NEONATAL HYPOGLYCEMIA

 INTRODUCTION
 DEFINITION
 PATHOGENESIS
 Diminished glucose supply
 - Inadequate glycogen stores
 - Impaired glucose production
 Inborn errors of metabolism
 Endocrine disorders
 Other causes
 Increased glucose utilization due to hyperinsulinism
 Increased glucose utilization without hyperinsulinism
 Neurohypoglycemia
 CLINICAL MANIFESTATIONS
 EVALUATION
 Who should be evaluated
 How and when is glucose screening performed
 - Laboratory measurement
 Persistent hypoglycemia
 MANAGEMENT
 Oral feeds
 Parenteral glucose infusion
 Persistent hypoglycemia
 - Glucocorticoids
 - Glucagon
 Persistent hyperinsulinism
 NEURODEVELOPMENTAL OUTCOME
 Preterm infants
 SUMMARY AND RECOMMENDATIONS

Author
See Wai Chan, MD, MPH
Section Editors
Joseph A Garcia-Prats, MD
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Melanie S Kim, MD

Disclosures

Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last
updated: Thu Jun 09 00:00:00 GMT 2011 (More)

INTRODUCTION — Transient low blood glucose levels in neonates are common as

the source of glucose at delivery changes from a continuous supply from the mother to
the intermittent supply from feeds. It is estimated that ten percent of normal term
newborns cannot maintain a plasma glucose concentration above 30 mg/dL (1.7
mmol/L) if their first feeding is delayed for three to six hours after birth [1,2]. Although
transient asymptomatic hypoglycemia in healthy infants appears to be part of the normal
transition to extrauterine life, persistent or recurrent hypoglycemia can result in
neurologic sequelae. (See 'Neurodevelopmental outcome' below.)

The pathogenesis, clinical manifestations, evaluation, and management of neonatal

hypoglycemia will be discussed here.

DEFINITION — It has been difficult to define pathologic neonatal hypoglycemia as a

precise numerical blood glucose level. Low blood glucose levels normally occur after
birth, and most infants are asymptomatic despite very low blood glucose levels.
However, some infants are symptomatic at the same or even higher blood glucose
levels. This variability is due to a number of factors that affect the infant’s response to a
decrease in blood glucose level, including the infant’s gestational age, postnatal age, the
presence of other sources of energy (eg, ketone bodies), and other factors that affect
glucose metabolism. Thus, the diagnosis of clinically significant hypoglycemia is
dependent on the clinical setting and cannot solely be based on a specific blood glucose
level.

Ideally, neonatal hypoglycemia would be defined as the blood glucose concentration at

which intervention should be initiated to avoid significant morbidity, especially
neurologic sequelae. However, this definition remains elusive because the blood glucose
level and duration of hypoglycemia associated with poor neurodevelopmental outcome
has not been established [3,4]. (See 'Neurodevelopmental outcome' below.)

In 2000, a consensus statement proposed the use of practical operational thresholds for
glucose concentrations at which intervention should be considered [3]. These values
would provide a margin of safety for the management of neonatal hypoglycemia. (See
'Management' below.)

In 2011, a report from the American Academy of Pediatrics (AAP) also discussed the
challenge of defining clinically significant hypoglycemia based on blood glucose
concentrations [5]. This report noted that the generally adopted level used to define
neonatal hypoglycemia is less than 47 mg/dL (2.6 mmol/L) and proposed an operational
threshold of 45 mg/dL (2.5 mmol/L) as a target glucose level prior to routine feeds.

In our practice, intervention including treatment or further evaluation is considered in

all symptomatic neonates and in asymptomatic neonates with a plasma glucose
concentration at the following operational thresholds:

 Less than 40 mg/dL (2.2 mmol/L) during the first 24 hours of life
 Less than 50 mg/dL (2.8 mmol/L) after 24 hours of age

Others have suggested using thresholds of plasma glucose of 36 mg/dL (2 mmol/L) in

asymptomatic infants, and 45 mg/dL (2.5 mmol/L) in symptomatic infants [3].

Glucose concentration measured in whole blood is approximately 15 percent lower than

that in plasma and may be further reduced if the hematocrit is high. (See 'Laboratory
measurement' below.)
PATHOGENESIS — With loss of the continuous transplacental infusion of glucose,
plasma glucose concentration in the healthy term newborn falls during the first two
hours after delivery, reaching a nadir that usually is no lower than 40 mg/dL, and then
stabilizes by four to six hours of age in the range of 45 to 80 mg/dL [6].

Immediately after birth, the plasma glucose concentration is maintained by the

breakdown of hepatic glycogen (glycogenolysis) in response to increased plasma
epinephrine and glucagon concentrations, and falling insulin levels. Glycogen stores are
depleted during the first 8 to 12 hours of life. Thereafter, plasma glucose levels are
maintained by the synthesis of glucose from lactate, glycerol, and amino acids
(gluconeogenesis). As feeds with adequate carbohydrate are established, maintenance of
plasma glucose concentrations is no longer solely dependent on gluconeogenesis.

Hypoglycemia is caused by a lower rate of glucose production than glucose utilization.

(See "Etiology of hypoglycemia in infants and children".)

 Inadequate glucose supply

-Inadequate glycogen stores

-Impaired glucose production (ie, glycogenolysis or gluconeogenesis)

 Increased glucose utilization primarily due to hyperinsulinism

Diminished glucose supply

Inadequate glycogen stores — Inadequate glycogen stores can lead to a diminished

supply of glucose. Because glycogen is deposited during the third trimester of
pregnancy, infants born prematurely have diminished reserves. Infants with intrauterine
growth restriction (IUGR) also have reduced glycogen stores. The mechanism in IUGR
is thought to be related to both low intrauterine serum insulin concentrations [7] and, if
present, chronic intrauterine hypoxia, which results in inefficient anaerobic utilization of
glucose. After delivery, a poorly coordinated response of counterregulatory hormones
and peripheral insensitivity to these hormones may contribute to hypoglycemia in some
infants [8]. (See "Small for gestational age infant".)

Impaired glucose production — Impaired glucose production is due to the disruption of

either glycogenolysis or gluconeogenesis. Hyperinsulinemia also reduces glucose
production by impairing glycogen breakdown, which can be overcome with large doses
of glucagon. (See 'Glucagon' below and "Pathogenesis, clinical features, and diagnosis
of persistent hyperinsulinemic hypoglycemia of infancy", section on 'Clinical features'.)

Inborn errors of metabolism — Inborn errors of metabolism that may cause neonatal

hypoglycemia include (table 1):

 Disorders of glycogen metabolism resulting from mutations in genes that encode

proteins involved in glycogen synthesis, degradation, or regulation of these
processes. (See "Overview of inherited disorders of glucose and glycogen
metabolism".)
  Disorders of gluconeogenesis (eg, fructose-1,6-bisphosphatase deficiency,
pyruvate carboxylase deficiency), defects in amino acid metabolism (eg, maple
syrup urine disease, propionic acidemia, and methylmalonic academia),
disorders of carbohydrate metabolism (eg, hereditary fructose intolerance,
galactosemia), and fatty acid metabolism (eg, medium or long-chain acyl-CoA
dehydrogenase deficiency) [9]. (See "Presenting features of inborn errors of
metabolism", section on 'Hypoglycemia' and "Overview of the evaluation of
inborn errors of metabolism in children", section on 'Hypoglycemia' and
"Organic acidemias".)

Endocrine disorders — Deficiency of the hormones that regulate glucose homeostasis

result in hypoglycemia. These hormones include cortisol, growth hormone, epinephrine,
and glucagon. The hormonal deficiency can be isolated or associated with other
pituitary hormone deficiencies, or primary adrenocortical insufficiency.

Other causes — Other causes of impaired glucose production resulting in neonatal

hypoglycemia include:

 Maternal treatment with beta-sympathomimetic agents (eg, terbutaline) due to

interruption of the stimulation of glycogenolysis by epinephrine.
 Hypothermic infants who have diminished availability of glucose and increased
rates of glucose utilization.
 Severe hepatic dysfunction due to impairment of both glycogenolysis and
gluconeogenesis.

Increased glucose utilization due to hyperinsulinism — Increased glucose utilization

primarily results from hyperinsulinemia. The infant of a diabetic mother is the most
common clinical situation in which hyperinsulinism causes hyperinsulinemic
hypoglycemia. It is postulated that intermittent maternal hyperglycemia causes fetal
hyperglycemia, which leads to premature maturation of fetal pancreatic islets and
hypertrophy of the beta cells resulting in fetal and neonatal hyperinsulinemia. After
termination of the maternal glucose supply at delivery, hypoglycemia from persistent
hyperinsulinemia in the newborn usually is transient and typically resolves two to four
days after birth. (See "Infant of a diabetic mother".)

Other conditions associated with hyperinsulinism and transient hypoglycemia include:

 Beckwith-Wiedemann syndrome ─ 50 percent of patients with Beckwith-

Wiedemann syndrome (BWS) have transient or prolonged hypoglycemia caused
by hyperinsulinism. (See "Beckwith-Wiedemann syndrome".)
 Alloimmune hemolytic disease of the newborn. (See "Postnatal diagnosis and
management of alloimmune hemolytic disease of the newborn".)
 Perinatal asphyxia [10]. (See "Systemic effects of perinatal asphyxia".)
 Maternal intrapartum treatment with glucose or with anti-hyperglycemia agents
such as sulfonylureas.
 Abrupt interruption of an infusion of a solution with a high glucose
concentration. Rarely, glucose infusion through an umbilical artery catheter with
its tip near the celiac or superior mesenteric arteries will stimulate excessive
insulin release.
  Persistent hyperinsulinemic hypoglycemia of infancy ─ Infants with persistent
hyperinsulinemia typically develop severe hypoglycemia that requires high rates
of glucose infusion to maintain normal blood glucose levels in the first postnatal
days. Mutations in genes encoding enzymes that control intracellular metabolic
pathways of the pancreatic beta cell or transport of cations across the beta cell
membrane have been identified in as many as 50 percent of patients. The genes
most often affected control the sulfonylurea receptor (SUR1) and the inward
rectifier potassium channel (Kir6.2); these proteins form the functional ATP-
dependent potassium channel in the beta cell membrane. Persistent
hyperinsulinemic hypoglycemia of infancy is discussed separately. (See
"Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic
hypoglycemia of infancy".)
 Excess exogenous insulin given to newborns with hyperglycemia may result in
hypoglycemia [11]. (See "Neonatal hyperglycemia", section on 'Risk of
hypoglycemia'.)

Increased glucose utilization without hyperinsulinism — Conditions associated with

glucose utilization that exceeds production include the following:

 Conditions associated with anaerobic glycolysis due to decreased tissue

perfusion, poor oxygenation, or biochemical defects that interfere with aerobic
glucose metabolism [12]. The energy (ATP) per molecule of glucose produced
by anaerobic glycolysis is only about 5 percent of that produced by aerobic
glucose metabolism.
 Although the mechanism is not known, sepsis is sometimes associated with
hypoglycemia. Proposed contributing factors include increased glucose
utilization, depleted glycogen stores, or impaired gluconeogenesis.
 Hypoglycemia associated with polycythemia may result from greater glucose
utilization by the increased mass of red blood cells.
 Increased glucose consumption can occur with heart failure or perinatal
asphyxia; hyperinsulinism has also been documented in infants who experience
perinatal asphyxia [10].

Neurohypoglycemia — The transport protein GLUT1 facilitates glucose diffusion

across blood vessels into the brain and cerebrospinal fluid (CSF). Although blood
glucose concentrations are normal, deficiency of GLUT1 results in low CSF glucose
concentrations [13].

CLINICAL MANIFESTATIONS — Infants with hypoglycemia frequently are

asymptomatic and hypoglycemia is often detected by routine monitoring of blood
glucose in at-risk infants.

In the symptomatic infant, signs are nonspecific and include [5]:

 Jitteriness and/or tremors

 Hypotonia
 Change in level of consciousness (irritability, lethargy, or stupor)
 Apnea, bradycardia, and/or cyanosis
 Tachypnea
 Poor suck or poor feeding
  Weak or high-pitched cry
 Hypothermia
 Seizures

Because these are nonspecific signs and symptoms, further evaluation for other
underlying conditions (eg, sepsis) should be conducted if symptoms do not resolve after
normalization of the blood glucose concentration. (See "Clinical features and diagnosis
of sepsis in term and late preterm infants".)

EVALUATION

Who should be evaluated — Blood glucose concentration should be measured in infants

at risk for hypoglycemia and in infants who exhibit signs or symptoms consistent with
hypoglycemia [5].

Infants at risk for hypoglycemia include:

 Premature infants
 Infants who are large or small for gestational age
 Infants of diabetic mothers
 Infants who require intensive care (eg, sepsis and asphyxia)
 Infants whose mothers were treated with beta adrenergic or oral hypoglycemic
agents
 Infants with polycythemia (See "Neonatal polycythemia".)

Blood glucose concentration also is monitored at least weekly in infants receiving total
parenteral nutrition, even if they appear stable. We maintain plasma glucose levels
greater than 50 mg/dL (2.8 mmol/L) to provide a margin of safety, although levels
above 40 mg/dL (2.2 mmol/L) may be adequate. These infants have high plasma insulin
concentrations and, thus, have suppressed lipolysis and ketogenesis [3].

We do not routinely monitor blood glucose concentrations in healthy asymptomatic

term infants born after an uncomplicated pregnancy and delivery. Newborns normally
mobilize fat and form ketone bodies during fasting, and the fetal and neonatal brain can
use alternative fuels (ketone bodies and lactate) for oxidative metabolism [14-16]. This
adaptive mechanism may explain why breast-fed term infants remain asymptomatic
despite typically having lower blood glucose concentrations but higher concentrations
of ketone bodies than formula-fed infants [17]. Although term breast-fed infants may be
able to tolerate relatively low plasma glucose levels without clinical manifestations or
neurologic sequelae, the extent to which higher concentrations of ketone bodies is
protective is not known.

How and when is glucose screening performed — Glucose monitoring is performed

within one to two hours after birth in infants who are at-risk for hypoglycemia or
whenever symptoms consistent with hypoglycemia occur. Samples should be obtained
before feedings. Surveillance is continued for the first 12 to 24 hours of life, and after
24 hours of life, screening should continue in infants with low plasma glucose
concentrations (less than 45 mg/dL, 2.5 mmol/L) until feedings are well established and
glucose values have normalized [5].
Most nurseries perform capillary blood glucose measurements with a point of care
glucose meter as a rapid screening method. However, glucose meters show large
variations in values compared to laboratory methods, especially at low glucose
concentrations, and are of unproven reliability to document hypoglycemia in newborns
[18,19]. Thus, the plasma glucose concentration in an infant with a low glucose value
determined by a glucose meter should be confirmed by laboratory measurement [5].
Likewise, laboratory confirmation of the plasma glucose concentration should be
performed in any infant who show signs consistent with hypoglycemia. However,
treatment is started immediately after the blood sample is obtained and before
confirmatory results are available.

Continuous glucose monitoring using a sensor that measures interstitial glucose

concentration was reported to be reliable (when compared to blood glucose
measurement), safe, and tolerable in a study of 120 neonates at risk for hypoglycemia
[20]. However, it is unclear how to interpret the clinical significance of low interstitial
blood glucose levels and whether treatment should be initiated. Further studies are
needed to determine whether continuous interstitial glucose monitoring has a useful role
in the screening and management of neonatal hypoglycemia [21].

Laboratory measurement — Laboratory measurement of glucose concentration is

affected by the type of sample. Glucose concentration measured in whole blood is
approximately 15 percent lower than that in plasma and may be further reduced if the
hematocrit is high. Prompt analysis should be performed because blood glucose values
can decrease by 15 to 20 mg/dL per hour in samples at room temperature (without
separation of plasma).

Persistent hypoglycemia — If hypoglycemia is severe (eg, associated with seizures or

altered level of consciousness) in an otherwise healthy infant or if glucose infusions of
more than 8 to 10 mg/kg per minute are needed to maintain plasma glucose
concentrations greater than 50 mg/dL (2.8 mmol/L) for longer than one week, the infant
should be evaluated for rare causes of hypoglycemia.

Further evaluation should also be considered in any infant with persistent

hypoglycemia, and physical abnormalities that are suggestive of specific underlying
etiologies. These include hypotonia and hepatomegaly seen in patients with disorders of
glycogen metabolism, and omphalocele, macroglossia, and macrosomia seen in infants
with Beckwith-Wiedemann syndrome (See "Etiology of hypoglycemia in infants and
children" and "Overview of inherited disorders of glucose and glycogen
metabolism" and "Beckwith-Wiedemann syndrome".)

In addition, a family history of unexplained neonatal death or sudden infant death

syndrome, or unexplained delay in psychomotor development should prompt further
investigation.

In these infants, the following blood measurements should be obtained at the time of
hypoglycemia: serum insulin, cortisol, growth hormone, and amino acids. Obtaining
these tests after the hypoglycemia has resolved is not helpful to establish an etiology.
Ketones, reducing substances, and organic acids are measured in urine. Consultation
with a pediatric endocrinologist is recommended.
MANAGEMENT — Management of hypoglycemia is directed toward prevention or
resolution of symptoms due to hypoglycemia. As discussed previously, the following
optional thresholds are used for asymptomatic neonates in our practice:

 Less than 40 mg/dL (2.2 mmol/L) during the first 24 hours of life
 Less than 50 mg/dL (2.8 mmol/L) after 24 hours of age

Other centers may use different thresholds based on their clinical experience. (See
'Definition' above.)

The treatment of hypoglycemia is a stepwise process depending on the presence or

absence of symptoms and signs, and the response of the infant at each step as follows:

 Oral feedings of breast milk or formula in asymptomatic infants.

 Parenteral glucose infusion at a rate of at least 6 mg/kg per minute for infants
who are symptomatic, with severe hypoglycemia (plasma glucose less than 25
mg/dL [1.4 mmol/L]), who are unable to be enterally fed or who experience
persistent hypoglycemia despite frequent oral feedings. If hypoglycemia is
persistent, glucose infusion rates can be increased and glucose infusion rates
may exceed 12 mg/kg per minute.
 Administration of glucocorticoid therapy in infants requiring a glucose infusion
rate of 12 mg/kg per minute or greater for two or more days.
 Administration of glucagon in rare patients who remain hypoglycemic despite
continuous parenteral glucose infusion and administration of glucocorticoid
therapy while undergoing further evaluation and treatment.
 Other therapeutic options for persistent hyperinsulinemic hypoglycemia include
diazoxide, and pancreatectomy in patients with hyperinsulinemia unresponsive
to medical management. (See "Treatment and complications of persistent
hyperinsulinemic hypoglycemia of infancy", section on 'Diazoxide' and
"Treatment and complications of persistent hyperinsulinemic hypoglycemia of
infancy", section on 'Surgical therapy'.)
 In infants with persistent hypoglycemia, further evaluation is performed to
determine the cause of hypoglycemia. (See 'Persistent hypoglycemia' above.)

The above approach is consistent with that outlined by the 2011 AAP clinical report,
which uses slightly different blood glucose thresholds, as follows [5]:

 Parenteral glucose infusion for infants who are symptomatic with blood glucose
levels <40 mg/dL (2.2 mmol/L).
 An initial oral feeding is given to the following asymptomatic infants based on
the age of the neonate and blood glucose level, and the level is rechecked in one
hour:

 Infants less than 4 hours of life and blood glucose <25 mg/dl (1.4 mmol/L). If
blood glucose fails to increase, parental glucose is administered. If the blood
glucose increases to 25 to 40 mg/dL (1.4 to 2.2 mmol/L), oral feeding or
parenteral glucose is given.
 Infants between 4 and 24 hours of life and blood glucose <35 mg/dL (1.9
mmol/L). If blood glucose fails to increase, parental glucose is administered. If
 the blood glucose increases to 35 to 45 mg/dL (1.9 to 2.5 mmol/L), oral feeding
or parenteral glucose is given.

Oral feeds — Healthy infants are fed as soon as possible after birth. Although the
immediate effect of early feeding was negligible in one small study, establishing
feeding is a natural process and may prevent subsequent hypoglycemia [22]. Infants
who are at risk for hypoglycemia should be fed within the first hour of life, and a blood
glucose level should be obtained 30 minutes after the feed [5].

If the blood glucose is less than 40 mg/dL (2.2 mmol/L) on a screening measurement in
an asymptomatic term infant, we obtain a blood sample for laboratory measurement of
plasma glucose concentration and immediately offer breast or formula feeding. We
monitor the blood glucose level frequently, starting 20 to 30 minutes after the feeding,
and we continue to offer feedings at two- to three-hour intervals.

The same management approach is used in asymptomatic premature infants [3],

although parenteral nutrition, which includes glucose, is frequently used to supplement
enteral feedings. (See "Approach to enteral nutrition in the premature infant" and
"Approach to enteral nutrition in the premature infant", section on 'Our approach'.)

Parenteral glucose infusion — Parenteral glucose therapy is administered for the

following indications:

 Symptomatic infants
 Neonates with severe hypoglycemia defined as plasma glucose concentration
less than 20 to 25 mg/dL (1.1 to 1.4 mmol/L) [3]
 Neonates with persistent hypoglycemia after feeding defined as plasma glucose
concentration below 40 mg/dL (2.2 mmol/L)
 Neonates who are unable to feed or intolerant of enteral feedings with plasma
glucose concentrations below 40 mg/dL (2.2 mmol/L)

Parenteral glucose therapy is administered as an initial bolus infusion of 200 mg/kg

glucose (2 ml/kg of 10 percent dextrose in water) over one minute, followed by a
glucose infusion at 6 to 8 mg/kg per minute [23]. The small bolus minimizes
hyperglycemia that can provoke insulin secretion and possibly prolong hypoglycemia.

We check the blood glucose concentration 20 minutes after the bolus infusion and
adjust the infusion rate or dextrose concentration as needed to maintain plasma glucose
concentration greater than 50 mg/dL (2.8 mmol/L). Although the ideal level remains
uncertain, this operational therapeutic threshold allows a margin of safety. Infants who
depend upon high infusion rates or a dextrose concentration greater than 12.5 percent
require placement of a central venous catheter through the umbilicus or a peripheral
vein.

When the glucose concentration is stable, the glucose infusion rate can be tapered
slowly as feedings are advanced. The taper typically occurs over a period of two to four
days. While the intravenous glucose infusion is tapered, the pre-prandial blood glucose
level should be monitored every three to four hours depending upon the feeding
schedule.
Persistent hypoglycemia — In infants with persistent hypoglycemia, further evaluation
is performed to determine the cause of hypoglycemia. (See 'Persistent
hypoglycemia' above.)

Glucocorticoids — Glucocorticoid therapy is considered in infants whose hypoglycemia

persists after two to three days of receiving a glucose infusion greater than 12 mg/kg per
minute. The proposed mechanism of action of glucocorticoids is stimulation of
gluconeogenesis and reduction in peripheral glucose utilization. We give
hydrocortisone (5 mg/kg per day divided in two doses orally or intravenously);
alternatively, prednisone (2 mg/kg per day orally or intravenously) may be used.
Glucose levels usually will become stable over several days, and the glucocorticoid
therapy can be rapidly tapered. We measure serum cortisol and insulin levels before
beginning glucocorticoid treatment.

Glucagon — Glucagon is used in the rare neonate whose hypoglycemia persists despite

parenteral infusion of glucose and administration of glucocorticoid therapy.

A wide range of glucagon doses (20 to 200 mcg/kg, maximum dose of 1 mg) has been
described in case reports and series of neonates and infants with hypoglycemia.

 The lower dose, 20 mcg/kg, administered subcutaneously has been effective in

treating hypoglycemia in patients with type 1 diabetes who are below two years
of age [24,25].
 In the largest reported case series consisting of 55 newborns cared for at a
tertiary Canadian center over a five year period, intravenous glucagon infusion
at a dose of 10 to 20 mcg/kg per hour was effective in the treatment of persistent
significant hypoglycemia due to a variety of causes (eg, asphyxia, intrauterine
growth restriction, prematurity, and infant of diabetic mother) [26].
 An earlier small case series reported that a single intravenous 200 mcg/kg bolus
was effective in the treatment of hypoglycemia in neonates [27].

Based upon the currently available literature and our own clinical experience, we
administer glucagon at an initial dose of 20 to 30 mcg/kg to infants with persistent
hypoglycemia, despite parenteral glucose infusion and glucocorticoid therapy. Glucagon
can be given as a slow intravenous push over one minute, or by intramuscular or
subcutaneous injection. Intramuscular or subcutaneous administration is helpful as a
temporizing measure when intravenous access is difficult to establish. A rise in blood
glucose should occur within one hour of administration and should last approximately
two hours. Blood glucose levels should be monitored, as there may be a rebound
hypoglycemia. If the serum glucose does not rise within 20 minutes of glucagon
administration, then a repeat dose of glucagon is given. A failure to respond to glucagon
raises the possibility of a glycogen storage disorder or defect in glycogen synthesis. In
these patients, further evaluation is warranted. (See "Overview of inherited disorders of
glucose and glycogen metabolism".)

Glucagon should not be used in infants who are small for gestational age.

Persistent hyperinsulinism — The management of persistent hyperinsulinemic

hypoglycemia of infancy is discussed separately. (See "Pathogenesis, clinical features,
and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy".)
NEURODEVELOPMENTAL OUTCOME — Symptomatic hypoglycemia can result in
brain injury detected by magnetic resonance imaging (MRI), although there are no
available data that define the glucose concentration or the duration of hypoglycemia
associated with damage.

A systematic review of the literature published in 2006 reported inconclusive evidence

on the effect of neonatal hypoglycemia on neurodevelopment [28]. Two subsequent
studies suggest an association between hypoglycemia and brain injury [29,30].
Nonetheless, it remains uncertain whether hypoglycemia that could have been prevented
by better clinical management plays a significant role in brain injury and poor
developmental outcome.

Preterm infants — In preterm infants, controversy exists as to whether asymptomatic

hypoglycemia causes neurologic injury and whether glucose concentrations requiring
intervention should be lower in premature than term infants.

Retrospective analysis of data from a multicenter trial of nutrition in premature infants

showed a correlation between plasma glucose concentrations less than 47 mg/dL (2.6
mmol/L) on five different days during the first two months of age and lower Bayley
mental and psychomotor scores at 18 months corrected age [31]. Developmental delay
or cerebral palsy was 3.5 times greater (95% CI 1.3-9.4) in the hypoglycemic infants.
However, the frequency of glucose testing was variable and occurred more often in
sicker infants. Furthermore, at 7.5 to 8 years of age, only arithmetic and motor scores
were lower in hypoglycemic infants, while other differences were no longer seen [32].

The long-term impairment of neurodevelopment may be greater in preterm infants with

repeated hypoglycemic episodes who are also small for gestational age (SGA). In a
prospective study of 85 SGA preterm infants, repeated episodes of hypoglycemia were
associated with a smaller head circumference at 18 months corrected age and lower
scores on psychometric testing at five years of age [33].

SUMMARY AND RECOMMENDATIONS — Transient low blood glucose levels are

common after birth as the glucose supply to neonates changes from a continuous
transplacental supply from the mother to an intermittent supply from feeds. Persistent or
recurrent hypoglycemia can result in neurologic sequelae. (See 'Neurodevelopmental
outcome' above.)

 It has been difficult to establish a single numerical blood glucose level that
accurately predicts significant neonatal hypoglycemia at which intervention
should be initiated to prevent morbidity. As a result, operational thresholds have
been proposed to provide a margin of safety until additional data become
available to provide a more precise definition. (See 'Definition' above.)
 We suggest the following operational plasma glucose threshold for further
evaluation and intervention in asymptomatic neonates (Grade 2C). Others use
different plasma glucose thresholds including one approach that uses 36 mg/dL
(2mmol/L) in asymptomatic infants, and 45 mg/dL (2.5 mmol/L) in
symptomatic infants. The American Academy of Pediatrics uses an operational
level of 45 mg/dL (2.5 mmol/L) in asymptomatic neonates. (See
'Definition' above.)
 Less than 40 mg/dL (2.2 mmol/L) during the first 24 hours of life
 Less than 50 mg/dL (2.8 mmol/L) after 24 hours of age

 Hypoglycemia is caused by a rate of glucose production that is lower than the

rate of glucose utilization. (See 'Pathogenesis' above and "Etiology of
hypoglycemia in infants and children".)

 In neonates, diminished glucose supply is due to inadequate glycogen stores or

impaired glucose production (ie, glycogenolysis or gluconeogenesis). (See
'Inadequate glycogen stores' above.)
 Increased glucose utilization is primarily due to various causes of
hyperinsulinism, hormonal deficiencies (eg, cortisol and growth hormone),
hypothermia, or maternal treatment with insulin or hypoglycemic agents.
Disorders that result in increased glucose utilization without increased insulin
levels include sepsis, polycythemia, and conditions associated with poor tissue
perfusion or oxygenation. (See 'Increased glucose utilization due to
hyperinsulinism' above and 'Increased glucose utilization without
hyperinsulinism' above.)

 Infants with hypoglycemia are frequently asymptomatic or have nonspecific

symptoms and signs, which include jitteriness/tremors, hypotonia, changes in
level of consciousness, apnea/bradycardia, cyanosis, tachypnea, poor suck or
feeding, hypothermia, and/or seizures. (See 'Clinical manifestations' above.)
 Blood glucose should be measured in infants who are symptomatic or at risk for
hypoglycemia. At-risk infants include premature infants, infants who are large
or small for gestational age, infants of mothers with diabetes or who required
beta-adrenergic or oral hypoglycemic agents, and infants who require intensive
care or total parenteral nutrition. (See 'Who should be evaluated' above.)
 Glucose monitoring is performed within one to two hours after birth in infants
who are at-risk for hypoglycemia or in infants with symptoms consistent with
hypoglycemia. Most nurseries perform point of care capillary blood glucose
measurements with a glucose meter as a rapid screening method. A low
screening glucose value should always be confirmed by laboratory
measurement. Treatment is initiated after the blood sample is obtained, while
awaiting confirmatory laboratory results. (See 'How and when is glucose
screening performed' above.)
 We suggest the following stepwise management approach for neonatal
hypoglycemia, which is dependent upon the presence or absence of symptoms,
and the response of the infant at each step (Grade 2C). (See
'Management' above.)

 Oral feedings of breast milk or formula in asymptomatic infants.

 Parenteral glucose infusion of at least 6 mg/kg per minute in infants who are
symptomatic, have severe hypoglycemia (plasma glucose <25 mg/dL [1.4
mmol/L]), unable to feed, or who have persistent hypoglycemia despite frequent
oral feedings.
 Administration of glucocorticoids in infants with persistent hypoglycemia after
two to three days of glucose infusion greater than 12 mg/kg per minute.
  Administration of glucagon in the rare patient in whom hypoglycemia persists
despite continuous parenteral glucose infusion and administration of
glucocorticoids.
 Oral diazoxide in patients with persistent hyperinsulinemic hypoglycemia of
infancy.
 Near total pancreatectomy when medical therapy fails.

 Infants who require glucose infusions of greater than 8 mg/kg per minute to
maintain plasma glucose concentrations greater than 50 mg/dL (2.8 mmol/L) for
more than one week should be evaluated by a pediatric endocrinologist for
unusual causes of hypoglycemia. (See 'Persistent hypoglycemia' above.)

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