
There are no noninvasive methods for measuring concentrations of glucose and other energy substrates (intermittently or continuously); the existing minimally invasive methods need further refinement for their utility.
The role of neuroimaging and electroencephalogram (EEG) studies in the management and prediction of hypoglycemia-related neuronal injuries remains to be determined.
Etiology
Hyperinsulinemic hypoglycemia is recognized as a major cause of persistent recurrent hypoglycemia in newborns, and it may be associated with an increased risk of brain injury since 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, while others require more aggressive and prolonged treatment.
Historically, the most common example of hyperinsulinism is the infant of diabetic mothers (see Chap. 2).
Congenital genetic. Hyperinsulinism is seen in mutations of genes encoding the pancreatic beta cell ATP-sensitive potassium channel, such as ABCC8 and KCNJ11, which encode for sulfonylurea receptor (SUR1) and Kir6.2. Elevated insulin levels are also associated with loss of function mutations in HNF4A gene. Additional mutations continue to be identified.
Secondary to other conditions
Birth asphyxia
Developmental syndromes such as Beckwith-Wiedemann syndrome (macrosomia, mild microcephaly, omphalocele, macroglossia, hypoglycemia, and visceromegaly)
Congenital disorders of glycosylation and other metabolic conditions
Erythroblastosis (hyperplastic islets of Langerhans) (see Chap. 26)
Maternal tocolytic therapy with beta-sympathomimetic agents (terbutaline)
Malpositioned umbilical artery catheter used to infuse glucose in high concentration into the celiac and superior mesenteric arteries T11 to 12, stimulating insulin release from the pancreas
Abrupt cessation of high glucose infusion
After exchange transfusion with blood containing high glucose concentration
Insulin-producing tumors (nesidioblastosis, islet cell adenoma, or islet cell dysmaturity)
Large-for-gestational-age infants. Current prenatal obstetric care includes testing women for glucose intolerance, and the number of undiagnosed infants of gestational diabetic mothers has decreased. The incidence of hypoglycemia in this heterogeneous population is not accurately known, but this group continues to be considered at high risk for hypoglycemia and warrants routine screening.
Decreased production/stores
Prematurity
Intrauterine growth restriction (IUGR)
Inadequate caloric intake
Delayed onset of feeding
Increased utilization and/or decreased production. Any baby with one of the following conditions should be evaluated for hypoglycemia; parenteral glucose may be necessary for the management of these infants.
Perinatal stress
Sepsis
Shock
Asphyxia
Hypothermia (increased utilization)
Respiratory distress
Postresuscitation
S/p 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.
Defects in carbohydrate metabolism (see Chap. 60)
Glycogen storage disease
Fructose intolerance
Galactosemia
Endocrine deficiency
Adrenal insufficiency
Hypothalamic deficiency
Congenital hypopituitarism
Glucagon deficiency
Epinephrine deficiency
Defects in amino acid metabolism (see Chap. 60)
Maple syrup urine disease
Propionic acidemia
Methylmalonic acidemia
Tyrosinemia
Glutaric acidemia type II
Ethylmalonic adipic aciduria
Polycythemia. Hypoglycemia may be due to higher glucose utilization by the increased mass of red blood cells. The 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 Chap. 46).
Maternal therapy with beta-blockers (e.g., labetalol or propranolol). Possible mechanisms include the following:
Prevention of sympathetic stimulation of glycogenolysis
Prevention of recovery from insulin-induced decreases in free fatty acids and glycerol
Inhibition of epinephrine-induced increases in free fatty acids and lactate after exercise
Diagnosis
Symptoms that have been attributed to hypoglycemia are nonspecific.
Tremors, jitteriness, or irritability
Seizures, coma
Lethargy, apathy, and limpness
Poor feeding, vomiting
Apnea
Weak or high-pitched cry
Cyanosis
Many infants may have no symptoms
