Neonatal hypoglycemia can be transient (see chapter 75 on transient hypoglycemia) or persistent (hyperinsulinism, hypopituitaryism, disorders of gluconeogenesis, glycogenolysis, fatty acid oxidation, or inborn errors of metabolism). Hypoglycemia can be detrimental to the developing central nervous system, resulting in long-term effects. Neonatal hypoglycemia demands urgent diagnosis and treatment.
Definition of Hypoglycemia
Although the definition of persistent hypoglycemia continues to be debated and no consensus or research-based definition is available,1 many physicians use “operational threshold” levels of less than 45 mg/dL for diagnostic and 70 mg/dL for therapeutic purposes without scientific validation.2
Infants at higher risk of hypoglycemia should have their glucose checked soon postpartum, especially for infants who are small for gestational age (SGA), premature, or large for gestational age (LGA). Additional factors are a maternal history of diabetes during pregnancy (transient hyperinsulinism), history of consanguinity, or history of other children with unexplained deaths or glucose issues. The last 2 may suggest defects in glycogenolysis, gluconeogenesis, or ketogenesis. Timing of hypoglycemia may help differentiate etiology. Symptoms of hypoglycemia in the neonate may include seizures, cyanotic episode, apnea, “respiratory distress,” refusal to feed, brief myoclonic jerks, vomiting, somnolence, or subnormal temperature or there may be no overt symptoms. Intravenous glucose infusion rates (GIRs) in excess of 8 mg/kg/min suggest hypoglycemia secondary to hyperinsulinism.
Large for gestational age; SGA; prematurity; massive hepatomegaly; midline defects (cleft lip/palate, central incisor, holoprosencephaly, or in a male infant, small phallus); macroglossia; hemihypertrophy; or nystagmus should alert the clinician for possible hypoglycemia and its etiology.
If the hypoglycemia is not readily responsive to initial measures (see chapter 75 on transient hypoglycemia), obtain “critical” labs listed in Table 105-1. The blood glucose concentration must be determined immediately using a laboratory enzymatic reaction. Falsely low glucose levels will be reported if there is a delay in processing secondary to metabolism of glucose in the specimen by erythrocytes. A special procedure may be needed for collection of lactic acid or ammonia.
Table 105-1Critical Laboratory Values to Obtain at Time of Hypoglycemia ||Download (.pdf) Table 105-1Critical Laboratory Values to Obtain at Time of Hypoglycemia
Ketones (serum or urine)
Free fatty acids
Urine organic acids
Plasma amino acids
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia of infancy.3 For laboratory features consistent with hyperinsulinemic hypoglycemia, see Table 105-2. Genetic etiologies are summarized in Table 105-3
Table 105-2Laboratory Features of Hyperinsulinemic Hypoglycemia ||Download (.pdf) Table 105-2Laboratory Features of Hyperinsulinemic Hypoglycemia
Persistent hypoglycemia (<50 mg/dL)
Insulin (>2 μU/mL)
Serum ketones: β-hydroxybutyrate (<2 mmol/L)
Urine ketones: absent
Low serum free fatty acid (<1.5 mmol/L)
Normal cortisol and growth hormone
Glucagon stimulation test: positive (>30 mg/dL response to 1 mg glucagon)
Table 105-3Genetic Forms of Hyperinsulinisma ||Download (.pdf) Table 105-3Genetic Forms of Hyperinsulinisma
|Type ||Gene ||Inheritance ||Clinical ||Treatment |
|KATP channel || |
Focal: paternally inherited or loss of heterozygosity of maternal allele
|Pancreatectomy or “conservative” therapy with octreotide and continuous feedings |
|Dominant KATP channel || |
|AD ||Milder hypoglycemia ||Diazoxide |
|GDH HI (HIHA) ||GLUD1 ||AD ||Fasting and postprandial hypoglycemia; less severe than KATP HI; protein sensitivity; asymptomatic hyperammonemia ||Diazoxide |
|GK HI ||GCK ||AD ||Variable ||Diazoxide or pancreatectomy |
|SCHAD ||HADH ||AR ||Mild to severe hypoglycemia; abnormal acylcarnitine profile ||Diazoxide |
Mutations of the KATP Channel
The most common cause of hyperinsulinism is ABCC8 (SUR-1) or KCNJ11 (Kir6.2). Autosomal recessive (AR) mutations in these genes cause focal (AR in paternal allele or loss of heterozygosity of maternal allele) or diffuse islet cell hyperplasia. Usually, neonates are LGA with severe hypoglycemia after delivery. Frequently, this is diazoxide unresponsive. Autosomal dominant mutations of these genes cause less-severe hypoglycemia that usually is diazoxide responsive.
The second most common cause of hyperinsulinism is glutamate dehydrogenase; this causes symptomatic hyperinsulinism with asymptomatic hyperammonemia (HIHA). This usually presents when weaning from breast to cow’s milk formula and is a protein- (leucine-) sensitive hypoglycemia. This usually responds well to treatment with diazoxide and diet modification.
Short-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency
Short-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase deficiency (SCHAD) is a short-chain fatty acid oxidation defect affecting the HADH gene; it causes inappropriate insulin release without hyperammonemia. This form of hyperinsulinemia also usually responds to diazoxide.
Glucose sensor mutation lowers glucose set point so lower glucose levels are needed to stop insulin release.
Glycogen Storage Disorders
Glycogen Synthase Deficiency
Glycogen synthase deficiency (glycogen storage disorder [GSD] type 0) is AR with fasting hypoglycemia, postprandial hyperglycemia and increased lactate, and no glycemic response to glucagon. Neonates so affected do not have hepatomegaly associated with other forms of GSDs.
Glucose 6-Phosphatase Deficiency
For glucose 6-phosphatase deficiency, GSD type 1a is AR with massive hepatomegaly, fasting hypoglycemia with elevated lactate levels, hyperuricemia, hyperlipidemia, and modestly elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT). Type 1b is similar clinically but with neutropenia (oral lesions, perianal abscess, or chronic enteritis).
Amylo-1,6-Glucosidease Deficiency (Debrancher Deficiency, GSD Type 3)
Amylo-1,6-glucosidease deficiency (debrancher deficiency, GSD type 3) is AR with massive hepatomegaly, fasting hypoglycemia (less severe than GSD type 1), no elevation in lactate or uric acid, and elevated AST/ALT. Myopathy and cardiomegaly can be seen in this disorder.
Disorder of Gluconeogenesis: Fructose 1,6-Diphosphatase Deficiency
Fructose 1,6-diphosphatase deficiency is AR with hepatomegaly (secondary to lipid storage), fasting hypoglycemia, hyperketosis, elevated lactic acid, hyperlipidemia, and hyperuricemia.
Disorders of Fatty Acid Oxidation
Fatty acid oxidation disorders include defects of fatty acid and carnitine transport, β-oxidation, electron transport, and ketone production/utilization defects. This group of disorders presents with attacks of hypoketotic hypoglycemia, liver dysfunction, and elevation of urea, ammonia, and uric acid with prolonged fasting.
Inborn Errors of Metabolism
Ketotic hypoglycemia may represent an organic aciduria (propionic, methylmalonic, and isovaleric acidurias) or maple syrup urine disease. These disorders have specific blood or urine findings that facilitate their diagnosis as an inborn error of metabolism.
Other Etiologies of Hypoglycemia
Galactosemia (Galactose 1-Phosphate Uridyl Transferase)
Galactosemia (deficiency of galactose 1-phosphate uridyl transferase) presents with acute decline in multiple organ systems (renal tubular function, liver dysfunction, coagulopathy, neutropenia, or Escherichia coli sepsis) after galactose exposure.5 Any neonate with E. coli sepsis should be suspected of having galactosemia.
Pituitary Hormone Deficiency
Pituitary hormone deficiency can be associated with midline defects (cleft lip/palate, septo-optic dysplasia or optic nerve hypoplasia manifested as nystagmus, prolonged jaundice, or in a male neonate, small phallus with or without cryptorchidism).6 Growth hormone deficiency should be suspected in a male neonate with hypoglycemia and a small phallus. Cortisol deficiency as a result of adrenal disease, such as congenital adrenal hyperplasia, manifests with electrolyte disturbances or ambiguous genitalia rather than hypoglycemia.
An abrupt discontinuation or disruption of an intravenous dextrose infusion can cause hypoglycemia in the neonate. Hypoglycemia may be a result of an indwelling catheter placed close to the pancreas (eg, umbilical artery catheter near the celiac axis) such that dextrose infusion causes local hyperglycemia and stimulates insulin release.
Signs and symptoms of hypoglycemia can be mimicked by many clinical entities, including sepsis, neurological disorder, malnourishment, hyperviscosity syndrome, or primary cardiac disorder.
Once the critical sample is obtained, the results can be used to help determine the etiology of neonatal hypoglycemia (see Figure 105-1 for a diagnostic algorithm).
FAO, fatty acid oxidation; FFA, free fatty acid; GH, growth hormone; G-6-Pase, glucose 6-phosphatase. (Reproduced with permission from Kappy et al.4)
Postpartum, it is imperative to initiate early feeding and evaluation of glucose in the neonate if hypoglycemia is suspected given the birth and maternal history. A recent consensus statement proposed that asymptomatic late preterm, term SGA, infant of a diabetic mother, or LGA neonates be screened within the first 12 hours of life.2 Acute symptomatic hypoglycemia should be treated with a 0.2-g/kg bolus of dextrose (2 mL/kg of 10% dextrose in water [D10W]) as initial therapy, after which a dextrose infusion with a GIR of 8 mg/kg/min. Recheck the glucose level 15 minutes later to ensure resolution of hypoglycemia. Some types of persistent hyperglycemia, such as congenital hyperinsulinism, may benefit from starting diazoxide 5–15 mg/kg in divided doses 2 times per day. Often, a thiazide diuretic is started at the same time as diazoxide to help ameliorate edema seen with this medication. Octreotide (5–20 μg/kg divided every 6 hours) can be used in cases of diazoxide resistance for short-term management, but tachyphylaxis and risk of necrotizing enterocolitis (NEC) limit its usefulness. Medical management for congenital hyperinsulinism is the first-line treatment, but if the neonate is not maintaining glucose levels at 70 mg/dL or above, then surgical therapy may be considered (98% pancreatectomy for diffuse disease and focal resection for focal disease).
Continue to check glucose levels before feedings, 15 minutes after a glucose bolus, and 15 minutes after a change in the GIR.
Potential Side Effects of Treatment
Regarding potential treatment side effects, diazoxide can cause excessive hair growth, fluid retention, or liver dysfunction. Octreotide can cause diarrhea, decrease peritoneal blood flow (NEC), and suppress growth hormone and thyroid hormone.
The goal of treatment is to protect the brain and maintain euglycemia. Wean the GIR by small increments (10%) for glucose levels of 70 mg/dL or above for 2 readings and reassess glucose levels 15 minutes after weaning. The level of clinically important hypoglycemia is highly debated and still is largely empirical.2 Once the neonate can safely maintain glucose levels with an appropriate feeding or drug regimen, the family should be instructed how to check glucose levels on a home meter; when to increase the frequency of glucose checks (illness, prolonged fasting time, and symptoms of hypoglycemia); treatment of a low blood glucose (feeding, glucose gel, or if necessary, glucagon); and when to call the pediatric endocrinologist.
Close attention must be paid to the neonate at home. Parents and other caretakers must be trained to detect symptoms of hypoglycemia and how to avoid hypoglycemia. For the family, a home glucometer should be provided along with in-hospital teaching regarding its use and parameters for treating an episode of hypoglycemia.
After discharge from the neonatal intensive care unit, the neonate should be follow by the pediatrician to monitor growth parameters. The pediatric endocrinologist involved should help manage medication dose adjustment and glucometer downloads, as well as monitor for potential medication side effects. Individuals in other subspecialties may become involved based on the diagnosis of hypoglycemia (individuals working with genetics for familial causes or ophthalmology and neurology for structural defects of the brain causing hypopituitarism).
Neonates with hypoglycemia secondary to congenital hyperinsulinism need to be monitored closely for development of continued hypoglycemia or hyperglycemia as a result of the disease or its treatment. Neonates with genetic causes of hypoglycemia, including disorders of glycogenolysis, gluconeogenesis, and fatty acid oxidation defects, should be started on appropriate treatment and avoid prolonged periods of fasting.
Severe psychomotor retardation and epilepsy are more common with neonates with persistent hyperinsulinemic hypoglycemia who underwent surgical rather than medical management.7 Surgical management with near-total pancreatectomy can lead to persistent hypoglycemia or hyperglycemia.
Despite appropriate treatment of individual causes of hypoglycemia, long-term and progressive neurologic derangement may occur, such as in galactosemia.8 Although there is no clear evidence that a specific glucose range or duration of hypoglycemia causes brain injury, it is important to avoid long-term effects of the lack of the central nervous system energy source.9
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DL. An updated review of the long-term neurological effects of galactosemia. Pediatr Neurol
et al.. Knowledge gaps and research needs for understanding and treating neonatal hypoglycemia: workshop report from Eunice Kennedy Shriver National Institute of Child Health and Human Development. J Pediatr