Neonatal Hypoglycemia

Hypoglycemia is the most common metabolic problem in neonates. In children, a blood glucose value of less than 40 mg/dL (2.2 mmol/L) represents hypoglycemia. A plasma glucose level of less than 30 mg/dL (1.65 mmol/L) in the first 24 hours of life and less than 45 mg/dL (2.5 mmol/L) thereafter constitutes hypoglycemia in the newborn.

Patients with hypoglycemia may be asymptomatic or may present with severe central nervous system (CNS) and cardiopulmonary disturbances. The most common clinical manifestations can include altered level of consciousness, seizure, vomiting, unresponsiveness, and lethargy. Any acutely ill child should be evaluated for hypoglycemia, especially when history reveals diminished oral intake. (See History and Physical Examination.)

Sustained or repetitive hypoglycemia in infants and children has a major impact on normal brain development and function. Evidence suggests that hypoxemia and ischemia potentiate hypoglycemia, causing brain damage that may permanently impair neurologic development. (See Prognosis.)

Causes of hypoglycemia in neonates differ slightly from those in older infants and children. The causes in neonates include the following (see Etiology):

• Inappropriate changes in hormone secretion

• Inadequate substrate reserve in the form of hepatic glycogen

• Inadequate muscle stores as a source of amino acids for gluconeogenesis

• Inadequate lipid stores for the release of fatty acids

Hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is the most common cause of hypoglycemia in the first 3 months of life. It is well recognized in infants of mothers with diabetes. (See Etiology.)

Causes of hypoglycemia found in all ages include gram-negative sepsis, endotoxin shock, and ingestions, including of salicylates, alcohol, hypoglycemic agents, or beta-adrenergic blocking agents.

Excluding insulin therapy, almost all hypoglycemia in childhood occurs during fasting. Postprandial hypoglycemia is rare in children in the absence of prior gastrointestinal (GI) surgery. Management efforts are directed toward the immediate normalization of glucose levels and the identification and treatment of the various causes. (See Treatment and Medications.)

Patient education

Provide genetic counseling for families with affected children, including information about a possible 25% risk of recurrence. Educate pregnant women with diabetes.[1]

Glucose metabolism

Normal blood glucose is very narrowly regulated, usually from 80-90 mg/dL (4.4-5 mmol/L). Glucose levels increase transiently after meals to 120-140 mg/dL (6.6-7.7 mmol/L). Feedback systems return the glucose concentration rapidly back to the preprandial level, usually within 2 hours after the last absorption of carbohydrates.

Insulin and glucagon are the important hormones in the immediate feedback control system of glucose. When blood glucose increases after a meal, the rate of insulin secretion increases and stimulates the liver to store glucose as glycogen. When cells (primarily liver and muscle) are saturated with glycogen, additional glucose is stored as fat.

When blood glucose levels fall, glucagon secretion functions to increase blood glucose levels by stimulating the liver to undergo glycogenolysis and release glucose back into the blood. (See the diagram below.)

Normal hypoglycemic counterregulation.

In starvation, the liver maintains the glucose level via gluconeogenesis. Gluconeogenesis is the formation of glucose from amino acids and the glycerol portion of fat. Muscle provides a store of glycogen and muscle protein breaks down to amino acids, which are substrates utilized in gluconeogenesis in the liver. Circulating fatty acids are catabolized to ketones, acetoacetate, and B-hydroxybutyrate and can be used as auxiliary fuel by most tissues, including the brain.

The hypothalamus stimulates the sympathetic nervous system, and epinephrine is secreted by the adrenals, causing the further release of glucose from the liver. Over a period of hours to days of prolonged hypoglycemia, growth hormone and cortisol are secreted and decrease the rate of glucose utilization by most cells of the body.

In the newborn, serum glucose levels decline after birth until age 1-3 hours, then they spontaneously increase. Liver glycogen stores become rapidly depleted within hours of birth, and gluconeogenesis, primarily from alanine, can account for 10% of glucose turnover in the newborn infant by several hours of age.

The causes of neonatal hypoglycemia include the following:

• PHHI

• Limited glycogen stores (eg, prematurity, intrauterine growth retardation)

• Increased glucose use (eg, hyperthermia, polycythemia, sepsis, growth hormone deficiency)

• Decreased glycogenolysis, gluconeogenesis, or use of alternate fuels (eg, inborn errors of metabolism, adrenal insufficiency)

• Depleted glycogen stores (eg, asphyxia-perinatal stress, starvation)

With regard to the last item above, in ketotic hypoglycemia, easily depleted glycogen stores, in combination with inadequate production of glucose through gluconeogenesis, contribute to hypoglycemia. Thus, fatty acid oxygenation is required to provide substrate for gluconeogenesis and ketogenesis. Ketones, the byproduct of fatty acid metabolism, are found in urine and represent the starved state.

A study by Ogunyemi et al indicated that independent risk factors for neonatal hypoglycemia include macrosomia, cesarean section, lower gestational age, and treatment for chorioamnionitis. Small-for-gestational-age neonates are also at greater risk. The study included 318 neonates with hypoglycemia and 7955 controls.[2]

A retrospective study by Yamamoto et al indicated that in women with type 1 diabetes mellitus, large-for-gestational-age neonates have a 2.5-fold increased risk for hypoglycemia. The study looked at pregnancies in 161 women with type 1 diabetes.[3]

A study by Anwer et al indicated that the risk for neonatal hypoglycemia is 1.8-fold higher when maternal hyperglycemia occurs prior to delivery in mothers with gestational diabetes mellitus (GDM) that is being managed with medication. Such an increase was not found in the offspring of mothers with diet-controlled GDM.[4]

A retrospective study by Mitchell et al found that out of 175 infants born at less than 33 weeks’ gestation, 33.7% had hypoglycemia within the first 90 minutes after birth. The investigators also found that maternal hypertension increased the risk of neonatal hypoglycemia by about 3-fold; they suggested that beta blockers used in antihypertensive treatment may have contributed to the higher odds. In contrast, labor at the time of delivery was reported to reduce the likelihood of hypoglycemia.[5]

Causes of hypoglycemia in older infants, children, and teenagers include:

• Poisonings/drugs (eg, ethanol, isoniazid, insulin, propranolol, salicylates, oral hypoglycemics, pentamidine, quinine, disopyramide, unripe ackee fruit, Vacor [rat poison]).

• Liver disease (eg, Reye syndrome, hepatitis, cirrhosis, hepatoma)

• Amino acid and organic acid disorders (eg, maple syrup urine disease, propionic acidemia, methylmalonic acidemia, tyrosinosis, glutaric aciduria, 3-hydroxy-3-methylglutaric aciduria)

• Systemic disease (eg, sepsis, burns, cardiogenic shock, respiratory distress syndrome)

Hyperinsulinemia

Congenital hyperinsulinism is most commonly associated with an abnormality of beta-cell regulation throughout the pancreas. A focal disease, such as isolated islet adenoma, occasionally causes congenital hyperinsulinism.

Genetic defects have been delineated and now replace the older terms, such as nesidioblastosis, leucine-sensitive hypoglycemia, PHHI, and islet dysregulation syndrome. These defects are in the sulfonylurea receptor (SUR) and the beta-cell potassium adenosine triphosphate (ATP) channel gene located on the short arm of chromosome 11.

Drug-induced hyperinsulinism is secondary to surreptitious insulin administration or the use of oral hypoglycemic drugs. Exogenous administration of insulin is diagnosed with low serum levels of C-peptide. The sulfonylureas are commonly prescribed for adults; thus, they are available to children as unintentional ingestions. In these cases, hypoglycemia may persist for more than 24 hours. Diazoxide administration may be helpful by suppressing insulin secretion in severe cases.

Occurrence in the United States

The overall incidence of symptomatic hypoglycemia in newborns varies from 1.3-3 per 1000 live births. Incidence varies with the definition, population, method and timing of feeding, and the type of glucose assay. Serum glucose levels are higher than whole blood values. The incidence of hypoglycemia is greater in high-risk neonatal groups (see History).

Early feeding decreases the incidence of hypoglycemia. Inborn errors of metabolism that lead to neonatal hypoglycemia are rare but can be screened in infancy.[6] The incidences of these conditions are as follows:

• Carbohydrate metabolism disorders (>1:10,000)

• Fatty acid oxidation disorders (1:10,000)

• Hereditary fructose intolerance (1:20,000 to 1:50,000)

• Glycogen storage diseases (1:25,000)

• Galactosemia (1:40,000)

• Organic acidemias (1:50,000)

• Phosphoenolpyruvate carboxykinase deficiency (rare)

• Primary lactic acidosis (rare)

International occurrence

In a Japanese study, more than 80% of admissions from the nursery to the neonatal intensive care unit (NICU) after birth were due to apnea or hypoglycemia in neonates born at 35-36 weeks' gestation.[7]

Hypoglycemia is the most common metabolic problem in neonates. Still, the level or duration of hypoglycemia that is harmful to an infant's developing brain is not known. Major long-term sequelae include neurologic damage resulting in mental retardation, recurrent seizure activity, developmental delay, and personality disorders.

However, a study by Shah et al found that in mid-childhood (age 9-10 years), rates of low educational achievement did not significantly differ between children who had been exposed to neonatal hypoglycemia and those who had not been (45% vs 47%, respectively). The investigators also found a significantly lower likelihood that teachers would rate children in this age group who had been exposed to neonatal hypoglycemia “as being below or well below the curriculum level for reading,” compared with other students (24% vs 31%, respectively).[8]

Some evidence suggests that severe hypoglycemia may impair cardiovascular function.

Although the occipital lobes, which contain the primary visual cortex and several extrastriate visual areas, may be especially vulnerable to the effects of neonatal hypoglycemia, a literature review by Paudel et al found the evidence as to whether neonatal hypoglycemia negatively impacts eye and optic nerve development to be inconclusive.[9]

Remission of congenital hyperinsulinism generally does not occur, but the severity of the disease may decrease with time.

The clinical presentation of hypoglycemia reflects decreased availability of glucose for the CNS as well as adrenergic stimulation caused by a decreasing or low blood sugar level. During the first or second day of life, symptoms vary from asymptomatic to CNS and cardiopulmonary disturbances.

High-risk groups who need screening for hypoglycemia in the first hour of life include the following[10, 11] :

• Newborns who weigh more than 4 kg or less than 2 kg

• Large for gestational age (LGA) infants who are above the 90th percentile, small for gestational age (SGA) infants below the 10th percentile,[12] and infants with intrauterine growth restriction

• Infants born to insulin-dependent mothers (1:1000 pregnant women) or mothers with gestational diabetes (occurs in 2% of pregnant women)

• Gestational age less than 37 weeks

• Newborns suspected of sepsis or born to a mother suspected of having chorioamnionitis

• Newborns with symptoms suggestive of hypoglycemia, including jitteriness, tachypnea, hypotonia, poor feeding, apnea, temperature instability, seizures, and lethargy

Additionally, consider hypoglycemia screening in infants with significant hypoxia, perinatal distress, 5-minute Apgar scores of less than 5, isolated hepatomegaly (possible glycogen-storage disease), microcephaly, anterior midline defects, gigantism, macroglossia or hemihypertrophy (possible Beckwith-Wiedemann Syndrome), or any possibility of an inborn error of metabolism or whose mother is on terbutaline, beta blockers, or oral hypoglycemic agents

The onset of hyperinsulinemia is from birth to age 18 months. Insulin concentrations are inappropriately elevated at the time of documented hypoglycemia. Transient neonatal hyperinsulinism occurs in macrosomic infants of diabetic mothers (who have diminished glucagon secretion and in whom endogenous glucose production is significantly inhibited). Clinically, these infants are macrosomic and have increasing demands for feeding, intermittent lethargy, jitteriness, and frank seizures.[13]

Infants with prolonged neonatal hyperinsulinism can be described by the following:

• SGA

• Having perinatal asphyxia

• Born to mothers with toxemia

• Having high rates of glucose use and often requiring dextrose infusion for a prolonged period of time

Ketotic hypoglycemia is an uncommon, but dramatic, illness. It is observed in children younger than age 5 years, who usually become symptomatic after an overnight or prolonged fast, especially with illness and poor oral intake. Children often present as inexplicably lethargic or frankly comatose, having only marked hypoglycemia with ketonuria.

Clinical manifestations are broad and can result from adrenergic stimulation or from decreased availability of glucose for the CNS. Unlike older children, infants are not able to verbalize their symptoms and are particularly vulnerable to hypoglycemia.

Infants in the first or second day of life may be asymptomatic or have life-threatening CNS and cardiopulmonary disturbances. Symptoms can include the following:

• Hypotonia

• Lethargy, apathy

• Poor feeding

• Jitteriness, seizures

• Congestive heart failure

• Cyanosis

• Apnea

• Hypothermia

Clinical manifestations associated with activation of the autonomic nervous system include the following:

• Anxiety, tremulousness

• Diaphoresis

• Tachycardia

• Pallor

• Hunger, nausea, and vomiting

Clinical manifestations of hypoglycorrhachia or neuroglycopenia include the following:

• Headache

• Mental confusion, staring, behavioral changes, difficulty concentrating

• Visual disturbances (eg, decreased acuity, diplopia)

• Dysarthria

• Seizures

• Ataxia, somnolence, coma

• Stroke (hemiplegia, aphasia), paresthesias, dizziness, amnesia, decerebrate or decorticate posturing

Fingerstick glucose levels or bedside testing may lead to overtreatment of hypoglycemia, because the primary error with the chemically treated strips is an underestimation of the serum glucose value.

Serum or plasma glucose levels

Serum glucose level is higher than whole blood glucose level. Whole blood measurements of glucose may underestimate the plasma glucose concentration by approximately 10-15%, because red blood cells (RBCs) contain relatively low concentrations of glucose. Arterial and capillary samples may overestimate the plasma glucose concentration by 10% in nonfasting patients. Hold an extra tube of serum or plasma and refrigerate until laboratory glucose is known.

Serum insulin

When blood glucose is less than 40 mg/dL, plasma insulin concentration should be less than 5 and no higher than 10 µU/mL. This testing may not be available in the emergency department.

Urine

Obtain a first voided urine dipstick for ketones. Failure to find large ketones with hypoglycemia suggests that fat is not being metabolized from adipose tissue (hyperinsulinism) or that fat cannot be used for ketone body formation (enzymatic defects in fatty acid oxidation). Send urine for organic acid analysis.

Screening for metabolic errors

Electrospray ionization-tandem mass spectrometry in asymptomatic persons allows earlier identification of clearly defined inborn errors of metabolism. These disorders include aminoacidemias, urea cycle disorders, organic acidurias, and fatty acid oxidation disorders. Earlier recognition of these inborn errors of metabolism has the potential to reduce morbidity and mortality rates in infants with these conditions.[6] This testing may not be available in the emergency department.

Imaging studies

The detection of adenomas by celiac angiography has had limited success. The chance of detecting a tumor blush must be balanced against the potential risk of causing vascular trauma in infants younger than age 2 years. This testing may not be available in the emergency department.

Start a 5% or 10% dextrose drip when hypoglycemia is recurrent. In terms of prehospital care, stabilize acute, life-threatening conditions and initiate supportive therapy in patients with hypoglycemia. If a patient is alert and has intact airway protective reflexes, oral liquids containing sugar (eg, orange juice) can be administered.[14]

A study by Joshi et al suggested that in women with pregestational type 1 or type 2 diabetes, neonatal hypoglycemia can be avoided by aiming at an intrapartum blood glucose level of 4-7 mmol/L.[15]

A study by Coors et al indicated that in asymptomatic neonates at increased risk for hypoglycemia (ie, those who are late preterm, have a birth weight of < 2500 g or >4000 g, or are born to mothers with diabetes), the rates of transient neonatal hypoglycemia and neonatal intensive care unit (NICU) admissions for hypoglycemia are not reduced by the prophylactic use of dextrose gel.[16]

In contrast, a study by Makker et al reported that the adjunctive use of glucose gel in newborns at risk for neonatal hypoglycemia can reduce NICU admissions for treatment with intravenous dextrose. Reviewing outcomes for 1 year prior to the initiation of a revised newborn nursery protocol that included the use of glucose gel in at-risk infants to those at 1 year after the protocol’s initiation, transfer to the NICU for neonatal hypoglycemia therapy decreased from 8.1% to 3.7%.[17]

Emergency department care

Supportive therapy includes oxygen, establishing an intravenous (IV) line, and monitoring. Seizures unresponsive to correction of hypoglycemia should be managed with appropriate anticonvulsants. Marked acidosis (pH < 7.1) suggests shock or serious underlying disease and should be treated appropriately. The treatment goal is to maintain a blood glucose level of at least 45 mg/dL (2.5 mmol/L).

For the infant or child who does not drink but has intact airway protective reflexes, orogastric or nasogastric administration of oral liquids containing sugar may be performed.

Inpatient care

Any child with documented hypoglycemia not secondary to insulin therapy should be hospitalized for careful monitoring and diagnostic testing.

Surgery

If hypoglycemia is diagnosed in an infant younger than 3 months, surgical intervention may be necessary. Surgical exploration usually is undertaken in severely affected neonates who are unresponsive to glucose and somatostatin therapy. Near-total resection of 85-90% of the pancreas is recommended for presumed congenital hyperinsulinism, which is most commonly associated with an abnormality of beta-cell regulation throughout the pancreas. Risks include the development of diabetes.

Hypoglycemia should be treated as soon as possible to prevent complications of neurologic damage. Early feeding of the newborn with breast milk or formula is encouraged. For those unable to drink, a nasogastric tube can be used. The mainstay of therapy for children that are alert with intact airway protection includes orange juice at 20 mL/kg.

For those who cannot protect their airway or are unable to drink, nasogastric, intramuscular, intraosseous, or IV routes can be employed for the following drugs used to raise glucose levels: dextrose, glucagon, diazoxide, and octreotide. Case reports have shown that nifedipine may help to maintain normoglycemia in children with PHHI.

Cortisol should not be used, because it has minimal acute benefit and may delay the diagnosis of the cause of hypoglycemia. Cortisol stimulates gluconeogenesis and causes decreased use of glucose, which leads to overall elevated blood glucose and may mask the true cause of hypoglycemia.

Class Summary

These agents elevate blood glucose levels.

Dextrose

Dextrose is the treatment of choice. It is absorbed from the intestine, resulting in a rapid increase in blood glucose concentration when administered orally. Give IV dextrose to infants of diabetic mothers with transient neonatal hyperinsulinemia for several days until hyperinsulinemia abates. Avoid hyperglycemia evoking prompt insulin release, which may produce rebound hypoglycemia. SGA infants and those with maternal toxemia or perinatal asphyxia require dextrose IV infusion rates of more than 20 mg/kg/minute to control levels. Treatment may be necessary for 2-4 weeks.

Diazoxide (Proglycem)

Diazoxide increases blood glucose by inhibiting pancreatic insulin release and possibly through an extrapancreatic effect. A hyperglycemic effect starts within an hour and usually lasts a maximum of 8 hours with normal renal function. Diazoxide is reportedly effective in SGA infants and in those with maternal toxemia or perinatal asphyxia.

Octreotide (Sandostatin)

Octreotide is a long-acting analog of somatostatin that suppresses insulin secretion for the short-term management of hypoglycemia.

Glucagon (Glucagon Emergency Kit, GlucaGen)

Glucagon may be used to treat hypoglycemia secondary to hyperinsulinemia and can be administered to patients without initial IV access. Each mL contains 1 mg (ie, 1 U). Maximal glucose concentration occurs between 5-20 minutes after IV administration and about 30 minutes after intramuscular (IM) administration.