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Management and outcome of neonatal hypoglycemia

Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Management and outcome 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: Aug 2015. | This topic last updated: Aug 04, 2015.
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 if left untreated may lead to significant neurologic and developmental sequelae.
This topic will discuss the outcome and management of neonatal hypoglycemia, including evaluation of persistent
hypoglycemia. The physiology of normal transient neonatal low blood glucose levels, causes of persistent or
pathologic neonatal hypoglycemia, and the clinical manifestations and diagnosis of neonatal hypoglycemia are
discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)
GOALS AND CHALLENGES The goals of managing neonatal hypoglycemia are:
To correct blood glucose levels in symptomatic patients (see "Pathogenesis, screening, and diagnosis of
neonatal hypoglycemia", section on 'Clinical manifestations')
To prevent symptomatic hypoglycemia in at-risk patients
To avoid unnecessary treatment of infants with transitional low blood glucose, which will self-resolve without
intervention
To identify newborns with a serious underlying hypoglycemia disorder
The long-term goal is to prevent neurologic sequelae of neonatal hypoglycemia. However, a specific blood glucose
concentration and/or duration of hypoglycemia have not been established that accurately predict poor
neurodevelopmental outcome. As a result, significant neonatal hypoglycemia requiring intervention cannot be
defined by a precise numerical blood glucose concentration and there are no data that have demonstrated that any
management strategy is superior in reducing long-term neurologic adverse outcome. (See "Pathogenesis,
screening, and diagnosis of neonatal hypoglycemia", section on 'Challenge of defining neonatal hypoglycemia'.)
Nevertheless, clinical guidelines have been developed by the American Academy of Pediatrics (AAP) and the
Pediatric Endocrine Society (PES) because of the observed association between symptomatic neonatal
hypoglycemia and neurodevelopmental impairment [1,2] (see 'Neurodevelopmental outcome' below). The goals of
these recommendations from the AAP and PES are to reduce neurologic impairment due to neonatal
hypoglycemia, but also to minimize overtreatment of neonates with normal transitional low glucose concentrations,
which resolve without intervention and are not associated with any long-term sequelae. In addition, the PES
guidelines provide guidance on how and when to identify infants with a serious underlying persistent hypoglycemic
disorder.
Target blood glucose levels The threshold goals for intervention that we use at our center are consistent with
the guidelines developed by the AAP and the PES, which are based on limited available data [1,2]. The following
target plasma glucose levels are used to provide a margin of safety for infants who are at risk for neonatal
hypoglycemia (see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be
evaluated?'). They are dependent on the presence or absence of symptoms, age of the infant to reflect the normal
physiologic increase of low blood glucose levels after delivery, and whether or not there is a genetic underlying
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etiology.
Symptomatic patients (eg, jitteriness/tremors, hypotonia, changes in level of consciousness,
apnea/bradycardia, cyanosis, tachypnea, poor suck or feeding, hypothermia, and/or seizures) (see
"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Clinical manifestations'):
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)
(see "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be
evaluated?') or in patients in whom a low glucose concentration was identified as an incidental laboratory
finding:

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)

In newborns with a suspected or confirmed genetic hypoglycemia disorder (such as a family history of a
hypoglycemia disorder or physical exam features consistent with Beckwith-Wiedemann syndrome), the goal
is to maintain plasma glucose concentrations >70 mg/dL (3.9 mmol/L). This treatment goal is higher because
the risks of harm from repetitive low glucose concentrations in this population are significant [3,4]. In addition,
consultation with a specialist should be considered for further diagnostic testing to diagnose the underlying
disorder [2].
MANAGEMENT APPROACH 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. The following approach is
consistent with guidelines published by the American Academy of Pediatrics (AAP) and the Pediatric Endocrine
Society (PES) [1,2,5].
Symptomatic patients Outcome data have shown that symptomatic neonatal hypoglycemia may result in brain
injury (see 'Neurodevelopmental outcome' below). As a result, aggressive therapy that includes the use of parenteral
glucose (dextrose) is used to increase blood glucose levels in symptomatic patients [1,2].
Therapy should be initiated while awaiting laboratory confirmation of low blood glucose levels. Although most
symptomatic patients will have plasma glucose levels less than 25 mg/dL (2.2 mmol/L), there is great variability in
the clinical response in neonates to low blood glucose concentrations [6]; some newborns become symptomatic at
the same or even higher blood glucose concentrations than those observed in asymptomatic infants. As a result,
there is not a precise numerical blood glucose level that accurately predicts when and if a neonate will present with
symptoms. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Challenge of
defining neonatal hypoglycemia'.)
Parenteral glucose (dextrose) infusion For symptomatic patients, an intravenous (IV) bolus of dextrose,
the D-isomer of glucose (200 mg/kg), is given over 5 minutes (2 mL/kg of 10 percent dextrose in water [D10]). This
is followed by the continuous administration of parenteral dextrose infusion at a rate of 6 to 8 mg/kg of dextrose per
minute. If hypoglycemia is persistent, infusion rates should be increased as needed to restore and maintain
normoglycemia (see 'Target blood glucose levels' above). The maximum rate of glucose infusion for treatment is
limited by the maximum amount of fluids that can be administered to a patient (this is variable for each patient, but
we have used rates as high as 200 mL/kg per day while monitoring for evidence of hyponatremia and fluid overload)
and the maximum concentration of dextrose for the type of vascular access (see 'Target blood glucose levels'
above). In general, if the glucose infusion rate approaches 12 mg/kg per minute, other interventions should be
considered.
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In addition, parenteral administration is used for asymptomatic infants with severe hypoglycemia (plasma glucose
less than 25 mg/dL [1.4 mmol/L]), especially after 4 hours of age, who are unable to be fed enterally or who
experience persistent hypoglycemia despite oral feedings. (See 'Asymptomatic term or late preterm infants' below.)
The maximum dextrose concentrations for fluid administered through a peripheral IV catheter or a low lying
umbilical venous catheter is 12.5 percent, and through a central venous catheter (including a centrally positioned
umbilical venous catheter) is 25 percent. If no IV access has been established, dextrose at a concentration of 12.5
percent or less can be infused through an umbilical arterial catheter. In severe cases, rates of fluid administration
required to deliver sufficient glucose to treat hypoglycemia may be greater than the rate of maintenance fluids. In
these cases, the patient's fluid and clinical status should be monitored closely for volume overload, looking for
evidence of pulmonary edema, heart failure, and hyponatremia. Infants who depend upon high infusion rates or a
dextrose concentration greater than 12.5 percent require placement of a central venous catheter. In some cases
diuretics may be indicated.
Plasma glucose concentration should be determined 20 minutes after the bolus infusion, and the infusion rate or
dextrose concentration adjusted as needed to maintain plasma glucose concentration >50 mg/dL (2.8 mmol/L) in
the first 48 hours of life and >60 mg/dL (3.3 mmol/L) after 48 hours of age [2]. (See 'Target blood glucose levels'
above.)
Glucagon Administration of glucagon should be considered in the rare patients with persistent plasma
glucose <50 mg/dL (2.8 mmol/L) despite continuous maximum parenteral dextrose infusion. Glucagon can be given
intravenously or subcutaneously to symptomatic infants without IV access.
Although a wide range of glucagon doses (20 to 200 mcg/kg, maximum dose of 1 mg) have been described in
treating neonates and infants with acute severe hypoglycemia [7-10], we suggest that glucagon be administered at
an initial dose of 20 to 30 mcg/kg to infants with persistent hypoglycemia despite parenteral glucose infusion [9].
Glucagon is typically given as a temporizing measure administered as a slow IV push over one minute, or by
intramuscular or subcutaneous injection. A rise in plasma glucose of approximately 30 to 50 mg/dL should occur
within 15 to 30 minutes of administration and should last approximately two hours, though a more rapid decrease in
the glucose concentration may occur. Due to the short duration of action of glucagon, glucose concentrations
should be checked frequently and repeat doses of glucagon administered as needed. If the plasma 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 'Persistent hypoglycemia' below and "Overview of inherited disorders of glucose
and glycogen metabolism".)
One case series of newborns (n = 55) used a continuous IV infusion of 1 mg glucagon total for 24 hours (average
dose 10 to 20 mcg/kg per hour) [9]. This was effective in the treatment of persistent significant hypoglycemia. In
this cohort, cared for at a tertiary Canadian center, causes of hypoglycemia included asphyxia, fetal (intrauterine)
growth restriction, prematurity, and neonatal hyperinsulinism due to maternal diabetes (ie, infant of a diabetic
mother). Further confirmation is needed before continuous infusion of glucagon can be recommended for routine
use. However, continuous infusion may be a reasonable option if repetitive dosing of glucagon were being used to
maintain glucose.
Other therapeutic options
Glucocorticoids Administration of glucocorticoid therapy (hydrocortisone 2 to 6 mg/kg per day divided in
2 to 3 doses orally or intravenously) in infants requiring a glucose infusion rate of 12 mg/kg per minute or greater
has been used. However, due to the potential side effects of steroid administration, its use should be restricted to a
short course (1 to 2 days), unless a patient has documented adrenal insufficiency, in which case lifelong
glucocorticoid replacement will be necessary. The proposed mechanism of action of glucocorticoids is stimulation
of gluconeogenesis and reduction in peripheral glucose utilization. Serum cortisol and insulin concentrations during
an episode of hypoglycemia should be measured before beginning glucocorticoid treatment.
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Persistent hyperinsulinemic hypoglycemia Other therapeutic options for persistent hyperinsulinemic

hypoglycemia, which is not responsive to parenteral dextrose infusion and glucagon therapy, include drug therapy
(eg, diazoxide and somatostatin), 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 'Somatostatin analogues' and "Treatment and complications of persistent hyperinsulinemic hypoglycemia of
infancy", section on 'Surgical therapy'.)
Transition to oral feeds When the glucose concentration is stabilized and maintained at or above the
threshold value, 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 IV glucose infusion is tapered, the preprandial blood glucose
level should be monitored every three to four hours depending upon the feeding schedule. Blood glucose levels
should be maintained at the target thresholds as discussed above. (See 'Target blood glucose levels' above.)
Need for further evaluation For infants with severe hypoglycemia that require prolonged and/or high rates
of IV dextrose infusion to maintain glucose threshold levels, further laboratory evaluation is warranted, especially if
no underlying cause has been identified by either history or physical examination. In these uncommon situations,
consultation with a pediatric endocrinologist or a clinician with expertise in managing neonatal hypoglycemia is
recommended. (See 'Laboratory testing' below.)
Asymptomatic term or late preterm infants Asymptomatic patients are typically identified because they are
at risk for hypoglycemia. The management of these patients is focused on normalizing their blood glucose levels
and preventing them from becoming symptomatic. The first intervention for these patients is usually oral feeding.
(See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Who should be evaluated?'.)
Oral feeds Healthy infants are fed as soon as possible after birth. Infants who are at risk for hypoglycemia
should be fed within the first hour of life [1]. Blood glucose concentrations should be measured frequently starting
20 to 30 minutes after the initial and subsequent feedings. Feedings should be offered at two- to three-hour intervals
and the newborn monitored for symptoms consistent with hypoglycemia.
Although, as noted above, there is not a precise numerical blood glucose level that accurately predicts when and if
a neonate will present with symptoms, guidelines from the AAP and the PES recommend that additional oral
feeding should be given as quickly as possible for the following patients, based on the age of the neonate and
plasma glucose level.
The following is our management approach regarding when an additional oral feeding is given and the need for
further intervention based on the infant's response, which is consistent with these guidelines. Additional feeds are
given to:
Infants less than 4 hours of age with plasma glucose <25 mg/dL (1.4 mmol/L). If plasma glucose fails to
increase, parenteral glucose is administered. If the plasma glucose increases to above 25 mg/dL (1.4
mmol/L), oral feedings should continue every two to three hours with preprandial measurements of
plasma glucose.
Infants between 4 and 24 hours of age and with plasma glucose <35 mg/dL (1.9 mmol/L). If plasma
glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to above
35 mg/dL (1.9 mmol/L), oral feedings should continue every two to three hours with preprandial
measurements of plasma glucose. If a patient becomes symptomatic or if plasma glucose fails to
increase above 45 mg/dL (2.5 mmol/L) after three oral feedings, then parenteral glucose should be given
(2 mL/kg of 10 percent dextrose in water followed by a continuous infusion of 4 to 6 mg/kg/min with
repeat determinations of plasma glucose as noted above). (See 'Parenteral glucose (dextrose) infusion'
above.)
While breast milk is strongly preferred, formula feeding may be provided for infants when breast milk is not
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available. Buccal dextrose gel is emerging as an effective and safe therapy when used in conjunction with milk
feeding for at-risk infants [11]. However, further trials, including larger multicenter trials, are required before this
intervention can be recommended for use in routine clinical practice.
Prior to discharge, infants should be able to maintain plasma glucose above the threshold blood glucose goal even
if a feeding is skipped [5]. (See 'Discharge criteria' below.)
Preterm infants Preterm infants, especially those 34 weeks gestation, are at risk for low blood glucose
concentrations, likely due to immaturity of counter regulatory hormone systems and poor nutrient reserves [12]. In
addition, some patients are at particular risk of having low glucose concentrations as they transition from parenteral
nutrition to bolus enteral feeds [13]. Even on full bolus enteral feeds, preterm infants have episodes of both low and
high glucose concentrations [14,15]. It appears that infants who are at risk for growth failure are also at risk for
recurrent and persistent episodes of low glucose concentrations [12].
Although a safe glucose concentration for these infants has not been established, experts in the field, including the
author, suggest maintaining plasma glucose levels greater than 50 to 60 mg/dL (2.8 to 3.3 mmol/L). This is likely to
be a safe strategy to avoid long-term neurologic sequelae [2,16,17]. However, the setting of the targeted threshold
levels must also take into account the patient's overall clinical and nutritional status. (See 'Asymptomatic
hypoglycemia and preterm infants' below.)
The management approach is similar for asymptomatic preterm infants who are able to receive sufficient nutrition
through enteral feeds with initiation of early feeds and monitoring of plasma blood glucose levels [16]. For those who
are not expected to be able to receive enough enteral nutrition due to prematurity, parenteral nutrition, which
includes glucose, should be started quickly. (See "Approach to enteral nutrition in the premature infant" and
"Parenteral nutrition in premature infants", section on 'Glucose'.)
Persistent hypoglycemia
Definition and timing of evaluation Persistent hypoglycemia is defined as persistent low glucose
concentrations beyond the first 48 hours of life or the requirement of parenteral glucose infusion to treat
hypoglycemia beyond 48 hours of life [2]. This waiting period of at least 48 hours is necessary because it is difficult
to distinguish newborns with a pathological hypoglycemia disorder (transient or permanent) from normal newborns
with low transitional glucose concentrations since the biochemical features (mild hyperinsulinism) are similar. (See
"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Normal transitional low glucose
levels'.)
For example, the constellation of findings consistent with hyperinsulinemic hypoglycemia in an older child (ie,
inappropriately elevated serum insulin levels, low ketone body [beta-hydroxybutyrate] and free fatty acid
concentrations, and a brisk rise in glucose concentrations following glucagon administration) is also seen in an
asymptomatic and otherwise healthy term infant less than 48 hours old with normal low blood glucose levels. It
remains uncertain exactly when this group of biochemical findings changes from normal physiology to representing
a pathological hypoglycemic condition. However, for most healthy term newborns this transition is believed to take
place by 48 to 96 hours of age [2,18].
As a result, the evaluation for a persistent hypoglycemic disorder should be performed when the infant is 48
hours of age so that the transitional period of adjusting the source of glucose from a continuous supply provided
by the mother through the placenta to an intermittent supply from oral feeds has passed.
Evaluation Once persistent hypoglycemia is established, further evaluation is warranted to determine the
underlying cause. Most cases of persistent hypoglycemia in term infants will have biochemical features of
hyperinsulinism, which are usually caused by perinatal stress and typically resolve in the first few weeks of life.
However, some cases may persist and require ongoing medical management. This is true even in the absence of a
suspected or defined genetic hypoglycemia disorder [19,20]. Therefore, the clinician needs to determine the
appropriate and safe point at which glucose monitoring can be discontinued and when hospital discharge should
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occur, versus when it is likely that a permanent or ongoing hypoglycemic disorder exists, which requires further
intervention and/or evaluation [5]. In cases with prolonged persistent hypoglycemia, consultation with a pediatric
endocrinologist is recommended to help in the evaluation and management of these patients.
The evaluation consists of a thorough history, physical examination, and, in some cases, laboratory evaluation.
(See 'Laboratory testing' below.)
History A thorough history can help determine the underlying cause of hypoglycemia (see
"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Pathologic and/or persistent
hypoglycemia'). The following are historical etiologic clues:
Prematurity Preterm infants, as noted above, have poor nutrient reserves and immature counter regulatory
hormone systems, which increase their risk of hypoglycemia.
Fetal growth restriction (FGR) Infants with FGR are at risk for hypoglycemia due to poor nutrient reserves
and hyperinsulinism.
History of perinatal asphyxia or stress Hyperinsulinism and increased metabolism in neonates with perinatal
asphyxia or stress can contribute to hypoglycemia.
History of maternal diabetes Neonatal hyperinsulinism results in hypoglycemia. (See "Infant of a diabetic
mother", section on 'Hypoglycemia'.)
Positive family history of an infant with neonatal hypoglycemia may be indicative of an underlying genetic
disorder, including inborn errors of metabolism.
Physical findings The physical examination may provide clues to an underlying cause of neonatal
hypoglycemia as follows [2]:
Large for gestational age
Hemihypertrophy, macroglossia, and omphalocele are findings consistent with a diagnosis of BeckwithWiedemann syndrome (BWS) (see "Beckwith-Wiedemann syndrome", section on 'Clinical manifestations')
Ambiguous genitalia, hypertension, hyponatremia, and hyperkalemia are features that may be seen in
congenital adrenal insufficiency, which also is associated with hypoglycemia (see "Causes and clinical
manifestations of primary adrenal insufficiency in children", section on 'Congenital adrenal hyperplasia')
Hepatomegaly is seen in some glycogen storage and other hereditary metabolic diseases that can present
with hypoglycemia, and with BWS
Midline facial defects and ambiguous genitalia may be seen in cases of hypopituitarism
Laboratory testing
Who should be tested? Laboratory testing is warranted in patients who:
Present with severe symptomatic hypoglycemia that requires prolonged and/or high rates of intravenous
dextrose infusion for treatment.
Have persistent hypoglycemia.
Have neurologic symptoms.
Have historical or physical findings suggestive of an underlying etiology. In these patients, regardless of
whether hypoglycemia has been documented or not, consideration should be given to performing specific
tests to rule out a hypoglycemia disorder if there is a family history of a genetic hypoglycemia disorder or if
physical exam features suggest a syndromic hypoglycemia disorder (eg, BWS or congenital adrenal
hyperplasia).
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Consultation with a clinician with expertise in managing neonatal hypoglycemia (ie, pediatric endocrinologist)
should be considered in these cases, as the specific tests required to rule out a hypoglycemia disorder will vary
based on the clinical setting (eg, family history and physical exam) [2].
When should testing be performed ("critical" blood test sampling)? Because tests performed when the
blood glucose levels are normal are not helpful in determining the underlying cause of hypoglycemia, laboratory
testing is based on "critical samples" obtained when the plasma glucose level is <50 mg/dL (2.8 mmol/L). In
asymptomatic patients, when a bedside glucometer is used, samples should be obtained when the glucose
concentration is <40 mg/dL (2.2 mmol/L). This difference in suggested blood glucose threshold is due to the
inaccuracy of a bedside glucometer for diagnosing hypoglycemia. (See "Pathogenesis, screening, and diagnosis of
neonatal hypoglycemia", section on 'How glucose testing is performed'.)
For infants who are on enteral feeds, sampling may need to be obtained after a 6- to 8-hour fast (one skipped feed)
that results in an appropriately low glucose concentration. During the fast, frequent monitoring of vital signs, and
plasma glucose levels (every hour) should be performed. If the plasma glucose concentration drops to less than 50
mg/dL (2.8 mmol/L) prior to 6 to 8 hours, the critical labs should be obtained and the fast terminated.
For patients who are receiving parenteral glucose infusion, sampling can still occur as long as the plasma glucose
is <50 mg/dL (2.8 mmol/L). Interventions to normalize blood glucose levels (ie, feeding or an increase in the
dextrose infusion rate) are delayed until after the samples are obtained [2].
What tests to obtain? In our practice, while the patient has a plasma glucose <50 mg/dL, we obtain blood
samples to confirm hypoglycemia (<50 mg/dL) and measure plasma insulin, beta-hydroxybutyrate, blood pH,
bicarbonate, and free fatty acids. These initial tests are used to distinguish diagnostic categories for neonatal
hypoglycemia and help determine if other blood tests should be obtained including plasma C-peptide, growth
hormone, cortisol, acylcarnitine profile, plasma free and total carnitine levels, serum amino acids, urine organic
acids, or specific genetic tests (algorithm 1). These specific blood tests should be performed in consultation with a
pediatric endocrinologist or other appropriate specialist. Many of these blood tests are rapidly altered by changes in
blood glucose levels including serum insulin, C-peptide, beta-hydroxybutyrate, cortisol, growth hormone, and free
fatty acids [2].
Discharge criteria It is important to ensure that neonates are able to maintain plasma glucose concentrations
in a normal range through cycles of feeding and fasting prior to discharge. In our practice, for infants who are at risk
for hypoglycemia, preprandial glucose concentrations through three feed-fast cycles should be >50 mg/dL (2.8
mmol/L) in infants less than 48 hours of age, and >60 mg/dL (3.3 mmol/L) in those who are 48 hours of life [2,5].
In general, if a neonate can maintain a plasma glucose concentration >60 mg/dL (3.3 mmol/L) after a 6- to 8-hour
fast, it is likely that the infant is safe for discharge [2].
NEURODEVELOPMENTAL OUTCOME
Symptomatic hypoglycemia Symptomatic hypoglycemia can result in brain injury that can be detected by
magnetic resonance imaging (MRI). However, there are no available data that clearly define the glucose
concentration or the duration of hypoglycemia associated with brain damage detected by MRI or other long-term
neurologic sequelae.
A systematic review of the literature published in 2006 reported inconclusive evidence on the effect of neonatal
hypoglycemia on neurodevelopment [21]. Two subsequent studies using brain MRI suggest an association between
hypoglycemia and brain injury in term infants [22,23]. Although it remains uncertain whether timely treatment of
hypoglycemia will prevent brain injury and poor developmental outcome, experts in the field, including the author,
recommend symptomatic neonatal hypoglycemia should be aggressively treated given the potential significant
adverse effects based on the available data [1,2,5].
Asymptomatic hypoglycemia and preterm infants In preterm infants, controversy exists as to whether
asymptomatic hypoglycemia causes neurologic injury and whether glucose concentrations requiring intervention
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should be lower in premature than in term infants. However, several studies report neurodevelopmental sequelae
due to repeated or prolonged asymptomatic episodes of neonatal hypoglycemia in preterm patients. As a result,
experts in the field, including the author, use a lower blood glucose level for intervention in preterm infants. (See
'Preterm infants' above.)
Supporting data for this approach include the following studies:
Retrospective data analysis of a multicenter trial in premature infants showed a correlation between prolonged
hypoglycemia (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
[24]. 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, only arithmetic and motor scores were lower in hypoglycemic infants at 7.5 to 8 years of age [6].
In a study of preschool-age children who were born moderately premature (gestational age 32 to less than 36
weeks), multivariate analysis showed that hypoglycemia was associated with increased incidence of parentreported developmental delay when the children were 43 to 49 months old (odds ratio: 2.19, 95% CI 1.08-4.46)
[25].
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 psychometric testing scores at 3.5 and 5 years of age [26].
In contrast, a study of premature infants (gestational age <32 weeks) with daily measurements of blood glucose
obtained at a fixed time each morning for the first 10 days of life reported no differences in developmental status or
physical disability based on psychometric assessment between 47 patients who had neonatal blood glucose
concentration 45 mg/dL (2.5 mmol/L) on 3 days compared with matched control patients during follow-up at 2
and 15 years of age [27].
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
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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 information: 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.
It is important to differentiate this normal physiologic transitional response from disorders that result in
persistent or recurrent hypoglycemia, which if left untreated may lead to significant neurologic and
developmental sequelae. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section
on 'Normal transitional low glucose levels' and "Pathogenesis, screening, and diagnosis of neonatal
hypoglycemia", section on 'Pathologic and/or persistent hypoglycemia' and 'Neurodevelopmental outcome'
above.)
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The goals of managing neonatal hypoglycemia are to correct blood glucose levels in symptomatic patients,
prevent symptomatic hypoglycemia in at-risk patients, and identify newborns with a serious underlying
hypoglycemic disorder, while avoiding unnecessary treatment of infants with normal transitional low blood
glucose, which will resolve without intervention. The long-term goal is to prevent long-term neurologic
complications. (See 'Goals and challenges' above and "Pathogenesis, screening, and diagnosis of neonatal
hypoglycemia", section on 'Challenge of defining neonatal hypoglycemia'.)
In our practice, target plasma glucose levels consistent with the American Academy of Pediatrics (AAP) and
Pediatric Endocrine Society (PES) guidelines are used to provide a margin of safety for infants who are at risk
for neonatal hypoglycemia. (See 'Target blood glucose levels' above.)
For at-risk neonates without a suspected or confirmed genetic hypoglycemia disorder, the goal is to
maintain plasma glucose concentrations >50 mg/dL (2.8 mmol/L) in the first 48 hours of life, and >60
mg/dL (3.3 mmol/L) after 48 hours of life.
In neonates with a suspected or confirmed genetic hypoglycemia disorder, the goal is to maintain
plasma glucose concentrations >70 mg/dL (3.9 mmol/L).
Treatment of neonatal hypoglycemia is a stepwise process depending on the presence or absence of
symptoms and signs, and the response of the infant at each step. The following approach is consistent with
guidelines published by the AAP and the PES. (See 'Management approach' above.)
For symptomatic infants, we recommend administering parenteral glucose (Grade 1C). Therapy should
be started while awaiting laboratory confirmation. We begin with an intravenous (IV) bolus of dextrose
(200 mg/kg) given over 5 minutes (2 mL/kg of 10 percent dextrose in water). This is followed by the
continuous administration of parenteral glucose infusion at an initial rate of 6 to 8 mg/kg per minute. If
hypoglycemia is persistent, glucose infusion rates should be increased as needed. In the rare patients
who fail to maintain target blood glucose levels despite maximal glucose infusion rates, we suggest the
administration of glucagon at an initial dose of 20 to 30 mcg/kg (Grade 2C). (See 'Symptomatic
patients' above.)
For asymptomatic term and late preterm infants at risk for hypoglycemia, an initial oral feeding should
be given within the first hour of life as follows, based on the age of the patient and plasma glucose.
Blood glucose concentrations should be measured frequently, starting 20 to 30 minutes after the initial
feed and then before subsequent feedings. (See 'Asymptomatic term or late preterm infants' above.)
- Infants less than 4 hours of age and with plasma glucose <25 mg/dL (1.4 mmol/L). If plasma
glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to
above 25 (1.4 mmol/L), oral feedings should continue every two to three hours with preprandial
measurement of plasma glucose.
- Infants between 4 and 24 hours of age and with plasma glucose <35 mg/dL (1.9 mmol/L). If plasma
glucose fails to increase, parenteral glucose is administered. If the plasma glucose increases to
above 35 to mg/dL (1.9 mmol/L), oral feedings should continue every two to three hours with
preprandial measurement of plasma glucose. If a patient becomes symptomatic or if plasma
glucose fails to increase above 45 mg/dL (2.5 mmol/L) after three oral feedings, then parenteral
glucose should be given.
For more premature infants (gestational age <35 weeks) who are able to maintain adequate nutrition by
enteral feeds, the management is the same as that used in term infants, with initial oral feeding within
the first hour of life and ongoing monitoring of blood glucose levels. For those who are not expected to be
able to receive enough enteral nutrition due to prematurity, parenteral nutrition, which includes glucose,
should be started quickly. (See 'Preterm infants' above.)
Further diagnostic testing is usually reserved for infants with persistent hypoglycemia (who are not able to
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maintain preprandial plasma glucose concentrations >60 mg/dL [3.3 mmol/L] after 48 hours of age without IV
dextrose, have severe hypoglycemia requiring prolonged and/or high rates of IV dextrose infusion after 48
hours of life to treat hypoglycemia, have a family history of a genetic hypoglycemia disorder, or have physical
exam features suggestive of a syndromic hypoglycemia disorder). A waiting period beyond the first 48 hours
of life is necessary because it is difficult to distinguish newborns with a pathological hypoglycemia disorder
(transient or permanent) from normal newborns with low transitional glucose concentrations because the
biochemical features (mild hyperinsulinism) are similar. (See 'Laboratory testing' above and 'Persistent
hypoglycemia' above.)
Laboratory testing is based on "critical samples" obtained when the plasma glucose level is <50 mg/dL (2.8
mmol/L). Initial tests that are used to distinguish diagnostic categories for neonatal hypoglycemia are plasma
insulin, beta-hydroxy butyrate, bicarbonate, lactate, and free fatty acids. The results of these tests help
determine if other blood tests should be obtained to determine the underlying cause of persistent
hypoglycemia (algorithm 1). (See 'Laboratory testing' above.)
It is important that neonates are able to maintain plasma blood glucose in a normal range through cycles of
feeding and fasting prior to discharge. In our practice, discharge criterion for infants who are at risk for
hypoglycemia is a preprandial glucose concentration through three feed-fast cycles >50 mg/dL (2.8 mmol/L)
in infants less than 48 hours of age, and >60 mg/dL (3.3 mmol/L) in those who are 48 hours of age.
Symptomatic neonatal hypoglycemia has been associated with brain damage, demonstrated on magnetic
resonance imaging, and poorer developmental outcome. However, there are no available data that clearly
define the glucose concentration or the duration of hypoglycemia that correlate with long-term neurologic
sequelae.
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REFERENCES
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Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr 2015;
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6. Cornblath M, Schwartz R. Outcome of neonatal hypoglycaemia. Complete data are needed. BMJ 1999;
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7. Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes.
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intravenous glucagon and intragastric medium chain triglyceride. Arch Dis Child 1993; 68:255.
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11. Harris DL, Weston PJ, Signal M, et al. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a
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feeding: report of three cases. Pediatr Int 2013; 55:e25.
16. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia:
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Pediatr 1986; 109:114.
19. Hoe FM, Thornton PS, Wanner LA, et al. Clinical features and insulin regulation in infants with a syndrome of
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hypoglycaemia in infants born small-for-gestational age. Arch Dis Child Fetal Neonatal Ed 2013; 98:F356.
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26. Duvanel CB, Fawer CL, Cotting J, et al. Long-term effects of neonatal hypoglycemia on brain growth and
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GRAPHICS
Diagnostic testing for persistent neonatal hypoglycemia

Initial diagnostic testing for persistent neonatal hypoglyc emia (low gluc ose c onc entrations that persist
beyond 48 hours of life) differentiates major etiologic c ategories of hypoglyc emia based on laboratory
testing (bic arbonate, beta-hydroxybutyrate, and free fatty ac id) from a c ritic al sample (obtained when t
plasma gluc ose level is <50 mg/dL [2.8 mmol/L]). Additional spec ific testing (eg, plasma insulin, C-peptide
and c arnitine and ac yl-c arnitine levels) using a c ritic al sample is used to c onfirm the diagnosis of the
underlying c ause of hypoglyc emia.
HCO 3 : bicarbonate; BOHB: beta-hydroxybutyrate; FFA: free fatty acid; GH: growth hormone.
Original figure modified for this publication. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the
Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and
Children. J Pediatr 2015. Illustration used with the permission of Elsevier Inc. All rights reserved.
Graphic 101681 Version 1.0

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Disclosures
Disclosures: Paul J Rozance, MD Nothing to disclose. Joseph A Garcia-Prats, MD Nothing to
disclose. Joseph I Wolfsdorf, MB, BCh Nothing to disclose. Melanie S Kim , MD Nothing to disclose.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for references
to be provided to support the content. Appropriately referenced content is required of all authors and
must conform to UpToDate standards of evidence.
Conflict of interest policy

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