Neonatal hyperglycemia

Authors
See Wai Chan, MD, MPH
Ann R Stark, MD Section Editors
Steven A Abrams, MD
Joseph I Wolfsdorf, MB, BCh Deputy Editor
Melanie S Kim, MD

Last literature review version 17.3: September 2009 | This topic last updated: February
2, 2009 (More)

INTRODUCTION — Glucose supply and metabolism are of central importance for

growth and normal brain development in the fetus and newborn. Disorders in glucose
supply or metabolism can result in hypoglycemia or hyperglycemia.

PARENTERAL GLUCOSE — Most infants who are preterm or ill require parenteral
administration of glucose because adequate enteral feeding is delayed. Neonatal
hyperglycemia often occurs in this setting.

Immediately after birth, sufficient glucose is provided to avoid hypoglycemia, typically

at a rate of 5 to 8 mg/kg per minute. As an example, administration of 10 percent
dextrose solution at 100 mL/kg per day provides glucose at a rate of 7 mg/kg per
minute. Although dextrose is a hydrated form of glucose and is 91 percent glucose, the
correction usually is not applied in clinical practice.

The glucose infusion rate is increased to approximately 11 to 12 mg/kg per minute in

the first two to three days after birth to provide calories for growth. In general, glucose
infusion rates >15 mg/kg per minute are avoided, as this exceeds the ability of most
infants to oxidize glucose and may promote excessive lipogenesis.

DEFINITION — The definition of hyperglycemia is uncertain. It is often defined as

blood glucose >125 mg/dL (6.9 mmol/L) or plasma glucose >150 mg/dL (8.3 mmol/L).
These glucose levels are frequently observed during glucose infusions in newborns,
especially in extremely preterm infants, and may not require intervention [1] .

Plasma osmolality increases by 1 mosmol/L for each 18 mg/dL increase in plasma

glucose concentration. Thus, a rise in glucose concentration from 110 to 200 mg/dL (6.1
to 11.1 mmol/L) only increases osmolality by 5 mosmol/L, which is a relatively small
change. More marked hyperglycemia is required to produce the osmotic diuresis and
hyperosmolality that may be clinically important. Most neonatologists become
concerned about hyperglycemia when the blood glucose concentration exceeds
approximately 180 to 200 mg/dL (10 to 11.1 mmol/L).

Glucosuria — Glucose excretion in the urine in hyperglycemic neonates is determined

by the degree of hyperglycemia and renal tubular reabsorptive capacity for glucose.
Newborns have variable reabsorptive capacity for glucose, which may be particularly
reduced in those who are ill or premature.

The net effect is that glucosuria alone is not a good marker for hyperglycemia since it
can occur at normal blood glucose concentrations. In one study of sick preterm infants
25 to 33 weeks gestation, for example, fractional glucose excretion varied widely and
glucosuria was often seen at normal blood glucose concentrations [2] . These variations
presumably are related to immaturity of the proximal tubule.

On the other hand, mild hyperglycemia may be associated with little or no glucosuria in
infants with mature proximal tubules. This was illustrated in a study of newborns who
were given glucose infusions; at a mean blood glucose concentration of 197 mg/dL (11
mmol/L), there was little glucosuria and no significant osmotic diuresis [3] .

PATHOGENESIS — Hyperglycemia typically occurs when a newborn cannot adapt to

parenteral glucose infusion by decreasing endogenous glucose production or increasing
peripheral glucose uptake [4] . This is usually related to an associated clinical condition.

Hyperglycemia is more common in preterm than in term infants, although the

mechanism is uncertain. Glucose production rate and regulation are comparable in
moderately preterm and term infants. In both [4] : Hepatic glucose production is
suppressed by infusion of glucose (with or without amino acids), hyperglycemia, and
insulin. Glucose production is not changed by intravenous lipid infusion. Circulating
insulin concentrations increase appropriately with hyperglycemia and increase hepatic
and peripheral glucose uptake.

However, insulin responses may be inappropriate in extremely low birth weight

(ELBW) infants. In one study, 23 of 56 ELBW infants became hyperglycemic during
intravenous glucose infusions that were incrementally increased to a maximum rate of
12 mg/kg per minute between days two and six of age [5] . Baseline insulin levels were
similar in hyperglycemic and euglycemic infants, but only 15 of 23 hyperglycemic
infants had a normal insulin response.

The inappropriate insulin response in hyperglycemic ELBW infants may be related to

defective islet beta cell processing of proinsulin. In a study comparing 15
hyperglycemic to 12 normoglycemic ELBW infants during the first week of life,
proinsulin levels were significantly higher in the hyperglycemic ELBW infants, who
also needed higher insulin levels to reach euglycemia compared to normoglycemic
infants [6] .

Suppression of hepatic glucose production in response to glucose infusion also varies in

very immature infants and may be incomplete. In a series of 10 infants born at 25 to 30
weeks gestation, glucose production rates decreased from 4.3 to 1.4 mg/kg per minute
as glucose infusion was increased from 1.7 to 6.5 mg/kg per minute [7] . Plasma
concentrations of glucose and insulin also increased.

What remains unclear is why the same degree of glucose infusion produces variable
elevations in blood glucose in newborns. A possible contributing factor is increased
secretion of counterregulatory hormones associated with stress (particularly epinephrine
and cortisol). (See "Physiologic response to hypoglycemia in normal subjects and
patients with diabetes mellitus", section on Response to hypoglycemia in normal
subjects).

The role of stress was demonstrated in a report of metabolic responses to glucose

infusion in preterm infants (weight 700 to 1550 g) [8] . Measurements were made
before and after infusion in controls and in infants who required assisted ventilation and
were considered stressed. Stressed infants had higher levels of glucose and cortisol
compared to controls and were more likely to have hyperglycemia (13 of 18 versus 1 of
12 infants). This difference was not due to decreased insulin or increased cortisol levels,
because, among the stressed infants, insulin levels were higher and cortisol levels lower
in the hyperglycemic compared to euglycemic newborns.

CAUSES — In general, neonatal hyperglycemia is associated with a clinical condition,

rather than a specific disorder of glucose metabolism, and occurs in infants receiving
intravenous glucose infusions. A rare cause of hyperglycemia is neonatal diabetes
mellitus.

High rates of glucose infusion — Administration of 10 percent dextrose solution to

meet maintenance fluid requirements in the first few days after birth typically results in
glucose infusion rates of approximately 5 to 8 mg/kg per minute. Rates that exceed 10
to 12 mg/kg per minute (in infants who do not have hyperinsulinemic hypoglycemia)
may result in hyperglycemia, particularly in ELBW infants [5] .

Extremely low birth weight — Hyperglycemia during glucose infusion is most likely
to occur in ELBW infants with very high fluid requirements, often >200 mL/kg per day.
As noted above, some of these infants have an impaired insulin response to glucose [5] .

However, ELBW infants frequently develop hyperglycemia in the absence of high rates
of glucose infusion [9] . The mechanisms include reduced insulin secretion, incomplete
suppression of hepatic glucose production, and a stress response.

In three retrospective studies, multivariate analysis demonstrated that lower gestational

age was associated with an increased risk of hyperglycemia [10,11] , and low birth
weight had either a weaker [10] or no association [11] with hyperglycemia. Although
both studies evaluated long-term outcome, results varied because of different definitions
of hyperglycemia and outcome measures as follows: In the first study of 213 ELBW
infants cared for at two tertiary neonatal intensive care units (NICU), severe early
hyperglycemia, defined as mean morning serum glucose ≥ 180 mg/dL (10 mmol/L) in
the first three days of life, was associated with increased mortality or late-onset culture
proven infection [10] . In the second study of 169 ELBW infants cared for at a single
tertiary NICU, hyperglycemia, defined as plasma glucose >150 mg/dL (8.3 mmol/L) on
at least 2 separate occasions during the first 14 days of life, was not associated with
death, bronchopulmonary dysplasia, intraventricular hemorrhage, or prolonged hospital
stay [11] . However, hyperglycemia increased the risk of retinopathy of prematurity.

These studies demonstrate the lack of consensus in defining both hyperglycemia and the
outcome measures to demonstrate its effect in ELBW infants [12] . Without a better
understanding of the consequences of hyperglycemia and which infants require therapy,
it is difficult to assess the long-term effect of treatment of hyperglycemia. (See
"Definition" above and see "Insulin therapy" below).

In one report of 93 ELBW infants cared for at a single tertiary unit, persistent
hyperglycemia during the first week of life, defined as plasma glucose >150 mg/dL (8.3
mmol/L), was associated with an increased risk of early death and severe (grade III and
IV) intraventricular hemorrhage by 10 days of life [13] .

Stress — The stress response to critical illness (epinephrine and cortisol) may result in
hyperglycemia, especially in preterm infants who require mechanical ventilation. The
stress response also may be responsible for hyperglycemia occurring after surgery. In
this setting, increased rates of fluid administration may also contribute.

Sepsis — Hyperglycemia may be a presenting sign of sepsis in an infant with

previously normal blood glucose concentrations and no change in glucose infusion rate.
Potential mechanisms include the stress response, decreased insulin release, and reduced
peripheral utilization of glucose [14] .

Drugs — Administration of certain drugs can result in hyperglycemia. Hyperglycemia

is a common complication of glucocorticoid therapy, especially in ELBW infants [15] .
It also has been noted following phenytoin administration; the mechanism may be
suppression of insulin release or insulin insensitivity [16] . Plasma glucose levels
increase slightly following theophylline administration in preterm infants, but the effect
is not clinically significant [17] .

Neonatal diabetes mellitus — Neonatal diabetes is a rare cause of hyperglycemia, with

an estimated incidence of one in 500,000 births [18] . It is defined as persistent
hyperglycemia occurring in the first months of life that lasts more than two weeks and
requires insulin for management. The majority of infants are small for gestational age,
which may be related to decreased insulin secretion in the fetus [4] . They present with
weight loss, volume depletion, hyperglycemia, and glucosuria with or without ketonuria
and ketoacidosis.

The course of neonatal diabetes is variable. In a series of 57 infants presenting before

one month of age with hyperglycemia requiring insulin therapy for more than two
weeks, the disorder was transient in 18, transient with recurrence between seven and 20
years of age in 13, and permanent in 26 [18] . Genetic mutations of the KIR6.2 subunit
of the KAKTP channel can result in permanent neonatal diabetes mellitus, whereas
mutations of the SUR1 subunit can result in either permanent or transient neonatal
disease.

Transient — Either paternal uniparental disomy of chromosome 6 or an unbalanced

duplication of paternal chromosome 6 is present in the majority of cases of transient
neonatal diabetes [19-23] . Mutations of the imprinting gene ZAC/PLAG1, a
transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating
polypeptide, (an important regulator of insulin secretion), at chromosome 6q24 has been
shown to be the major cause of neonatal transient DM [20-23] .
Activating mutations of the ABCC8 gene that encodes SUR1, the type 1 subunit of the
sulfonylurea receptor, can cause either transient or permanent neonatal diabetes as
discussed in the next section.

Permanent — About one-half of patients with neonatal diabetes mellitus have a

permanent form that is primarily due to gene mutations related to the ATP-sensitive
potassium channel. In rare cases, permanent neonatal diabetes mellitus is due to
pancreatic agenesis or hypoplasia. In one case series of four patients with
developmental failure of the pancreas, who were products of a consanguineous kinship,
a specific gene defect was not identified [24] .

Most patients with permanent neonatal diabetes mellitus have mutations that affect the
ATP-sensitive potassium channel (KATP channel), which regulates the release of insulin
from pancreatic beta cells. Activating mutations increase the number of open KATP
channels at the plasma membrane, hyperpolarizing the beta cells, and preventing the
release of insulin.

In contrast, inactivating mutations, described in children with persistent

hyperinsulinemic hypoglycemia of infancy, reduce the number of open KATP channels,
resulting in depolarization of the beta cells and persistent hypersecretion of insulin [25] ,
(show figure 1). (See "Pathogenesis, clinical features, and diagnosis of persistent
hyperinsulinemic hypoglycemia of infancy").

The KATP channel is composed of a small subunit Kir6.2 that surrounds a central pore
and four regulatory SUR1 subunits. Activating gene mutations that affect these subunits
can prevent insulin release, resulting in hyperglycemia. KCNJ11 gene encoding Kir6.2
— The most common cause of permanent neonatal diabetes is due to activating
mutations in the KCNJ11 gene, which encodes Kir6.2 [26-28] . The diagnosis is made
within the first two months of life [26] . Infants are small for gestational age but exhibit
postnatal catch-up growth with insulin therapy [29] . Affected patients can also have
neurologic abnormalities including severe developmental delay, epilepsy, muscle
weakness, and dysmorphic features [26] . These findings are also known as the DEND
syndrome (developmental delay, epilepsy, neonatal diabetes) [30] .

Subcutaneous insulin was routinely used in the past to treat patients with this disorder.
However, oral sulfonylurea therapy appears to be more effective in controlling
hyperglycemia [31,32] . In a study of 49 patients with neonatal diabetes due to
activating mutations of KCNJ11 gene, 44 were able to discontinue insulin therapy after
starting oral sulfonylurea therapy [31] . In patients switched to sulfonylurea therapy,
insulin secretion and glycated hemoglobin (8.1 to 6.4 percent) improved. SUR1 —
Activating mutations of the ABCC8 gene, which encodes SUR1 (the type 1 subunit of
the sulfonylurea receptor), can cause both transient and permanent forms of neonatal
diabetes. In a series of 73 patients with neonatal diabetes, nine had activating mutations
of the ABCC8 gene [33] . Two had permanent diabetes and the others had transient
diabetes. The patients were diagnosed at a median of 32 days (range 3 to 125 days).
Oral sulfonylurea therapy normalized glycemic control in patients with genetic
mutations of SUR1.

Neonatal diabetes mellitus has also been associated with mutations in other genes
including IPF-1, EIF2AK3, GCK, FOXP3, PTF1A, GLIS3, and the Ins2 genes [34-49] .
In some cases, these mutations result in pancreatic agenesis or hypoplasia, or absent
beta cells. As an example, patients with permanent neonatal diabetes mellitus due to
Wolcott-Rallison syndrome (diabetes mellitus, exocrine pancreatic insufficiency, and
multiple epiphyseal dysplasia) have been shown to have hypoplastic pancreatic islets
and a mutation in the EIF2AK3 gene that encodes translation initiation factor 2-alpha
kinase 3 [38,39] . FOXP3 mutations cause a rare, x-linked disorder that presents in
infancy with autoimmune endocrinopathy, enteropathy, and eczema. (See "IPEX:
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked").

MANAGEMENT — Interventions to reduce the blood glucose concentration are

initiated at values above 180 to 200 mg/dL (10 to 11.1 mmol/L). The first step in
management is to decrease the glucose infusion rate. Reducing the rate to 4 to 6 mg/kg
per minute usually lowers the blood glucose concentration. In most cases, this is
accomplished by reducing the concentration of the dextrose solution from 10 to 5
percent. If provided with parenteral nutrition solution and lipid emulsion, infants can
maintain normoglycemia with the reduced glucose supply by gluconeogenesis from
glycerol and amino acids [50] .

However, reducing the glucose infusion rate is a short-term solution because it results in
decreased caloric intake and compromises growth. Glucose tolerance typically improves
when enteral feedings are established. (See "Nutritional composition of human milk and
preterm formula for the premature infant").

Insulin therapy — Insulin improves glucose tolerance, allows provision of more

calories, and promotes growth in infants who remain hyperglycemic at reduced glucose
infusion rates. The exact indications for insulin therapy are not well defined. Most
neonatologists would begin an insulin infusion in infants with persistent hyperglycemia
(>200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate,
and in infants who fail to thrive because of reduced caloric intake.

The efficacy of insulin therapy was illustrated by a study of 24 ELBW infants with
glucose intolerance who were randomly assigned to receive standard intravenous
therapy with glucose and total parenteral nutrition with or without a continuous insulin
infusion [51] . Over a mean duration of 15 days, insulin therapy resulted in significantly
higher glucose infusion rates (20.1 versus 13.2 mg/kg per min), greater nonprotein
energy intake (124 versus 86 kcal/kg per day), and greater weight gain (20.1 versus 7.8
g/kg per day) compared to control. There were no differences between groups in
hypoglycemia, electrolyte abnormalities, chronic lung disease, or mortality.

Benefit from insulin therapy was also demonstrated in a trial of 23 ELBW infants who
became hyperglycemic while receiving glucose at a rate up to 12 mg/kg per min [5] .
The infants were randomly assigned to reduced glucose intake or to insulin infusion.
The duration of caloric intake less than 60 kcal/kg per day was significantly shorter with
the insulin infusion (4.1 versus 8.6 days). There were no differences in morbidity or
mortality between the two groups.

In infants receiving parenteral nutrition, improvement in glucose tolerance by

continuous insulin infusion appears to be comparable with and without the addition of
lipid emulsion [52] .
 Routine early insulin therapy - The routine use of early insulin therapy in premature
infants has been proposed to prevent catabolism, improve glucose control, and increase
energy intake, which might improve growth. However, early insulin therapy does not
appear to improve growth and may be associated with an increased risk of mortality at
28 days of age and hypoglycemia.

This was illustrated in a multicenter, open-label trial of 389 very low birth weight
(VLBW) infants (birth weights <1500 g) who were randomly selected to receive either
standard care for glycemic control or a parenteral infusion of 20 percent dextrose with
early insulin therapy (0.05 U/Kg per hour) starting within 24 hours of birth until seven
days of age [53] . The following findings were noted: The early insulin group had lower
mean glucose levels compared to the standard care group (112 vs 121 mg/dL [6.2 vs 6.7
mmol/L]), were less likely to be hyperglycemic (defined as serum glucose greater than
180 mg/dL [10 mmol/L]) for more than 10 percent of the first week of life (21 versus 33
percent), were able to receive greater amounts of glucose infusion (51 versus 43 kcal/kg
per day), and had less weight loss during the first week of life. More patients who
received early insulin had episodes of hypoglycemia (29 versus 17 percent), which was
defined as serum glucose levels less than 47 mg/dL (2.6 mmol/L) for more than one
hour. There were no differences between the groups in the primary end point of
mortality at the expected date of delivery or in the secondary end points of sepsis,
necrotizing enterocolitis, retinopathy of prematurity, and growth parameters (ie, weight,
length, and head circumference) at 28 days of age. However, the early insulin group had
a higher mortality rate at 28 days of life.

This trial was ended early because of concerns of futility with regard to outcomes and
concern for potential harm from insulin therapy. Follow-up is ongoing to determine
whether the increased incidence of hypoglycemia in the early insulin group had a
detrimental effect on neurodevelopmental outcomes. (See "Neonatal hypoglycemia",
section on Prognosis).

Based upon these data, routine insulin therapy should NOT be used in VLBW infants.
Insulin should, however, be used to treat hyperglycemia when reducing the glucose
infusion rate to approximately 6 mg/kg per minute is ineffective or not possible.

Amino acid infusion — Insulin infusion during euglycemia reduces proteolysis and
protein synthesis in preterm infants who are not also given amino acids. In a report of
four ELBW infants at two to five days of age, whole body proteolysis and protein
synthesis decreased by 20 percent during a continuous infusion of insulin (0.05 units/kg
per hour) and glucose (without amino acids) [54] . Glucose utilization doubled (8 to
16.7 mg/kg per min) but there was no net anabolic effect. In addition, plasma lactate
concentration tripled (2.1 to 5.7 mmol/L), possibly because the high rate of glucose
infusion exceeded the maximal capacity for glucose oxidation. Whether administration
of amino acids during insulin infusion would further reduce proteolysis or increase
protein synthesis and improve protein balance is uncertain.

Based upon the limited current data, we suggest amino acid solution and lipid emulsion
also should be administered to infants receiving glucose infusion to provide substrate
for gluconeogenesis, spare glucose utilization, and stimulate insulin release.
Risk of hypoglycemia — The blood glucose concentration should be monitored
frequently during insulin infusion, although the risk of hypoglycemia appears to be
small. This was documented in a retrospective review of 34 ELBW infants who
developed hyperglycemia and glucosuria while receiving parenteral nutrition and were
treated with insulin [55] . Before therapy, mean blood glucose concentration was 195
mg/dL (11.1 mmol/L) while receiving glucose at a mean rate of 7.9 mg/kg per min.
During insulin infusion, given for 1 to 58 days, blood glucose values of 25 to 40 mg/dL
(1.4 to 2.2 mmol/L) were detected in fewer than 0.5 percent of samples (26 episodes of
hypoglycemia in 7368 samples) and no values <25 mg/dL were seen.

Similar findings were noted in another study of 10 ELBW infants treated with insulin
[56] . Glucose measurements were normal (46 to 130 mg/dL [2.6 to 7.2 mmol/L]) in 78
percent of samples and less than 24 mg/dL (1.3 mmol/L) in less than 1 percent [56] .
(See "Neonatal hypoglycemia").

Dose — Regular insulin (100 U/mL) should be diluted in normal saline to a

concentration of 1 U/mL. It is then administered as a continuous intravenous infusion in
5 percent dextrose solution. Insulin is started at an initial rate of 0.01 units/kg per hour
and is adjusted in small increments up to a maximum rate 0.1 units/kg per hour to
maintain glucose levels of 150 to 200 mg/dL (8.3 to 11 mmol/L).

An alternative approach is to use an initial insulin dose of 0.05 to 0.1 units per gram of
glucose. This dose can be increased in increments of 0.05 to 0.1 units per gram of
glucose until the target blood glucose concentration is achieved.

As glucose tolerance improves, the insulin infusion should be tapered and discontinued
to avoid hypoglycemia. In general, reductions in the insulin infusion rate can be made
more rapidly than can increases.

Adherence of insulin to plastic tubing — Plastic tubing used for infusion should be
primed with insulin for at least 20 minutes before treatment because insulin
nonspecifically binds to the tubing, resulting in decreased availability to the patient. In
one report, recovery of insulin from effluent of primed polyvinyl chloride tubing at a
flow rate of 0.2 mL/h was greater at one, two, four, and eight hours (42, 85, 91, and 95
versus 22, 38, 67, and 75 percent, respectively) compared to unprimed tubing [57] .

Monitoring — The blood glucose concentration should be monitored within 30 minutes

to one hour of the start of the infusion and after any change in the rate of glucose or
insulin infusion. Glucose concentration should be monitored hourly until stable, and
then less frequently.

RECOMMENDATIONS — Blood glucose concentration should be monitored in all

infants receiving intravenous glucose infusions. For most infants, daily monitoring is
recommended until blood glucose concentration is stable. For ELBW, stressed, or septic
infants, or those receiving insulin infusion, more frequent monitoring is needed. In
infants with blood glucose concentration greater than 180 to 200 mg/dL (10 to 11.1
mmol/L), the glucose infusion rate should be decreased; this should be done by
decreasing the concentration of infused glucose, as long as it does not go below 5
percent. Insulin infusion should be considered in infants with persistent hyperglycemia
(>200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose infusion rate
and in those who fail to thrive because of reduced caloric intake. Regular insulin in 5
percent dextrose solution should be infused at an initial dose of 0.01 units/kg per hour
after priming the infusion tubing with the insulin solution. Blood glucose concentration
should be monitored frequently and the dose of insulin adjusted in small increments up
to 0.1 units/kg per hour to maintain glucose levels of 150 to 200 mg/dL (8.3 to 11
mmol/L). The insulin infusion should be tapered and discontinued as soon as glucose
tolerance improves. Enteral feedings should be initiated as soon as possible.

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