Neonatal Nutrition Series #4

Neonatal Glucose Metabolism:

Differential Diagnoses, Evaluation,
and Treatment of Hypoglycemia
Richard M. Cowett, MD, FAAP
Jeffrey L. Loughead, MD, FACN, FAAP

AINTENANCE OF EUGLYCEMIA NORMAL BLOOD

route of delivery, medications administered, and type and volume of intravenous (IV) fluids administered to the mother.
glucose concentrationis often difficult, especially
The infants plasma glucose concentration declines after a
in the sick or low birth weight neonate, and has been the subnormal delivery (a term delivery
ject of recent evaluations. 13
without complications) from
Whereas a fetus depends comABSTRACT
6080 percent of maternal
pletely on the mother for gluHypoglycemia is one of the most common clinical care
serum glucose concentration
cose and other nutrient transfer
issues facing the neonatal practitioner. Increasing evidence
to approximately 50 mg/dl
across the placenta, and an adult
indicates that neonatal hypoglycemia may have long-term
(2.8 mmol/liter) by 2 hours of
is independent, a newly born
neurologic effects. Care is complicated by the lack of a
age; it stabilizes at approximately
neonate is considered to be in
clearly defined threshold for hypoglycemia in term and
70 mg/dl (3.9 mmol/liter) at
transition. Substrate delivery is
preterm infants, however, and by highly variable clinical
72 hours after birth.4 As long
continuous when the fetus is in
signs and symptoms. Furthermore, many infants with low
utero; for the neonatal period
ago as 1965, Cornblath and
blood glucose measurements do not exhibit obvious signs
and beyond, the hallmark is variReisner suggested that a conof impairment. The complexity of neonatal glucose
able and intermittent oral intake.
centration below 40 mg/dl
metabolism is illustrated by the variety of conditions proMultiple conditions are associat(2.2 mmol/liter) or above
ducing or associated with both neonatal hypo- and hyperglycemia. Maintenance of euglycemia is especially
ed with neonatal hypo- and
125 mg/dl (6.9 mmol/liter)
challenging in the sick or low birth weight neonate. This
hyperglycemia. The following
four days or longer after birth
article defines euglycemia by its range and reviews the difdiscussion addresses the chalwas abnormal based on data
ferential diagnoses and etiology of hypoglycemiaas well
lenges facing the neonatal
from their evaluation of blood
as the principles of its managementin the neonatal
practitioner in understanding
glucose concentration over
period.
and appropriately treating the
time.5
common forms of neonatal
In the 1980s, Srinivasan and
hypoglycemia.
colleagues evaluated the plasma glucose concentration in term
neonates who weighed between 2,500 and 4,000 gm, were
DEFINITION OF NEONATAL EUGLYCEMIA
appropriate for gestational age (AGA), and were between 37
Despite the volume of research on neonatal glucose
and 42 weeks gestational age (GA).6 The predicted glucose
metabolism, no uniformly accepted standards are used to
concentrations during the first week of life are noted in
define hypo- or hyperglycemia. Although the neonates plasFigure 1. They found the plasma glucose of these neonates to
ma glucose concentration at delivery parallels the adult eugbe at its lowest concentration between 1 and 2 hours after
lycemic range, actual concentration depends upon factors
bir th, with a significant rise during the third hour.
such as timing of the last maternal meal, duration of labor,
Investigators suggested that a plasma glucose concentration
Accepted for publication November 2001.

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FIGURE 1

Plasma glucose concentrations in term neonates weighing 2.5 to 4.0 kg.

From: Srinivasan G, et al. 1986. Plasma glucose values in normal neonates:

A new look. Journal of Pediatrics 109(1): 115. Reprinted by permission.

<35 mg/dl (1.9 mmol/liter) during the first 3 hours of postnatal life should be of concern. An infant with a plasma glucose concentration <40 mg/dl (2.2 mmol/liter) between
TABLE 1

3 and 24 hours and <45 mg/dl (2.5 mmol/liter) after 24

hours should be considered hypoglycemic.6 The predicted
glucose concentrations during the first week of life are noted
in Figure 1. Similarly, Heck and Erenberg evaluated term
neonates during the first 48 hours after birth. They concluded that a ser um glucose concentration <30 mg/dl
(1.7 mmol/liter) on the first day of life and <40 mg/dl
(2.2 mmol/liter) on the second day of life indicated hypoglycemia.7 More recently, Cornblath and associates suggested
that an infant with a plasma glucose value <36 mg/dl
(2 mmol/liter) should be followed closely and treated if the
glucose concentration remains at this level.8
Few studies of the limits of euglycemea in the preterm
neonate have been reported. One study, however, evaluated
glucose homeostasis in a group of extremely low birth weight
(ELBW) infants (<1,000 gm). Eighty-six neonates (BW 770
+ 150 gm, range 4601,000 gm, GA 26 + 2 weeks, range
2332 weeks) had 1,718 glucose determinations (20 + 14
determinations per neonate, range 090) performed over the
course of the first month. Table 1 depicts the plasma glucose
concentration subdivided into birth weight categories. A significant decline in mean plasma glucose concentration generally occurred by incremental birth weight over the range of
weights of the neonates (p<.0001). Excluding the
400499 gm and 1,000 gm weight groups because of sample
size, plasma glucose concentration appears to decline in general as birth weight increases. These data could indicate
improving adaptation, as plasma glucose concentration
declined from a high of 218 224 mg/dl (12.1
12.43 mmol/liter) in the 500599 gm weight group to
124 62 mg/dl (6.9 3.4 mmol/liter) in the 900999 gm
weight group. Analysis of exogenous glucose, provided to
each neonate by either IV or oral route, revealed a significant
relationship between plasma glucose concentration and the
amount of IV glucose administered (p <.0002). Investigators
concluded that plasma glucose concentration in the ELBW

Plasma Glucose Concentration by Incremental Birth Weight Criteria

Please refer to the print version of

Neonatal Network

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FIGURE 2

Plasma glucose concentration for the four groups of

neonates studied during the first nine hours of life.

TABLE 2

Signs and Symptoms of Neonatal Hypoglycemia

Abnormal cry
Apnea
Cardiac arrest
Coma
Convulsions
Cyanosis
Hypothermia
Hypotonia
Jitteriness
Lethargy
Tachypnea
Tremors

ease, and thermal stress.11 Controversy remains as to an ageappropriate definition of hypoglycemia and the best treatment methods, but plasma glucose concentration <45 mg/dl
(2.5 mmol/liter) appears to be abnormal for both the
preterm and the term infant and should be addressed with
early feeding or other substrate delivery.
Complicating the establishment of a firm definition of
hypoglycemia, consistent and specific signs of disease are lacking. Table 2 lists recognized signs of hypoglycemia, none of
which is unique to that condition. Importantly, these signs
may be present at different blood glucose concentrations in
different neonates and may not be evident at all in some
neonates even with severe hypoglycemia.12 Hence, the practitioner must be constantly vigilant for subtle signs of disease.
Routine screening of all at-risk neonates should be established
to identify infants with asymptomatic hypoglycemia.

From: Stanley CA, et al. 1979. Metabolic fuel and hormone response to
fasting in newborn infants. Pediatrics 64(5): 615. Reprinted by
permission.

infant is related to physiologic immaturity, rate of IV glucose

administered, and degree of complicating illnesses.9
What should be apparent is the variation not only in what
is euglycemia, but in the normal concentration of glucose
at any particular point in time depending on the clinical characteristics of the particular neonate. This is emphasized by the
data in Figure 2. In the four types of neonates commonly
cared for in a neonatal unit in the first hours after
birthterm, AGA; term, small for gestational age (SGA);
preterm, AGA; and preterm, SGAplasma glucose concentration changed constantly and in an apparently random
fashion.10

CLINICAL HYPOGLYCEMIA IN THE

NEONATE
The neonate undergoes a period of rapid adjustment with
birth and the abrupt isolation from his previous glucose
source. Especially in the low birth weight neonate, this
adjustment is delicate and is challenged by a lack of glycogen
reserves, immature ability to make glucose (gluconeogenesis), and coexisting illnesses such as sepsis, pulmonary dis-

CAUSES OF NEONATAL HYPOGLYCEMIA

Different classification systems have been used to categorize the various causes of hypoglycemia in the neonatal period. Cornblath and Schwartz and others have analyzed these
causes, emphasizing time of presentation, duration, severity,
and response to therapy.4,13,14 All classifications define two
basic causal groups: (1) conditions associated with diminished hepatic glucose production and (2) conditions associated with hyperinsulinism, or excessive insulin production.
Tables 3 and 4 outline risk factors that suggest the need for
screening. Conditions in the first group, the more common
causes of hypoglycemia, involve decreased availability of substrate (e.g., glycogen, lactate, glycerol, and amino acids),
altered sensitivity to neural or hormonal factors, and immature or altered enzymatic pathways. Conditions in the second
group, the less common causes of hypoglycemia, include the
infant of a diabetic mother (IDM) (especially the large for
gestational ageor LGAinfant) and intrinsic hyperplasia of
pancreatic islets, as with Beckwith-Wiedemann syndrome or
nesidio-blastosis.

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TABLE 3

Differential Diagnosis: Conditions Associated with

Imprecise/Diminished Hepatic Glucose Production

Cold stress
Congenital heart disease/congestive heart failure
Inborn errors of metabolism: defective gluconeogenesis/glucogenolysis
Intrauterine growth retardation
Prematurity
Perinatal stress/hypoxia
Sepsis

Hypoglycemia with Diminished

Hepatic Glucose Production
Neonatal hypoglycemia is most commonly caused by
diminished hepatic glucose production (see Table 3).13
Neonatal conditions that produce hypoglycemia because of
either imprecise control of glucose production or diminished
substrate availability include intrauterine growth retardation
(IUGR), prematurity, perinatal stress/hypoxia, cold stress,
sepsis, and congenital heart disease/congestive heart failure.
Rarely, hypoglycemia may be caused by a metabolic error
such as glucagon deficiency or by deficits in intermediary
metabolic pathways such as with glycogen storage disease
Type I, galactosemia, or fructose 1,6-diphosphatase deficiency. In these hereditary metabolic disorders, hypoglycemia may
be the initial or most obvious presenting feature; such disorders must always be considered in severe or recurrently hypoglycemic infants.
Intrauterine Growth Retardation. A relatively high frequency of hypoglycemia in IUGR neonates has been reported
ever since Cornblath and colleagues described its occurrence
in eight infants born to mothers with toxemia.15 The incidence of hypoglycemia has been shown to be highest (61 percent) in neonates born to toxemic mothers with relatively low
urinary estrogens.15,16 Reduced fetal glycogen deposition
combined with increased substrate utilization may account for
the appearance of hypoglycemia.
Prematurity. The preterm AGA neonate may develop
clinically significant hypoglycemia. The first report of hypoglycemia among premature infants concerned the growthretarded neonate.15 Subsequent studies have documented
hypoglycemia in the AGA low birth weight neonate. In 1968,
Raivio and Hallman reported a frequency of hypoglycemia of
1.4 percent in these AGA neonates.17 Later, Fluge reported a
frequency as high as 14 percent.13
Diminished oral and parenteral intake in the low birth
weight neonate may explain the lower plasma glucose concentration. Because of their functionally immature hepatocytes
and impaired gluconeogenic and glycogenolytic enzyme systems, preterm neonates depend upon substantial and continuous exogenous nutrition. The proportionally large size of the
neonatal brain (i.e., 13 percent of the body mass in a neonate

vs 2 percent in an adult) is likely responsible for the greater

proportion of glucose utilization during a period of fasting.
Because of this increased neurologic need, the preterm
neonate is at greater risk for hypoglycemia and for important
neurologic side effects.
Perinatal Stress/Hypoxia. Neonates who sustain hypoxic stress may utilize glucose at an increased rate and are
therefore prone to hypoglycemia. One contributing factor is
the reduced rate of glucose formation in anaerobic glycolysis
compared to in aerobic glycolysis. Only 2 moles of the energy molecule ATP are generated by the anaerobic pathway,
whereas 36 moles are produced by aerobic oxidation.
Eighteen times more glucose is therefore required to generate the same amount of energy in periods of hypoxia. Beard
has emphasized the association between hypoxia and hypoglycemia in the low birth weight neonate and noted
increased metabolic need out of proportion to substrate
availability. 18,19 The difficulties are accentuated in the
neonate who is unable to replace substrate from the usual
oral sources because of hypoxia or other morbidity. Tejani
and colleagues reported metabolic acidosis and lactic
acidemia during the first 24 hours of life in 4 term and 11
preterm neonates whose Apgar scores had been 5 at one
minute after birth and who were fed oral glucose loads. They
concluded that these neonates not only may have depleted
endogenous stores of glucose, but also may be unable to tolerate and/or digest an exogenous glucose load, an important
clinical consideration when treating hypoglycemia in infants
following a problematic birth.20
Cold Stress. Hypoglycemia has been identified in
neonates with cold injury. Mann and Elliott described 14
neonates who had suffered neonatal cold injury following
prolonged exposure to environmental temperatures below
90F. Marked hypoglycemia was documented in 3 of 6
neonates.21 In another investigation, hypoglycemia was presumed to be the result of free fatty acid elevation secondary
to cold-induced norepinephrine response.22 Recognition of
potential hypoglycemia following significant cold stress
should result in the consideration of parenteral glucose
administration in conjunction with warming of the neonate.
In addition, this relationship needs to be considered for the
neonate with temperature instability or for the neonate who
has been in a suboptimal thermal environment (e.g., following an unexpected home delivery).
Sepsis. Yeung reported hypoglycemia in 20 of 56 neonates
with signs of sepsis. Although inadequate caloric intake may
predispose the infected neonate to hypoglycemia, an increased
metabolic rate was considered to be the cause of the hypoglycemia, because the infants had been infused intravenously
with 100 kcal/kg/day of glucose.23 Further, a decreased rate
of gluconeogenesis has been documented in laboratory animals following Gram-negative bacterial infection.24 The possibility of increased peripheral utilization because of enhanced

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insulin sensitivity in sepsis has also been considered.25 One or more of these factors likely produces the resultant hypoglycemia.
Congenital Heart Disease/Congestive
Heart Failure. An inverse relationship has
been noted between the amount of cardiac
glycogen and the maturity of the neonate.
Cardiac glycogen reserves are rapidly depleted
during hypoxia. 26 Benzing and colleagues
reported on 27 patients with the simultaneous
occurrence of hypoglycemia and acute congestive heart failure in association with congenital
heart disease. 27 Others have noted hypoglycemia with congestive heart failure in a
neonate without a significant heart defect.28
The pathophysiology of hypoglycemia in cyanotic congenital heart disease was studied in six
children between 13 and 67 months of age.
Glucose, amino acid (alanine), and alanine
turnover studies utilizing stable isotope labeling were compared to controls. A subtle defect
in hepatic gluconeogenesis was suspected, possibly secondary to decreased hepatic blood
flow. 29 Given this finding, the practitioner
should consider the association between hypoglycemia and congestive heart failure when
either one is present.
Inborn Error of Metabolism: Defective
Gluconeogenesis/Glycogenolysis. A specific
enzymatic deficiency that may affect gluconeogenesis in the neonate is Type I glycogen storage disease with glucose-6-phosphatase
deficiency (G6PD). The deficiency, an autosomal recessive genetic defect, may occasionally
present in the neonatal period with severe hypoglycemia and hepatomegaly. A second enzymatic
defect, fructose-1,6-diphosphatase deficiency,
has also been associated with hypoglycemia.30
Although a complete listing of all inborn errors
that may cause hypoglycemia is beyond the
scope of this discussion, an error of metabolism
must be considered in all patients with prolonged hypoglycemia.

HYPOGLYCEMIA SECONDARY TO
HYPERINSULINISM
Hypoglycemia secondary to increased plasma
insulin concentration has now been linked with
several discrete conditions affecting the pancreatic islet cells (see Table 4). These conditions
include IDM; Rh incompatibility; BeckwithWiedemann syndrome; nesidioblastosis, islet cell
adenomas, and/or adenomatosis; adrenal insuf-

TABLE 4

Differential Diagnosis: Conditions

Associated with Hyperinsulinism

Infant of a diabetic mother

Rh incompatibility
Beckwith-Wiedemann syndrome
Nesidioblastosis, islet cell adenomas, and adenomatosis
Adrenal insufficiency
Iatrogenic causes
-Sympathomimetic exposure
Exchange transfusion
High umbilical artery catheter

ficiency; and iatrogenic conditions including

beta sympathomimetic exposure, high umbilical
lines, or blood volume exchanges.
Infant of a Diabetic Mother. IDMs make
up one of the most common subgroups of
neonates to experience hypoglycemia: As many
as 40 percent of these patients have hypoglycemia. 31 IDMs have a combination of
impaired glucose production and excessive
insulin levels resulting from intrauterine exposure to elevated blood glucose levels. The IUGR
IDM has markedly reduced stores of glucose
and glycogen, leading to nearly complete dependence upon an exogenous energy source. In
contrast, the LGA IDM has excessive glycogen
and lipid stores but cannot utilize these effectively despite pancreatic islet cell hyperplasia and
markedly elevated blood insulin concentrations.
High insulin concentrations often lead to
marked and sustained hypoglycemia. Further,
insulin impairs ketone production, glycogenolysis, lipolysis, and gluconeogensis, leaving the
infant unable to produce glucose or ketones and
dependent upon exogenous glucose to meet his
metabolic needs.
Rh Incompatibility. Hyperinsulinism has
been implicated as the cause of hypoglycemia in
neonates with severe Rh isoimmunization.32,33
These neonates are invariably severely sensitized,
with profound anemia and hepatosplenomegaly
at birth. Cardiovascular collapse may be caused
primarily by profound hypoglycemia. Immediate
glucose administration in addition to measures to
correct anemia may be necessary and lifesaving.
The infant of the diabetic mother and the
severely Rh-affected neonate share several pathologic hallmarks. In addition to hyperinsulinism
and islet cell hyperplasia, both show placental
edema and excessive islands of extramedullary
hematopoiesis in the liver and spleen. Although

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this latter finding may be the result of insulin stimulation, the

precise cause of the hyperinsulinism itself remains uncertain in
the Rh-sensitized neonate. An increase in reduced glutathione,
an insulin secretagogue resulting from massive hemolysis of
red blood cells, may act as a stimulus to insulin release.
Beckwith-Wiedemann Syndrome. In 1964, both
Beckwith and colleagues and Wiedemann described a syndrome characterized by omphalocele, muscular macroglossia,
and visceromegaly.34,35 The etiology of the syndrome remains
unclear, but islet cell hyperplasia of the pancreas has been
demonstrated. Hypoglycemia occurs in approximately 50 percent of the cases reported, with hyperinsulinism responsible
for both the hypoglycemia and the somatic and visceral
growth abnormalities. The hypoglycemia is ultimately selflimiting, but it may be quite protracted and difficult to control. Treatment may require such extreme measures as high
glucose delivery (as much as 1520 mg/kg/minute) or diazoxide therapy to suppress the insulin secretion.36 Normal
glucose control is usually achieved in the first weeks of life,
with slow resolution of the visceromegaly and gigantism.
Macroglossia may remain for years.
Nesidioblastosis, Islet Cell Adenomas, and
Adenomatosis. Nesidioblastosis, discrete islet cell adenoma,
and adenomatosis have been reported in the neonate and
have been successfully treated.3740 Hyperinsulinism without
other apparent cause and resistant hypoglycemia should raise
these rare possibilities. Preoperative diagnosis by means of
ultrasound examination, radiographic studies, or abdominal
angiography may be useful, but surgical exploration may be
necessary as a definitive diagnostic modality with subtotal
pancreatectomy a therapeutic measure. Inheritance is likely an
autosomal recessive defect; a specific defect in the short arm
of chromosome 11 has been noted. The incidence has been
estimated at 1 in 50,000 live births in a random mating population but is much higher in some areas, such as in Saudi
Arabia, where the incidence is 1 in 2,675 births. Investigators
suggest that the gene responsible for nesidioblastosis is likely
to have an important role in the regulation of insulin release
and normal pancreatic beta cell development.41,42
Adrenal Insufficiency. Artavia-Loria and colleagues
reported a survey of the frequency of hypoglycemia in 165
children who had primary adrenal insufficiency. Eighteen percent had hypoglycemia, and half of the hypoglycemic
episodes were in the neonatal period. Episodes of hypoglycemia were isolated in 13 children, 4 neonates with
congenital adrenal hyperplasia, and 1 male with 11-betahydroxylose deficiency. A significant correlation was noted
between plasma glucose concentration and cortisol concentration during these episodes of hypoglycemia.43

Iatrogenic Causes
Beta Sympathomimetic Exposure. Beta sympathomimetic tocolytics (e.g., ritodrine and terbutaline sulfate), often uti-

TABLE 5

An Approach to the Patient with Hypoglycemia Based on

the Appearance of Ketosis

Ketones Present in Urine or Blood

Ketotic hypoglycemia
Hormonal deficiency
Galactosemia and/or fructosemia
Organic acidemia
Defects of glycogenolysis
Defects of gluconeogenesis
Ketones Absent from Urine or Blood
Hyperinsulinemic states
Fatty acid oxidation disorders
Adapted from: Al-Essa MA, and Ozand PO. 1998. Manual of Metabolic
Diseases. Riyadh, Saudi Arabia: Scientific Publications Office of the
Research Centre, King Faisal Specialist Hospital and Research Centre, 55.

lized to inhibit the premature onset of labor, have been associated with neonatal hypoglycemia. Increased secretion of
insulin is a possible cause.44,45 A prospective double blind
study of patients in preterm labor failed to note any difference
between ritodrine and control groups, however. Investigators
concluded that chronic oral administration did not significantly affect the neonate.46
Exchange Transfusion. Hypoglycemia may be a significant problem following exchange transfusion, although it is
rarely considered in that case. The choice of exchange blood
and its preservatives are critically important in the neonate,
especially in a double blood volume exchange, because of the
relatively large volume of blood administered.
Heparinized blood contains no added glucose. Moreover,
heparin raises the free fatty acid concentration in the blood,
thereby contributing to the hypoglycemic potential; under
some circumstances, its use would be contraindicated (e.g.,
severe Rh incompatibility with hyperinsulinism). The more
common type of blood product given to neonates is citrated
blood, containing acid-citrate-dextrose (ACD) or citrate
phosphate dextrose (CPD). Citrated blood presents another
type of glucose stress. Because ACD and CPD blood contains
as much as 300 mg/dl glucose, a glucose bolus is given
with the blood. When that bolus is suddenly terminated at
the end of the exchange procedure, a state of hyperinsulinism
follows.47 Studies have shown a precipitous postexchange
decline in blood glucose concentration to a value well below
baseline.48 Recognition of this possibility should lead to monitoring and treatment.
High Umbilical Artery Catheter. Placement of the
umbilical artery catheter has been reported to be a factor in
hypoglycemia. Administration of glucose solutions in the
proximal aorta may lead to high concentrations of glucose
delivered directly into the pancreas via the celiac artery. Puri
and colleagues reported neonatal hypoglycemia associated

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TABLE 6

Algorithm for Treatment of Neonatal Hypoglycemia

Initial Measurement of Blood Glucose at 1 Hour after Birth Based on Differential Diagnosis in the Neonate
Blood Glucose 45 mg/dl*
Symptomatic
If symptomatic with 1 or more of the following (See
Table 2): appearance of apnea, jitteriness, tremors,
etc.
Draw confirmatory laboratory specimen if initial
measurement by meter or strip in clinical care area
Concurrently, give a glucose bolus of 200 mg/kg
(2 ml/kg of D10W) and begin IV glucose
administration at 68 mg/kg/minute
Check blood glucose after 30 minutes to 1 hour 2;
alter therapy until treatment produces euglycemia
and confirm
Begin breastfeeding or age-appropriate formula by
gavage/ orally when clinically appropriate

Blood Glucose 45 mg/dl*

Asymptomatic
If clinically asymptomatic, draw confirmatory
laboratory specimen if initial measurement by meter
or strip in clinical care area
Concurrently, if blood glucose is 3045 mg/dl (1.72.5
mmol/liter) initiate breastfeeding or age-appropriate
formula by gavage/orally at appropriate intervals
If blood glucose is <30 mg/dl (1.7 mmol/liter) give a
glucose bolus of 200 mg/kg (2 ml/kg of D10W) and
start IV glucose administration at 68 mg/kg/minute
Check blood glucose 30 minutes to 1 hour after feeding
and then before feeding to confirm euglycemia
If blood glucose is 45 mg/dl after feeding, begin IV
glucose administration at 68 mg/kg/minute
Gradually increase feedings and decrease parenteral
fluid administration while confirming maintenance of
euglycemia

Blood Glucose 45 mg/dl*

When clinically reasonable, begin
breastfeeding or ageappropriate formula by
gavage/orally at appropriate
intervals
Gradually increase feedings as
tolerated while confirming
maintenance of euglycemia
before feeding

* Values represent suggested treatment levels. Glucose: 45 mg/dl = 2.5 mmol/liter.

with umbilical artery catheters correctly positioned between the sixth and ninth thoracic vertebrae. When a catheter was moved to the low
position (L3L4), the hypoglycemia resolved
without further intervention.49 Investigators
speculated that streaming high concentrations of
glucose to the celiac artery and then to the pancreas resulted in excessive insulin secretion.50

EVALUATION OF THE NEONATE

WITH HYPOGLYCEMIA
Whether hypoglycemia is identified in the
neonate through routine screening or through
the presentation of symptoms, the cause must be
determined so that appropriate therapy can be initiated. A detailed maternal history and thorough
physical examination are required to determine
the etiology of the hypoglycemia. Maternal history (including a family or personal history of diabetes or other glucose intolerance), drug
ingestion (e.g., chlorpropamide, diazoxide,
diuretics, salicylates, and/or alcohol), blood
group incompatibility, preeclampsia or pregnancyinduced hypertension, risk factors for sepsis, and
rate of the dextrose solution administered to the
mother during labor should alert the practitioner
to the potential cause of hypoglycemia.
Examination will indicate whether the neonate
is appropriately grown and what the gestational
age is. The appearance of the infant of the wellcontrolled diabetic of Whites classes A, B, and C
can usually be differentiated from that of the

infant of more severely affected classes D, E, and

F, who may be growth retarded. Clinical signs of
sepsis, respiratory distress, polycythemia, hypoxia,
or cold stress should be noted. The neonate with
Beckwith-Wiedemann syndrome is usually obvious, with evidence of a protuberant tongue,
umbilical hernia, and macrosomia. Prolonged
jaundice and cataracts, which may not be apparent until one month of age, may indicate galactosemia, as may the presence of reducing
substances in the urine. Unexplained hepatomegaly and acidosis may indicate glycogen
storage disease. Abnormalities, including abnormal genitalia and cleft lip and/or palate, may
indicate a central nervous system defect such as a
pituitary abnormality. Laboratory evaluation for
severe hypoglycemia should include thyroid
function testing and blood levels of glucose,
insulin, growth hormone, and cor tisol.
Evaluation of blood pH, lactate, pyruvate, and
ketone concentrations may also be indicated.
Studies are best obtained when hypoglycemia is
present or following a fast of three to four hours.
Tolerance tests are reserved for confirmation of
some of the more unusual diagnoses such as
glycogen storage disease.
Al-Essa and Ozand published a treatise on
the diagnosis of metabolic diseases in 1998.
They re-emphasized that the presence of ketones
is helpful in determining the etiology of hypoglycemia (Table 5). The presence of ketones can
differentiate such conditions as the systemic

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FIGURE 3

Plasma glucose concentrations in neonates treated with

200 mg/kg minibolus followed by 8 mg/kg/minute
constant glucose infusion compared with plasma
glucose concentration of neonates treated with
constant infusion alone.

Please refer to the print

version of Neonatal Network

metabolic disorders from the hyperinsulinemic states. Most

importantly, the presence of ketones can quickly differentiate
between the two basic groups of hypoglycemiacaused by
lack of substrate vs excess insulin. Knowing which subgroup
the patient belongs to is vitally important when treating
hypoglycemia because rapid glucose infusions in hyperinsulinemic patients may lead to further increases in insulin production and to worsening rebound hypoglycemia.51

TREATMENT OF HYPOGLYCEMIA
Treatment of neonatal hypoglycemia begins with identification of the neonate at risk and documentation of the existence of the condition by appropriate laborator y
measurement. Corrective measures follow (Table 6). Whereas
parenteral administration of glucose was advocated in the past
for all neonates diagnosed with hypoglycemia, current practice has demonstrated that many asymptomatic neonates may
be successfully treated orally. Oral administration of breast
milk or age-appropriate formula is used to treat mild to moderate (3045 mg/dl) (1.72.5 mmol/liter) asymptomatic
hypoglycemia, followed in 30 minutes by repeat blood sugar
testing.52 If the neonate cannot maintain euglycemia or is
symptomatic, parenteral administration of glucose clearly
needs to be instituted. Attempts should be made to avoid
fluctuation in glucose delivery that may result in variable
insulin release. With severe hypoglycemia (<30 mg/dl)

(1.7 mmol/liter), however, or when neurologic signs are

present, a glucose bolus of 200 mg/kg (2 ml/kg of D10W)
infused over one minute may be necessary.53 Delivery of an
infusion of 8 mg/kg/minute of glucose (4.8 ml/kg/hour of
D 10 W) or more may be required to maintain neonatal
glucose homeostasis (Figure 3).
Repeated measurement of blood or plasma glucose concentration is necessary. If IV fluids are administered, the glucose infusion rate should be gradually reduced rather than
abruptly terminated so as to avoid sudden reactive hypoglycemia due to hyperinsulinism. Once oral feedings are initiated, evaluation of serum glucose concentration one hour
after feeding and just before a subsequent feeding will provide
documentation of the neonates glycemic status and guide a
stepwise decrease in the IV administration of dextrose.
The goal of therapy should be to obtain a blood glucose
concentration of at least 45 mg/dl (2.5 mmol/liter) while
weaning the neonate from IV fluids and advancing enteral
feedings. The preferred route of infusion is through a
peripheral vein rather than through an umbilical vessel.
Except in an emergency, however, rates greater than
15 mg/kg/minute or concentrations greater than D12.5W
should be infused through a central venous route. A rate
greater than 20 mg/kg/minute is usually contraindicated
by either route.
There are reports of the use of lipid infusion to assist in
preventing hypoglycemia. Sann and colleagues evaluated the
effect of oral lipids on preventing neonatal hypoglycemia in
28 low birth weight neonates (mean gestational age 36 1
week, birth weight 1,778 230 gm) compared to a control
group of 23 neonates of comparable demographics.
Hypoglycemia (<31 mg/dl) occurred in 8 of 23 neonates
(35 percent) in the control group vs in 2 of 28 (7 percent) in
the supplemented group receiving 2.9 gm/day of a solution
containing 67 percent medium-chain triglycerides. The
authors reported that lipid supplementation could help prevent hypoglycemia in the low birth weight neonate.54 Further
research is necessary before this practice is likely to receive
widespread acceptance.
Specific agents are available for treatment of hypoglycemia
when parenteral glucose therapy >15 mg/kg/minute is not
effective in maintaining euglycemia. Corticosteroids have
been shown to be effective in the therapy of hypoglycemia.
The steroids enhance several glucose-producing reactions, but
the major effect is probably that of gluconeogenesis from
noncarbohydrate (i.e., protein) sources and decreased peripheral glucose utilization. Hydrocortisone may be given in a
dose of up to 5 mg/kg/day either intravenously or orally
every 12 hours, or prednisone may be given in a dose of
2 mg/kg/day orally.55 As with all forms of therapy, gradually
decreasing the dosage, in concert with decreasing parenteral
concentration of glucose and increasing oral intake of nutrients, should successfully wean the patient.

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Glucagon administration provides a highly effective

method of releasing glycogen from the liver and can be used
therapeutically to assess whether the liver contains adequate
stores of glycogen. Failure of glucagon to produce a rise in
blood glucose is considered to be evidence of a lack of hepatic
glycogen stores. The IDM, however, often fails to respond to
the usual glucagon dose (0.2 mg/kg). The IDM neonate frequently responds to a higher dose. Glucagon may stimulate
insulin release, so its administration should be accompanied
by an IV glucose infusion.
Like glucagon, epinephrine is capable of promoting gluconeogenesis, but to a lesser degree. The hyperglycemic potential of epinephrine in blocking glucose uptake by peripheral
muscle presupposes an adequate initial blood glucose concentration and is of little practical benefit in a hypoglycemic state.
Epinephrine is a powerful anti-insulin hormone and may be
useful in the IDM as well as in other hyperinsulinemic
neonates.
A dose of 10 to 15 mg/kg/day of diazoxide, an antihypertension drug, probably exerts its effect by suppressing pancreatic insulin secretion, although some investigators have
suggested a direct effect on hepatic glucose production.56,57
The drug should be used only when other modalities have
failed. Diazoxide has been shown to be effective for prolonged periods (i.e., years) without significant side effects.
Surgical intervention is indicated when an islet cell adenoma
or adenomatosis has been confirmed.
Somatostatin, a growth hormoneregulating polypeptide,
has been utilized to suppress insulin and glucagon secretion
clinically as well as experimentally.58,59 The usefulness of
somatostatin is limited by its extremely short half-life (three
minutes).

SUMMARY
Neonatal hypoglycemia is a common but complex condition of both the preterm and term neonate. Recent investigations reveal that undetected or untreated early hypoglycemia
may lead to long-term neurologic complications. Detection
and care of this condition are complicated by nonspecific and
subtle signs easily missed by the unwary clinician. Further,
controversy remains as to an age-appropriate definition of
hypoglycemia and the best treatment methods. For now, it
appears that plasma glucose concentration <45 mg/dl
(2.5 mmol/liter) is abnormal for both the preterm and term
infant and should be addressed with early feeding or other
substrate delivery. The mainstay of therapy remains provision
of enteral substrate through breastfeeding or formula.
Intravenous dextrose delivery is reserved for symptomatic
infants or for infants unresponsive to enteral therapies. Care
must be taken when treating hyperinsulinemic patients to
provide a smooth and continuous source of substrate to avoid
rebound insulin release and worsened hypoglycemia.
Prolonged or severe hypoglycemia should alert the practition-

er to the potential of rare and life-threatening diseases such as

inborn errors of metabolism, nesidioblastosis, or adrenal
insufficiency. Prevention, early detection through a carefully
constructed policy of screening, and early intervention remain
critical for ensuring the best outcome for all at-risk
neonates.

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About the Authors

Richard M. Cowett has been interested in the area of neonatal glucose
homeostasis for almost 30 years. Besides publishing extensively in this area,
he is the editor of the highly regarded, widely read textbook entitled
Principles of Perinatal-Neonatal Metabolism. The second edition
appeared in 1998. More recently, he was guest editor of the March 2000
issue of Clinics in Perinatology, which was entitled Nutrition and
Metabolism of the Micropremie. He currently resides in Shaker Heights,
Ohio.
Jeffrey L. Loughead is the author of many articles and chapters on
neonatal nutrition, especially in the areas of bone mineral metabolism.
He is the medical director of the neonatal intensive care unit at Central
DuPage Hospital in Chicago and director of business development for
Midwest NeoPed Asssociates, Ltd., the largest provider of neonatal care
in Illinois.
For further information, please contact:
Richard M. Cowett, MD
E-mail: rmcowettmd@att.net

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