Pathogenesis, screening, and diagnosis of neonatal hypoglycemia

Author:
Paul J Rozance, MD
Section Editors:
Joseph A Garcia-Prats, MD
Joseph I Wolfsdorf, MB, BCh
Deputy Editor:
Melanie S Kim, MD
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Feb 2018. | This topic last updated: Nov 21,
2017.

INTRODUCTION — During the normal transition to extrauterine life, blood 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. It is important to differentiate
this normal physiologic transitional response from disorders that result in persistent or
recurrent hypoglycemia, which may lead to neurologic sequelae.

This topic will discuss the normal transient neonatal low glucose levels, causes of
persistent or pathologic neonatal hypoglycemia, and the clinical manifestations and
diagnosis of neonatal hypoglycemia. The management of neonatal hypoglycemia,
including evaluation of persistent hypoglycemia and outcome of neonatal
hypoglycemia, is discussed separately. (See "Management and outcome of neonatal
hypoglycemia".)

CHALLENGE OF DEFINING NEONATAL HYPOGLYCEMIA — Clinically significant

neonatal hypoglycemia requiring intervention cannot be defined by a precise numerical
blood glucose concentration because of the following:

●Normal low neonatal blood glucose levels − Low blood glucose concentrations
normally occur in the first hours after birth and may persist for up to several days.
Although most newborns remain asymptomatic despite very low blood glucose
concentrations, some newborns become symptomatic at the same or even higher
blood glucose concentrations than are observed in asymptomatic infants. This
variability in the clinical response in neonates to low blood glucose concentrations
is due to a number of factors that include the infant's gestational age and
postnatal age, the presence of other sources of energy (eg, lactate and ketone
bodies), and circumstances that affect glucose metabolism and cerebral glucose
uptake and utilization.

●Lack of outcome data − Ideally, clinically significant 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 concentration
and duration of hypoglycemia associated with poor neurodevelopmental outcome
has not been established [1,2].
 A large prospective study was undertaken of newborns (gestational age ≥35
weeks) at risk for hypoglycemia (ie, maternal diabetes, large for gestational age,
fetal growth restriction, and prematurity [gestational age <37 weeks]) (see 'Who
should be evaluated?' below) who underwent regular measurements of blood
glucose for up to 48 hours of life and were treated to maintain blood glucose
concentrations greater than 47 mg/dL (2.61 mmol/L) regardless of postnatal age.
Neurodevelopmental outcome at two years of age was similar between infants in
whom intervention was provided for hypoglycemia compared with those without
evidence of hypoglycemia [3]. However, at 4.5 years of age follow-up assessment
demonstrated that children with treated neonatal hypoglycemia had poorer
executive and visual motor functions [4]. Of note, despite intensive capillary blood
glucose monitoring, 25 percent of the infants had levels below the targeted level
for at least five hours as detected by continuous interstitial glucose monitoring
(which was masked to the clinical providers). These results do notprovide a
definitive threshold for treating neonatal hypoglycemia in all newborns.

Nevertheless, most guidelines used in clinical practice provide arbitrary treatment

thresholds of blood glucose concentrations to initiate intervention and bypass the
controversies surrounding the definition of hypoglycemia [1,5]. This approach tries to
reduce the harm due to hypoglycemia, identify newborns with a serious underlying
hypoglycemia disorder, and at the same time, minimize overtreatment of newborns with
normal transitional low glucose concentrations that resolve without intervention. This
has resulted in guidelines that favor simplicity and ease of use over an emphasis on
the physiology of normal neonatal glucose homeostasis, the normal age-related
increase in glucose concentrations over the first few days of life, and the varying
pathophysiological conditions that may lead to clinical hypoglycemia.
(See "Management and outcome of neonatal hypoglycemia".)

When using guidelines based on low glucose concentrations, it is important to

recognize that glucose concentrations measured in whole blood are approximately 15
percent lower than those in plasma and may be further reduced if the hematocrit is
high. In addition, when reviewing the literature and guidelines one must be careful to
note whether the normal values are mean glucose values (used in this topic review), as
opposed to using a threshold range of glucose values (below the 5th percentile used in
the American Academy of Pediatrics [AAP] guidelines). (See 'How glucose testing is
performed' below.)

NORMAL TRANSITIONAL LOW GLUCOSE LEVELS — Transient low blood glucose

concentrations in neonates are normal, as the source of glucose at delivery changes
from a continuous supply from the mother to an intermittent supply from milk feeds [6].
With loss of the continuous transplacental supply 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 (2.2 mmol/L), and then
stabilizes by four to six hours of age in the range of 45 to 80 mg/dL (2.5 to
4.4 mmol/L) [1,2,7,8]. Mean concentrations then rise more slowly in the next few days
to concentrations similar to those seen in older children and adults.
Immediately after birth, the plasma glucose concentration is maintained by the
breakdown of hepatic glycogen (glycogenolysis) in response to increased plasma
epinephrine and glucagonconcentrations, 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.
However, if the first feeding is delayed for three to six hours after birth, approximately
10 percent of normal term newborns cannot maintain a plasma glucose concentration
above 30 mg/dL (1.7 mmol/L) [9,10].

PATHOLOGIC AND/OR PERSISTENT HYPOGLYCEMIA — Hypoglycemia is caused

by a lower rate of glucose production than glucose utilization. The underlying
mechanisms of neonatal hypoglycemia in at-risk neonates that usually require
intervention (pathologic or persistent) include the following (see "Causes of
hypoglycemia in infants and children"):

●Inadequate glucose supply

•Inadequate glycogen stores

•Impaired glucose production (ie, glycogenolysis or gluconeogenesis)

●Increased glucose utilization

•Excessive insulin secretion

•Other causes

Diminished glucose supply

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

supply of glucose and present in the following settings:

●Prematurity – Because glycogen is deposited during the third trimester of

pregnancy, infants born prematurely have diminished glycogen reserves.

●Fetal growth restriction (FGR) – Infants with FGR, also referred to as intrauterine
growth restriction (IUGR), may have reduced glycogen stores or may rapidly
deplete their glycogen stores if the transition to extrauterine life is difficult, which
increases their metabolic needs (ie, increased glucose utilization). After delivery,
there may also be impaired glucose production due to a poorly coordinated
response to hypoglycemia by counter regulatory hormones (epinephrine
and glucagon) and increased insulin sensitivity [7,11]. (See "Infants with fetal
(intrauterine) growth restriction", section on 'Hypoglycemia'.)

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

of either glycogenolysis or gluconeogenesis. (See "Causes of hypoglycemia in infants
and children", section on 'Disorders of glycogenolysis' and "Causes of hypoglycemia in
infants and children", section on 'Disorders of glycosylation' and "Causes of
hypoglycemia in infants and children", section on 'Disorders of gluconeogenesis'.)

Inborn errors of metabolism — Inborn errors of metabolism that may cause neonatal
hypoglycemia include (table 1):

●Disorders of glycogen metabolism (glycogenolysis) 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" and "Causes of hypoglycemia in infants and children",
section on 'Disorders of glycogenolysis'.)

●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) [12]. (See "Causes of hypoglycemia in infants and children", section on
'Disorders of gluconeogenesis' and "Causes of hypoglycemia in infants and
children", section on 'Disorders of amino acid metabolism' and "Causes of
hypoglycemia in infants and children", section on 'Disorders of fatty acid
oxidation' and "Inborn errors of metabolism: Metabolic emergencies", section on
'Hypoglycemia' and "Organic acidemias" and "Inborn errors of metabolism:
Metabolic emergencies", section on 'Hypoglycemia'.)

Endocrine disorders — Deficiency of the hormones (eg, cortisol and growth hormone)
that regulate glucose homeostasis result in hypoglycemia. The hormonal deficiency
can be isolated or associated with other pituitary hormone deficiencies, or primary
adrenocortical insufficiency. (See "Causes of hypoglycemia in infants and children",
section on 'Hormone deficiencies'.)

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

hypoglycemia include:

●Maternal treatment with beta-sympathomimetic agents (eg, terbutaline and beta-

blockers), which interrupts glycogenolysis by blocking epinephrine's effect [13]

●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

Hyperinsulinism — Increased glucose utilization primarily results from

hyperinsulinism. Excess insulin also suppresses hepatic glucose production. The infant
of a diabetic mother is the most common neonatal clinical situation in which
hyperinsulinism causes hyperinsulinemic hypoglycemia. In this setting, it is postulated
that intermittent maternal hyperglycemia causes fetal hyperglycemia, which leads to
hypertrophied and hyperfunctioning beta cells resulting in fetal and neonatal
hyperinsulinemia. After termination of the maternal glucose supply at delivery,
hypoglycemia from persistent hyperinsulinism in the newborn usually is transient and
typically resolves two to four days after birth. (See "Infant of a diabetic mother", section
on 'Hypoglycemia'.)

Other conditions associated with hyperinsulinism and transient hypoglycemia include:

●Fetal growth restriction (FGR) − In addition to a decrease

in glucose/glycogen stores (as noted above), hyperinsulinism may contribute to
hypoglycemia in newborns with FGR [7,14]. (See "Infants with fetal (intrauterine)
growth restriction".)

●Beckwith-Wiedemann syndrome (BWS) − About half of all neonates with BWS

have transient or prolonged hypoglycemia caused by hyperinsulinism.
(See "Beckwith-Wiedemann syndrome", section on 'Metabolic abnormalities'.)

●Perinatal asphyxia or stress [7,15,16]. (See "Systemic effects of perinatal

asphyxia".)

●Maternal intrapartum treatment with glucose or with antihyperglycemic 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 [17]. (See "Neonatal hyperglycemia", section on 'Risk of
hypoglycemia'.)

●Neonatal conditions associated with excess insulin secretion include alloimmune

hemolytic disease of the newborn (see "Postnatal diagnosis and management of
hemolytic disease of the fetus and newborn"), meconium aspiration syndrome
 (see "Clinical features and diagnosis of meconium aspiration syndrome"),
hypothermia, and polycythemia [7]. (See "Neonatal polycythemia", section on
'Hypoglycemia'.)

Without hyperinsulinism — Conditions associated with glucose utilization that

exceeds production without hyperinsulinism include the following:

●Asymmetric neonates with FGR have relatively large (spared) head and brain
size compared with their birth weight. Because the neonatal brain accounts for a
large proportion of total glucose utilization, many of these infants become
hypoglycemic if provided a glucose supply that seems appropriate relative to body
weight (4 to 6 mg/kg/min) rather than the higher appropriate glucose supply
required to prevent hypoglycemia relative to the larger head size.

●Conditions associated with anaerobic glycolysis due to decreased tissue

perfusion, poor oxygenation, or biochemical defects that interfere with aerobic
glucose metabolism [18]. The energy (ATP) per molecule of glucose produced by
anaerobic glycolysis is only about 5 percent of that produced by aerobic glucose
metabolism.

●Hypoglycemia associated with polycythemia may result from greater glucose

utilization by the increased mass of red blood cells. (See "Neonatal polycythemia",
section on 'Hypoglycemia'.)

●Increased glucose consumption can occur with heart failure or perinatal

asphyxia; hyperinsulinism has also been documented in infants who experience
perinatal asphyxia [15].

●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.

Neuroglycopenia — 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, a rare condition, results in low CSF
glucose concentrations and neurologic symptoms associated with hypoglycemia [19].

CLINICAL MANIFESTATIONS — Infants with low blood glucose concentrations

frequently are asymptomatic; hypoglycemia in these cases is usually detected by
screening of blood glucose in at-risk infants or as an incidental laboratory finding.

In the symptomatic infant, signs are nonspecific and reflect responses of the nervous
system to glucose deprivation. These can be categorized as neurogenic or
neuroglycopenic findings [8]:

●Neurogenic (autonomic) symptoms result from changes due to neural

sympathetic discharge triggered by hypoglycemia.

•Jitteriness/tremors
 •Sweating

•Irritability

•Tachypnea

•Pallor

●Neuroglycopenic symptoms are caused by brain dysfunction from impaired brain

energy metabolism due to a deficient glucose supply.

•Poor suck or poor feeding

•Weak or high-pitched cry

•Change in level of consciousness (lethargy, coma)

•Seizures

•Hypotonia

In newborns, additional signs of hypoglycemia include apnea, bradycardia, cyanosis,

and hypothermia.

Because these findings are nonspecific, further evaluation for other possible causes
(eg, sepsis) should be conducted if symptoms do not resolve after normalization of the
blood glucose concentration. (See 'Differential diagnosis' below.)

EVALUATION

Who should be evaluated? — Blood glucose concentrations should not be

measured in healthy asymptomatic term infants born after an uncomplicated
pregnancy and delivery [7,8]. Blood glucose concentration should be measured in
infants at risk for hypoglycemia and in infants who exhibit signs or symptoms consistent
with hypoglycemia [8]. (See 'Clinical manifestations' above.)

Infants at risk for hypoglycemia include:

●Preterm infants including late preterm infants with gestational age less than 37
weeks (see "Late preterm infants", section on 'Hypoglycemia')

●Infants who are large for gestational age (see "Large for gestational age
newborn", section on 'Hypoglycemia')

●Infants with fetal growth restriction (FGR) (see "Infants with fetal (intrauterine)
growth restriction", section on 'Hypoglycemia')

●Infants of diabetic mothers (see "Infant of a diabetic mother", section on

'Hypoglycemia')

●Infants who have experienced perinatal stress due to:

 •Birth asphyxia/ischemia; this includes infants delivered by Cesarean birth for
fetal distress (see "Systemic effects of perinatal asphyxia", section on 'Organ
involvement')

•Maternal preeclampsia/eclampsia or hypertension

•Meconium aspiration syndrome (see "Clinical features and diagnosis of

meconium aspiration syndrome", section on 'Clinical features')

•Erythroblastosis fetalis (see "Postnatal care of hydrops fetalis")

•Polycythemia (see "Neonatal polycythemia")

●Postmature infants, as these infants are at risk for placental insufficiency due to
either the infant "outgrowing the placenta" or due to decreasing placental function
as a result of aging (see "Postterm infant")

●Infants who require intensive care

●Infants whose mothers were treated with beta adrenergic or oral hypoglycemic
agents

●Family history of a genetic form of hypoglycemia

●Congenital syndromes (eg, Beckwith-Wiedemann) and abnormal physical

features (eg, midline facial malformations, and microphallus) associated with
hypoglycemia

Reports from an ongoing prospective study have shown that the incidence of
hypoglycemia, defined as blood glucose concentration ≤47 mg/dL (2.6 mmol/L), occurs
in half of at-risk neonates (ie, large or small for gestational age, infant of diabetic
mother, late preterm infants) [3,20]. In addition, 20 percent of these at-risk infants had a
blood glucose concentration ≤36 mg/dL (2 mmol/L), and 20 percent had more than one
episode of a documented low blood glucose level [20]. Most of the low glucose
concentrations occurred within the first 24 hours of life and were in asymptomatic
infants. However, in some newborns, their first low glucose concentration occurred
after 48 hours of age and/or after three glucose concentrations greater than
47 mg/dL (2.6 mmol/L).

Blood glucose concentration should also be monitored at least weekly in infants

receiving total parenteral nutrition (TPN), and in infants transitioning from parenteral to
enteral nutrition. No single concentration has been shown to be "safe" for preterm
infants who are enterally fed prior to 40 weeks postconceptual age as there is a
significant amount of variability in patients' glucose concentrations (both hyper- and
hypoglycemic episodes) throughout the day [21,22]. For preterm infants, many experts
in the field, including the author, would suggest a target blood glucose concentration of
50 to 60 mg/dL (2.8 to 3.3 mmol/L) [1,23]. In all neonatal cases, glucose concentrations
should be considered in the context of the patient's overall clinical and nutritional
status.
Timing and frequency of glucose screening — The schedule for glucose screening
is dependent on the clinical setting as follows:

●Glucose concentrations should be determined whenever symptoms consistent

with hypoglycemia occur.

●In infants who are at risk for hypoglycemia, glucose screening is performed after
the first feed, which should occur within one hour after birth. Surveillance should
be continued by measuring a prefeeding glucose concentration every three to six
hours for the first 24 to 48 hours of life because many at-risk newborns present
with their first documented low glucose concentrations during this period [20].

●In neonates identified with low blood glucose concentrations, monitoring should
continue until concentrations can be maintained with regular feedings in a normal
range: >50 mg/dL (2.8 mmol/L) in newborns <48 hours old, and
>60 mg/dL (3.3 mmol/L) in newborns >48 hours old [7].

●If an infant is unable to maintain glucose concentrations >60 mg/dL after 48

hours of age, a hypoglycemia disorder should be considered and further
evaluation is warranted [7]. (See "Management and outcome of neonatal
hypoglycemia", section on 'Persistent hypoglycemia'.)

How glucose testing is performed — Most nurseries perform capillary blood glucose
measurements using a point of care glucose meter as a rapid screening method.
However, glucose meters show large variations in values compared with laboratory
methods, especially at low glucose concentrations, and are of unproven reliability to
document hypoglycemia in newborns [24,25]. Thus, the plasma glucose concentration
in an infant with a low glucose value determined by a glucose meter should be
confirmed by laboratory measurement [8]. Likewise, laboratory confirmation of the
plasma glucose concentration should be performed in any infant who shows signs
consistent with hypoglycemia. However, treatment should be started immediately
after the blood sample is obtained and before confirmatory results are available.

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 delays in processing and assaying glucose can
reduce the glucose concentration by up to 6 mg/dL/hour (0.3 mmol/L/hour) due to red
cell glycolysis [7].

Continuous glucose monitoring using a sensor that measures interstitial glucose

concentration was reported to be reliable (when compared with blood glucose
measurement), safe, and tolerable [26-28]. 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 [29].
DIAGNOSIS — As discussed previously, pathologic neonatal hypoglycemia cannot be
defined by a precise numerical blood glucose concentration because of the lack of
outcome data that accurately identify a threshold level of blood glucose at which
intervention should be initiated to prevent morbidity (see 'Challenge of defining
neonatal hypoglycemia' above). Nevertheless, defining a clinical diagnosis of neonatal
hypoglycemia is important to provide guidance for when and if therapy should be
initiated to increase blood glucose levels.

We use the following parameters outlined by the 2011 American Academy of Pediatrics
(AAP) clinical report and guidelines from the Pediatric Endocrine Society to make the
diagnosis of neonatal hypoglycemia requiring medical intervention [7,8]
(see "Management and outcome of neonatal hypoglycemia"):

●Symptomatic patients (eg, jitteriness/tremors, hypotonia, changes in level of

consciousness, apnea/bradycardia, cyanosis, tachypnea, poor suck or feeding,
hypothermia, and/orseizures) (see 'Clinical manifestations' above):

•Who are less than 48 hours of life with plasma glucose levels
<50 mg/dL (2.8 mmol/L)

•Who are greater than 48 hours of life with plasma glucose levels
<60 mg/dL (3.3 mmol/L)

●Asymptomatic patients at risk for hypoglycemia (eg, preterm infant or an infant

with fetal growth restriction) or patients in whom low glucose was identified as an
incidental laboratory finding (see 'Who should be evaluated?' above):

•Who are less than 4 hours of life with plasma glucose levels
<25 mg/dL (1.4 mmol/L)

•Who are between 4 and 24 hours of life with plasma glucose

<35 mg/dL (1.9 mmol/L)

•Who are between 24 and 48 hours of life with plasma glucose levels
<50 mg/dL (2.8 mmol/L)

•Who are greater than 48 hours of life with plasma glucose levels
<60 mg/dL (3.3 mmol/L)

DIFFERENTIAL DIAGNOSIS — Because the clinical manifestations are nonspecific,

the following disorders can present with similar findings. In general, neonatal
hypoglycemia is differentiated from these conditions by the resolution of symptoms as
blood glucose levels normalize. However, in some cases, it is still challenging to
confirm the underlying diagnosis, as interventions that address these other disorders
may be administered during the same time period.

●Sepsis – In neonates, nonspecific signs of sepsis are often similar to those of

hypoglycemia, such as irritability, lethargy, and tachypnea. Because of the serious
consequences, empiric antibiotic therapy should be provided (after cultures are
 obtained) to infants with suspected sepsis pending definitive culture-based
diagnosis, in addition to administrating interventions directed towards
hypoglycemia. (See "Clinical features, evaluation, and diagnosis of sepsis in term
and late preterm infants" and "Clinical features and diagnosis of bacterial sepsis in
the preterm infant (<34 weeks gestation)".)

●Inborn errors of metabolism – Metabolic diseases that often present between 12

and 72 hours of age after the initiation of oral feeding include hyperglycinemia,
urea cycle disorders, and branched-chain organic acidemias. Hypoglycemia may
also be an associated finding in patients with some metabolic diseases (table 1)
and will persist despite measures to increase blood glucose levels. The diagnosis
of inborn errors of metabolism and specific disorders is discussed separately.
(See "Inborn errors of metabolism: Metabolic emergencies", section on 'Initial
evaluation' and "Inborn errors of metabolism: Identifying the specific disorder",
section on 'Laboratory evaluation'.)

●Hyponatremia – Patients typically are not symptomatic until serum or plasma

sodium falls below 125 mEq/L, and present with neurologic manifestations
including lethargy, obtundation, and, eventually, seizures. The diagnosis of
hyponatremia is made by obtaining serum electrolyte levels. (See "Hyponatremia
in children", section on 'Clinical manifestations'.)

●Neonatal encephalopathy due to perinatal asphyxia – Neonatal encephalopathy

can present with lethargy and irritability, but symptoms fail to improve with an
increase in blood glucose levels. Evidence by magnetic resonance imaging of
acute brain injury confirms the diagnosis of encephalopathy. (See "Clinical
features, diagnosis, and treatment of neonatal encephalopathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces
are written in plain language, at the 5th to 6th grade reading level, and they answer the
four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)

●Basics topic (see "Patient education: Newborn hypoglycemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Transient low blood glucose concentrations are common in healthy term infants
after birth as the glucose supply changes from a continuous transplacental supply
from the mother to an intermittent supply from feeds. (See 'Normal transitional low
glucose levels' above.)

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

glucose utilization. (See 'Pathologic and/or persistent hypoglycemia' above
and "Causes of hypoglycemia in infants and children".)

•In neonates, diminished glucose supply is due to inadequate energy 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 (eg, infant of a diabetic mother) or conditions associated with
increased metabolic needs or anaerobic glycolysis. (See 'Increased glucose
utilization' above and 'Without hyperinsulinism' above.)

●Infants with low blood glucose concentrations frequently are asymptomatic, and
are usually detected by screening of at-risk infants. In symptomatic neonates, the
findings are nonspecific and 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.)

●We do not recommend screening for neonatal hypoglycemia in healthy

asymptomatic term infants born after an uncomplicated pregnancy and delivery
(Grade 1C).

●We recommend blood glucose concentration should be measured in infants at

risk for hypoglycemia (eg, preterm infants, infants who are large or small for
gestational age, infants of mothers with diabetes or who required beta adrenergic
or oral antihyperglycemic agents, and infants who have some evidence of
perinatal stress) and in infants who exhibit signs or symptoms consistent with
hypoglycemia (Grade 1C). (See 'Who should be evaluated?' above.)

●Timing of glucose testing is dependent on the clinical setting (see 'Timing and
frequency of glucose screening' above):

•Glucose should be measured whenever an infant presents with symptoms

consistent with hypoglycemia.

•In infants who are at risk, glucose screening is performed after the first feed,
which should occur within one hour after birth.

●Most nurseries perform point of care capillary blood glucose measurements

using a glucose meter as a rapid screening method. A low screening glucose
value should always be confirmed by laboratory measurement. However,
treatment is initiated after the blood sample is obtained while awaiting
confirmatory results. (See 'How glucose testing is performed'above.)
 ●Although it is not possible to establish a single numerical blood glucose
concentration that accurately predicts significant neonatal hypoglycemia at which
intervention should be initiated to prevent morbidity, defining a clinical diagnosis of
neonatal hypoglycemia is important to provide guidance for when and if therapy
should be initiated to increase blood glucose levels. (See 'Challenge of defining
neonatal hypoglycemia' above and 'Diagnosis' above.)

We make a clinical diagnosis of neonatal hypoglycemia based on the presence or

absence of symptoms, the age of the newborn, and the plasma glucose level as
follows:

•Symptomatic patients:

-Who are less than 48 hours of life with plasma glucose levels
<50 mg/dL (2.8 mmol/L)

-Who are greater than 48 hours of life with plasma glucose levels
<60 mg/dL (3.3 mmol/L)

•Asymptomatic patients at risk for hypoglycemia (eg, preterm infant or an

infant with fetal growth restriction) or in patients in whom low glucose was
identified as an incidental laboratory finding (see 'Who should be
evaluated?' above):

-Who are less than 4 hours of life with plasma glucose levels
<25 mg/dL (1.4 mmol/L)

-Who are between 4 and 24 hours of life with plasma glucose

<35 mg/dL (1.9 mmol/L)

-Who are between 24 and 48 hours of life with plasma glucose levels
<50 mg/dL (2.8 mmol/L)

-Who are greater than 48 hours of life with plasma glucose levels
<60 mg/dL (3.3 mmol/L)

●The differential diagnosis for neonatal hypoglycemia is broad because of the

overlap of nonspecific findings (eg, lethargy and irritability). Neonatal
hypoglycemia is differentiated from these other disorders (eg, sepsis) with signs of
clinical improvement as the blood glucose level normalizes. (See 'Differential
diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge

See Wai Chan, MD, MPH, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of
neonatal hypoglycemia: suggested operational thresholds. Pediatrics 2000; 105:1141.
2. Hay WW Jr, Raju TN, Higgins RD, 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
2009; 155:612.
3. McKinlay CJ, Alsweiler JM, Ansell JM, et al. Neonatal Glycemia and
Neurodevelopmental Outcomes at 2 Years. N Engl J Med 2015; 373:1507.
4. McKinlay CJD, Alsweiler JM, Anstice NS, et al. Association of Neonatal Glycemia With
Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatr 2017; 171:972.
5. Screening guidelines for newborns at risk for low blood glucose. Paediatr Child Health
2004; 9:723.
6. Tin W, Brunskill G, Kelly T, Fritz S. 15-year follow-up of recurrent "hypoglycemia" in
preterm infants. Pediatrics 2012; 130:e1497.
7. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating "transitional neonatal
hypoglycemia": mechanism and implications for management. J Pediatr 2015;
166:1520.
8. Committee on Fetus and Newborn, Adamkin DH. Postnatal glucose homeostasis in
late-preterm and term infants. Pediatrics 2011; 127:575.
9. Stanley CA, Baker L. The causes of neonatal hypoglycemia. N Engl J Med 1999;
340:1200.
10. Lubchenco LO, Bard H. Incidence of hypoglycemia in newborn infants classified by
birth weight and gestational age. Pediatrics 1971; 47:831.
11. Hawdon JM, Weddell A, Aynsley-Green A, Ward Platt MP. Hormonal and metabolic
response to hypoglycaemia in small for gestational age infants. Arch Dis Child 1993;
68:269.
12. Worthen HG, al Ashwal A, Ozand PT, et al. Comparative frequency and severity of
hypoglycemia in selected organic acidemias, branched chain amino acidemia, and
disorders of fructose metabolism. Brain Dev 1994; 16 Suppl:81.
13. Bateman BT, Patorno E, Desai RJ, et al. Late Pregnancy β Blocker Exposure and
Risks of Neonatal Hypoglycemia and Bradycardia. Pediatrics 2016; 138.
14. Miralles RE, Lodha A, Perlman M, Moore AM. Experience with intravenous glucagon
infusions as a treatment for resistant neonatal hypoglycemia. Arch Pediatr Adolesc
Med 2002; 156:999.
15. Collins JE, Leonard JV. Hyperinsulinism in asphyxiated and small-for-dates infants with
hypoglycaemia. Lancet 1984; 2:311.
16. Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in
infants with a syndrome of prolonged neonatal hyperinsulinism. J Pediatr 2006;
148:207.
17. Sinclair JC, Bottino M, Cowett RM. Interventions for prevention of neonatal
hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev 2009;
:CD007615.
18. Sue CM, Hirano M, DiMauro S, De Vivo DC. Neonatal presentations of mitochondrial
metabolic disorders. Semin Perinatol 1999; 23:113.
19. Seidner G, Alvarez MG, Yeh JI, et al. GLUT-1 deficiency syndrome caused by
haploinsufficiency of the blood-brain barrier hexose carrier. Nat Genet 1998; 18:188.
20. Harris DL, Weston PJ, Harding JE. Incidence of neonatal hypoglycemia in babies
identified as at risk. J Pediatr 2012; 161:787.
21. Pertierra-Cortada A, Ramon-Krauel M, Iriondo-Sanz M, Iglesias-Platas I. Instability of
glucose values in very preterm babies at term postmenstrual age. J Pediatr 2014;
165:1146.
22. Mizumoto H, Honda Y, Ueda K, et al. Glycemic variability in preterm infants receiving
intermittent gastric tube feeding: report of three cases. Pediatr Int 2013; 55:e25.
23. Rozance PJ, Hay WW. Hypoglycemia in newborn infants: Features associated with
adverse outcomes. Biol Neonate 2006; 90:74.
 24. Balion C, Grey V, Ismaila A, et al. Screening for hypoglycemia at the bedside in the
neonatal intensive care unit (NICU) with the Abbott PCx glucose meter. BMC Pediatr
2006; 6:28.
25. Rosenthal M, Ugele B, Lipowsky G, Küster H. The Accutrend sensor glucose analyzer
may not be adequate in bedside testing for neonatal hypoglycemia. Eur J Pediatr 2006;
165:99.
26. Harris DL, Battin MR, Weston PJ, Harding JE. Continuous glucose monitoring in
newborn babies at risk of hypoglycemia. J Pediatr 2010; 157:198.
27. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Validation of the continuous
glucose monitoring sensor in preterm infants. Arch Dis Child Fetal Neonatal Ed 2013;
98:F136.
28. Wackernagel D, Dube M, Blennow M, Tindberg Y. Continuous subcutaneous glucose
monitoring is accurate in term and near-term infants at risk of hypoglycaemia. Acta
Paediatr 2016; 105:917.
29. Hay WW Jr, Rozance PJ. Continuous glucose monitoring for diagnosis and treatment
of neonatal hypoglycemia. J Pediatr 2010; 157:180.

Topic 5053 Version 28.0

GRAPHICS
Distinguishing biochemical findings of inborn errors of metabolism*

Disorders of Fatty acid

syrup Organic Urea cycle Mitochondrial Peroxisom
carbohydrate oxidation
isease acidemias defects disorders disorder
metabolism disorders

++ - ± ± ± -

- + - - - -

+ ++ - ± - -

± - + + ± -

H A A/H A/L A/H A

± - + ± ++ -

-: usually absent; ±: sometimes present; +: usually present; ++: always present; A: appropriate;

H: inappropriately high; L: inappropriately low.

* Within disease categories, not all diseases have all findings; for disorders with episodic

decompensation clinical and laboratory findings may be present only during acute crisis; for

progressive disorders, findings may not be present early in the course of disease.

Adapted from: Weiner DL. Metabolic Emergencies. In: Textbook of Pediatric Emergency Medicine,

5th ed, Fleisher GR, Ludwig S, Henretig FM (Eds), Lippincott, Williams & Wilkins, Philadelphia

2006. p.1193.
Graphic 76373 Version 6.0