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Persistent neonatal hypoglycemia:

Diagnosis and management
Sandra L Marles MD FRCPC FCCMG, Oscar G Casiro MD FRCPC, Section of Clinical Genetics and Metabolism and
Section of Neonatology, Department of Paediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba
SL Marles, OG Casiro. Persistent neonatal hypoglycemia: Diagnosis
and management. Paediatr Child Health 1998;3(1):16-19.

Le diagnostic et la prise en charge de

lhypoglycmie nonatale rfractaire.

Maintenance of plasma glucose depends on a normal endocrine system,

functional enzyme levels for glycogenolysis, gluconeogenesis and other
processes, and there must be an adequate supply of endogenous fat, glycogen and substrates of gluconeogenesis. Neonatal hypoglycemia should
be defined as serum glucose less than 2.2 mmol/L in the first 72 h of life
and less than 2.5 mmol/L thereafter. The purpose of this paper is to review
the more uncommon causes of hypoglycemia in the full term, apparently
healthy neonate. Most of these conditions are inborn errors of metabolism. A protocol for investigation of these conditions and some of the more
common diseases, such as hyperinsulinism, is provided, with a rationale
explaining why these tests may be helpful.

RSUM : La prise en charge du glucose dans le plasma dpend dun

systme endocrinien normal, de taux enzymatiques fonctionnels pour
la glycognolyse, la noglucogense et dautres processus, et dune
quantit suffisante de lipides endognes, de glycognes et de substrats
de la noglucogense. Lhypoglycmie nonatale se dfinit par une
glycmie infrieur 2,2 mmol/L au cours des premires 72 h de vie et
2,5 mmol/L par la suite. Le prsent article vise tudier les causes
plus rares dhypoglycmie chez le nouveau-n terme et
apparemment en sant. La plupart de ces pathologies sont causes
par des erreurs innes du mtabolisme. On fournit un protocole
dinvestigation de ces pathologies et de quelques-unes des maladies
plus courantes, comme lhyperinsulinisme, et on explique lutilit de
ces tests.

Key Words: Endocrine disorders, Fatty acid oxidation defects, Inborn

errors of metabolism, Hepatic enzyme deficiencies, Lack of substrate, Neonatal hypoglycemia

efore birth, the fetus receives glucose through the

maternoplacental circulation at a daily amount of
7 g/kg (1). When the umbilical cord is clamped, the neonate must meet several metabolic challenges, two of which
are the maintenance of adequate circulating levels of glucose or alternate fuels to the brain and other organs, and
adaptation to intermittent milk feedings. If these processes fail to occur, neonatal hypoglycemia develops (2).
The physiological serum glucose values in healthy newborns range between 3.3 and 5 mmol/L. Neonatal hypoglycemia should be defined as serum glucose less than
2.2 mmol/L in the first 72 h of life and less than
2.5 mmol/L thereafter. Lower values for defining hypoglycemia that were suggested in the past represent statistical normals based on older studies of infants subjected
to what now would be considered prolonged periods of
fasting (3).
Maintenance of physiological plasma glucose concentration depends on a normal endocrine system that inte-

grates and modulates substrate mobilization, interconversion and utilization. Enzymes of glycogenolysis, gluconeogenesis and other metabolic fuels must be functional,
and there must be an adequate supply of endogenous fat,
glycogen and gluconeogenic substrates (amino acids,
glycerol, lactate) (4). Preterm, small for gestational age
and intrauterine growth-retarded infants, and infants with
hyperinsulinism (infants of diabetic mothers, BeckwithWiedemann syndrome), asphyxia, sepsis or other medical conditions, such as cardiopulmonary disease, are at
risk of developing hypoglycemia (2,5,6). Management of
neonates with hypoglycemia related to these conditions is
not the focus of this paper; there are several articles available that discuss these topics (2,5,6). However, when a
full term, apparently healthy neonate without the predisposing signs and symptoms of the above conditions develops hypoglycemia, the etiology may not be immediately
obvious. The more uncommon causes of hypoglycemia,
such as inborn errors of metabolism, should be consid-

Correspondence: Dr Sandra Marles, FE229 Community Services Building, 685 William Avenue, Winnipeg, Manitoba R3E 0S2. Telephone 204-787-2474,
fax 204-787-1419


Paediatr Child Health Vol 3 No 1 January/February 1998

Persistent neonatal hypoglycemia

TABLE 1: Classification of neonatal hypoglycemia

I. Hepatic enzyme deficiencies
A. Hepatic glycogen storage diseases
B. Disorders of galactose metabolism
C. Disorders of fructose metabolism
D. Maple syrup urine disease
II. Mitochondrial fatty acid oxidation and ketogenesis defects
A. Carnitine/acylcarnitine defects
B. Acyl-CoA dehydrogenase defects
1. Very long chain acyl-CoA dehydrogenase
2. Long chain acyl-CoA dehydrogenase
3. Medium chain acyl-CoA dehydrogenase
4. Short chain acyl-CoA dehydrogenase
5. Long chain 3-OH-acyl-CoA dehydrogenase
III. Endocrine disorders
A. Hyperinsulinism
1. Primary
2. Secondary
a. Infant of diabetic mother
b. Beckwith-Wiedemann syndrome
c. Erythroblastosis fetalis
B. Hypopituitarism
C. Adrenal disorders
IV. Lack of substrate
A. Neonatal growth
1. Intrauterine growth retardation
2. Small for gestational age
3. Prematurity
B. Medical conditions
1. Sepsis
2. Asphyxia
3. Post exchange transfusion
4. Cardiopulmonary disease

ered. This paper briefly reviews some of the inborn errors

of metabolism that present with neonatal hypoglycemia.
The clinical diagnosis of inborn errors of metabolism presenting as hypoglycemia is often difficult because blood
and urine samples may not be helpful unless collected at
the time of the acute symptoms. This difficulty in diagnosis occurs because the disorder may produce only intermittent abnormalities (7). Table 1 lists many, but not all,
of the causes of neonatal hypoglycemia.
The signs of neonatal hypoglycemia are nonspecific
but reflect the involvement of two systems primarily, adrenergic stimulation of the sympathetic nervous system
(tachycardia, diaphoresis, pallor, tremulousness) and
impaired central nervous system function (lethargy, seizures, apnea, coma). Some infants may be asymptomatic
while hypoglycemic (3). Glucose test strips are useful for
screening neonates suspected of being hypoglycemic. All
abnormal or suspicious test strips should be confirmed
with a serum glucose sample.
Glycogen is the storage form of glucose in virtually all
animal cells, especially liver and muscle. When plasma
Paediatr Child Health Vol 3 No 1 January/February 1998

glucose is low, the liver releases glucose from glycogen

(glycogenolysis) for use by other tissues that cannot make
significant amounts, such as the brain (7). Glycogen storage diseases (GSD) are a group of inherited conditions
that affect glycogen metabolism in muscle, the liver or
both, so that glycogen is abnormal in quantity or quality.
The hepatic GSD present with hypoglycemia and hepatomegaly (7). Galactose-1-phosphate-uridyl-transferase
deficiency, the cause of classical galactosemia, presents
with vomiting and diarrhea within a few days of the introduction of milk; hypoglycemia may be associated (7).
Fructose, a six-carbon reducing sugar, is used in the liver,
kidney and small intestine because it can be converted
into intermediates for the glycolytic-gluconeogenic pathway. Of course, symptoms only occur after fructose is introduced into the diet; it is present in some infant formulas. Fructose 1,6-bisphosphatase is a key enzyme for
gluconeogenesis because it allows the endogenous formation of glucose from lactate, glycerol and amino acids
such as alanine (7,8). In the first week of life, the neonate
is very dependent on gluconeogenesis for glucose production (4).
The mitochondria play a major role in energy production because this is the organelle where fatty acids are degraded by the sequential removal of two-carbon
fragments (known as acetyl-CoA) from the carboxylterminal end of the molecule. This process is known as
beta oxidation. The liver uses 90% of its acetyl-CoA to
form ketone bodies that can be used as auxiliary fuel for
many tissues, including the brain. Fatty acids are also
metabolized in peroxisomes and in the cytoplasm by
omega oxidation (9).
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency, an autosomal recessive condition, is the most
common defect of fatty acid oxidation with an incidence of
1/20,000 (1/16,400-1/46,000) (10). It may present as
early as day four of life, usually following a prodromal illness with episodic hypoketotic hypoglycemia, apnea,
Reye-like encephalopathy or sudden infant death syndrome (11). Metabolic acidosis, hyperammonemia, elevated liver function tests, elevated acylcarnitine:free
carnitine ratio and secondary carnitine deficiency are associated laboratory findings. The acylcarnitine profile is
unique because cis-4-decenoate is seen in the plasma of
patients when ill or well (10). The gene is located on chromosome 1p31, and the most common mutation is A985G
(12). The combination of DNA analysis and acylcarnitine
profile can reliably detect all patients with MCAD deficiency (12).
Carnitine palmitoyltransferase deficiency types I and II
(CPT I and CPT II) may present in the neonatal period
with hypoketotic hypoglycemia. The plasma carnitine is
normal to increased and the plasma acylcarnitine is normal in CPT I. The plasma carnitine is decreased and the
plasma acylcarnitine is increased in CPT II (13).
Long chain 3-OH acyl-CoA dehydrogenase (LCHAD)
deficiency may present as early as the first day of life with

Marles and Casiro

hypoketotic hypoglycemia, liver dysfunction, hypotonia

and variable hypertrophic cardiomyopathy. Metabolic acidosis and urine dicarboxylic aciduria may be associated.
When the fetus has LCHAD deficiency, the heterozygous
mother may have had HELLP (hemolysis, elevated liver
enzymes and low platelets), hyperemesis gravidarum or
fatty liver of pregnancy (13).
Hyperinsulinism, regardless of the cause, increases
glucose utilization and glycogen formation. It reduces the
gluconeogenic precursors, including amino acids, free
fatty acids and ketone bodies. The diagnosis is confirmed
when the insulin to glucose ratio is greater than 38.7
pmol/L:mmol/L (7,14,15). Glucagon produces an elevated
glycemic response because of the large glycogen stores
(7). The anterior pituitary hormones are important in energy production. Growth hormone (GH) acts to stabilize
glucose and stimulate the release of free fatty acids from
adipose tissue during episodes of hypoglycemia, stress or
fasting. Adrenocorticotropin hormone (ACTH) also stimulates the release of free fatty acids and releases cortisol,
which stimulates gluconeogenesis. GH levels less than
8 mg/L and cortisol levels less than 500 nmol/L suggest abnormal hypothalamic-pituitary function. Male neonates
with a microphallus and neonates with abnormalities of
the palate or ADH secretion may have hypopituitarism
The following protocol is for investigation of persistent
hypoglycemia in a neonate when the cause is unclear or
the hypoglycemia is unexpectedly severe. The investigations will aid in the diagnosis of the conditions reviewed
in this paper and listed in Table 1.
A. For investigation of a second episode of true blood
sugar less than 2.2 mmol/L (glucose test strips
should always be confirmed with serum sample):
1. Obtain 3 mL blood in a serum separator tube for
insulin, cortisol, GH and ketone bodies.
2. Obtain 5 to 10 mL urine for a metabolic screen to
include ketones, amino acids, organic acids and
acylcarnitine profile.
Rationale: It is important to determine whether the
hypoglycemia is ketotic or nonketotic. Nonketotic
hypoglycemia is associated with disorders of fructose or galactose metabolism, hyperinsulinism, fatty
acid oxidation and GH deficiency. Ketotic hypoglycemia is associated with organic acidurias, maple syrup
urine disease, glycogen storage disease and adrenal
insufficiencies of central or peripheral origin (7).
B. Consider involvement of a consultant with expertise
in inborn errors of metabolism and consider the following investigations.
1. Repeat 3 mL blood in a serum separator tube,
while hypoglycemic. Obtain urine for ketones.
Rationale: It is important to have several measurements of ketones and counter regulatory hormones
while the patient is hypoglycemic. Diagnosis of en18

docrine disorders may be confirmed and appropriate management can be instituted. Appropriate
consultation with an endocrinologist is indicated.
2. Consider further investigations, not necessarily
while hypoglycemic, such as carnitine, asparate
aminotransferase (AST), alanine aminotransferase (ALT), uric acid, capillary gas, lactic acid,
plasma amino acids, creatine kinase (CK), ammonia, acylcarnitine profile and DNA for MCAD
mutation. The last two investigations can be
done from the neonatal screening bloodspots.
Rationale: Elevated AST, ALT, lactic acid and uric
acid with ketotic hypoglycemia and possibly acidosis suggests glycogen storage diseases or fructose
1,6-bisphosphatase deficiency. The acidosis is usually more severe in the latter. Galactosemia may be
associated with abnormal AST, ALT, metabolic acidosis and amino aciduria. Fatty acid oxidation defects usually show hypoketosis, urine organic acid
abnormalities, and carnitine and acylcarnitine abnormalities. Lactic acidosis is present, and ammonia, AST and ALT may also be elevated (3,7,11,13).
Treatment of the hypoglycemic infant may begin while
investigations continue. If the neonate is asymptomatic
and the hypoglycemia is mild (serum glucose 1.7 to 2.2
mmol/L), oral feeding of glucose, 0.5 to 1.0 g/kg, may be
appropriate. If the neonate is symptomatic or the serum
glucose is less than 1.7 mmol/L, an intravenous bolus of
10% dextrose in water (2 mL/kg) given over 5 mins may
be indicated. This should be followed by an infusion of 10%
dextrose in water at 5 to 10 mg/kg/min, or 90 mL/kg/24 h to
maintain serum glucose over 3.3 mmol/L (3).
The highest glucose concentration that can be administered through a peripheral vein is 12.5% dextrose in water. Central venous access is required for more concentrated solutions. When venous access is difficult or when
glucagon is indicated, 0.3 mg/kg/dose to a total dose of
1.0 mg/kg/day may be used (16). Steroid therapy is somewhat controversial in the treatment of persistent neonatal
hypoglycemia of unknown etiology. Steriods are not effective in hyperinsulinism or other disorders not due to adrenal insufficiency. Diazoxide may be used in cases of
hyperinsulinism (3).

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