ARTICLE

Neonatal Hypoglycemia
Jane E. McGowan, MD*
The infant was treated with dia-
OBJECTIVES zoxide with only limited success
After completing this article, readers should be able to: over the next 3 months. Develop-
ment continued but was “slow.” He
1. Describe the most common cause of prolonged neonatal was treated in the local emergency
hypoglycemia. department three times for tonic-
2. List the signs of hypoglycemia. clonic seizures, all requiring intrave-
3. Describe the condition that has been implicated as a mechanism of
hypoglycemic brain injury.
nous glucose to correct severe hypo-
glycemia. At 5 months of age, the
infant underwent a subtotal pancrea-
tectomy. While recovering, he had a
Case Study improved. One Touch® glucose con- severe, prolonged seizure and was
A term male infant was born after centrations obtained over the next noted to be in shock, requiring two
an uneventful pregnancy to a 24 hours were variable, but overall rounds of resuscitation. Escherichia
28-year-old gravida I woman who the concentration increased, with a coli meningitis was diagnosed and
had no evidence of hyperglycemia predischarge, preprandial value of treated successfully.
and no chronic diseases. The infant 2.78 mmol/L (50 mg/dL). At 1 year of age, the infant
had Apgar scores of 7 and 9 at The family failed to return to the showed little developmental gain
1 and 5 minutes, respectively. His hospital clinic the next day, but did from 6 months of age. At 5 years of
growth parameters were in the nor- see their primary care physician on age, he exhibited extremely poor
mal range, with weight at the 60th the fifth day of life at which time growth, had diabetes mellitus that
percentile, head circumference at the the infant acted hungry, was noted necessitated insulin treatment, and
50th percentile, and length at the to be “very active,” and weighed required pancreatic enzyme replace-
50th percentile. The baby was taken 113.4 g more than birthweight. At ment with feedings to treat malab-
to the well baby nursery, examined 2 weeks of life, the parents noted sorptive diarrhea. He was almost
and bathed, and then taken to the the infant to be very fussy and jit- completely deaf and had marked
mother for nursing at about 2 hours tery and to experience staring spells. developmental delay. His parents
of age. He appeared slightly jittery At a local emergency department, he sought legal counsel, claiming that
at that time and was not very inter- was noted to have lost weight, the treating physicians in the birth
ested in nursing or very aware. appeared somnolent but fussy when hospital failed to diagnose a “hyper-
A blood glucose concentration of aroused, and started having tonic- insulinism” condition that then led
1.39 mmol/L (25 mg/dL) was clonic jerking movements of all to delayed diagnosis and treatment,
obtained using a One Touch® instru- extremities. A “glucose concentra- followed by severe neurologic
ment. The baby was fed 25 mL of tion” was less than 0.55 mmol/L damage.
5% dextrose in water. The blood (10 mg/dL). The infant was treated Questions to consider (feel free to
glucose concentration obtained with intravenous glucose, and the send in your answers to these ques-
1 hour later was 2.22 mmol/L apparent seizure resolved. Over the tions and any questions of your own
(40 mg/dL), and the baby nursed for next several weeks, the infant for the “experts” to consider and
about 5 minutes at each breast with returned to the emergency depart- discuss about this case):
apparent satisfaction. Jitteriness and ment several times with similar 1. What is the likely diagnosis
“lack of interest” were improved. episodes. for this infant’s hypoglycemia?
Normal nursery routine was fol- When finally examined by the 2. What diagnostic tests could
lowed, with no comment in the chart primary care physician, the infant have been done in the birth hospital
by the nursing staff about the had gained 283.5 g and appeared to determine whether the infant had
infant’s feeding or behavior until the “puffy.” An “office glucose concen-
second day of life when he again tration” was 1.94 mmol/L (35 mg/
appeared jittery and fussy. Glucose dL). The infant was referred to a
concentration at that time was pediatric endocrinologist, who noted ABBREVIATIONS
1.11 mmol/L (20 mg/dL). The infant that the infant’s weight was AGA: appropriate for gestational
was fed by breast or bottle (routine approaching the 90th percentile, age
20 kcal/oz house formula) alternat- there was definite hepatomegaly, ATP: adenosine 59-triphosphate
ing every 2 hours, and clinical signs and the infant appeared “apathetic.” IDM: infant of a diabetic mother
In the hospital, several serum glu- IUGR: intrauterine growth
cose concentrations were measured retardation
at less than 2.22 mmol/L (40 mg/ LGA: large for gestational age
*Associate Professor of Pediatrics, MCP
Hahnemann University and St. dL), with plasma insulin concentra- NMDA: N-methyl-D-aspartate
Christopher’s Hospital for Children, tions all greater than 144 pmol/L SGA: small for gestational age
Philadelphia, PA. (20 mcU/mL).

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 ENDOCRINOLOGY
Hypoglycemia

transient or persistent placenta. This results in a fetal tion of glycogen synthesis and sup-
hypoglycemia? blood glucose concentration of pression of glycogenolysis by regu-
3. What could have been done approximately 70% of the maternal lating the activity of the hepatic
prior to discharge from the birth value. Although the enzymes neces- enzymes used for these processes.
hospital to provide evidence of the sary for both gluconeogenesis and Predominance of insulin maintains
infant’s ability to maintain a normal glycogenolysis are present in the glycogen synthase in its active form
blood glucose concentration with a human fetus by the end of the first and glycogen phosphorylase in its
normal feeding schedule? trimester, several studies have dem- inactive form via cAMP-dependent
4. What did the pancreatic onstrated that there is no significant effects on specific protein kinases
pathology examination likely show glucose production in the fetus and phophorylases, thus enhancing
at the time of subtotal unless there is a sustained decrease glycogen synthesis and minimizing
pancreatectomy? in umbilical glucose uptake. Glucose glycogenolysis. In most species,
5. How would you assess the utilization rates in the fetus have including humans, hepatic glycogen
clinical outcome in relation to the been estimated at 4 to 6 mg/kg per stores accumulate slowly during
primary diagnosis and its complica- minute. Approximately 60% to 70% early and midgestation, with a rapid
tions versus the E coli meningitis of fetal glucose utilization is increase in hepatic glycogen content
and shock? accounted for by oxidation of glu- occurring during the last 30% of
William W. Hay, Jr, MD cose carbon to CO2, with the fetal life. The marked increase in
Coeditor remainder available for synthesis of glycogen synthesis during this
glycogen and other macromolecules. period is associated with an increase
In the human fetus, oxidation of in circulating concentrations of both
Introduction glucose accounts for approximately insulin and cortisol. Because the
Glucose is the major source of 80% of fetal oxygen consumption, increase in cortisol seems to be nec-
energy for organ function. Although demonstrating that glucose is the essary for maximal activation of
all organs can use glucose, the major substrate for fetal oxidative glycogen synthase, fetal adrenal dys-
human brain uses it almost exclu- metabolism. function may limit hepatic glycogen
sively as a substrate for energy The rate at which the fetus uses accumulation late in gestation.
metabolism. Because cerebral glyco- glucose is primarily a function of Under conditions associated with
gen stores are limited, maintenance glucose concentration, although decreased fetal glucose concentra-
of adequate glucose delivery to the changes in insulin concentration tions and increased glucagon secre-
brain is an essential physiologic may have a modest influence as tion, such as chronic hypoglycemia
function. The high brain-to- well. Studies have demonstrated that or hypoxemia, glycogen phosphory-
bodyweight ratio in the newborn levels of fetal pancreatic insulin lase is activated, and synthase is
results in a proportionately higher secretion correlate with changes in converted to its inactive form,
demand for glucose compared with fetal glucose concentration, but the thereby suppressing glycogen syn-
the capacity for glucose production pancreatic response is blunted com- thesis and stimulating glycogenoly-
than that encountered in the adult, pared with the newborn or adult. sis with subsequent depletion of
with cerebral glucose use accounting Insulin secretion in response to fetal fetal glycogen stores. The high insu-
for as much as 90% of total glucose hyperglycemia increases glucose lin:glucagon ratio also suppresses
consumption. Although alternate utilization and oxidation rates, but it lipolysis, which allows for additional
fuels, such as lactate and ketone has little effect on fetal metabolic energy to be stored in the form of
bodies, can be used as a substrate rate or the rate of oxygen consump- subcutaneous fat. Thus, the fetal
for energy production, the new- tion, suggesting that oxidation of hormonal and metabolic milieu
born’s immature counterregulatory other substrates is reduced under establishes a ready substrate supply
response limits the availability of these conditions. Decreased oxida- that can be used during the meta-
these molecules. Thus, newborns are tion of substrates such as amino bolic transition from fetus to
extremely susceptible to any condi- acids and lactate results in increased newborn.
tion that impairs the establishment availability of those substrates for
of normal glucose homeostasis dur- tissue accretion and may account in
ing the transition from intrauterine part for the increased somatic Glucose Homeostasis in the
to independent extrauterine life. growth associated with fetal Newborn
hyperinsulinemia. The relative dependence of the fetus
In animal models, administration on a constant supply of maternal
Glucose Homeostasis in of glucagon does not appear to have glucose necessitates significant
Utero a direct effect on fetal glucose changes in regulation of glucose
Glucose is one of the major sub- metabolism. However, the ratio of metabolism at birth following the
strates for fetal metabolism. Under insulin to glucagon in the fetal cir- abrupt interruption of umbilical glu-
normal conditions (ie, normal mater- culation plays a critical role in regu- cose delivery. Although the exact
nal glucose levels), virtually all of lating the balance between glucose trigger is unknown, a number of
the glucose used by the fetus is sup- consumption and energy storage. physiologic changes equip the new-
plied from the maternal circulation The high insulin:glucagon ratio in born for maintenance of glucose
via facilitated diffusion across the the fetal circulation results in activa- homeostasis. Increased catechol-

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 ENDOCRINOLOGY
Hypoglycemia

amine concentrations immediately of any of these requirements leads and can occur over a range of glu-
following delivery stimulate gluca- to disruption of glucose homeostasis, cose concentrations, depending on
gon secretion, with a subsequent most commonly resulting in neona- the status of the infant. For example,
decrease in the insulin:glucagon tal hypoglycemia. a 2-hour-old healthy infant who has
ratio. Glycogen synthase is inacti- a blood glucose of 1.7 mmol/L
vated and glycogen phosphorylase is (30 mg/dL) might not demonstrate
activated, leading to stimulation of Incidence, Diagnosis, and impaired organ function, but a
glycogenolysis and inhibition of gly- Clinical Presentation stressed infant might demonstrate
cogen synthesis. Release of glucose physiologic hypoglycemia at a blood
from glycogen provides a rapidly INCIDENCE glucose concentration of 2.8 mmol/L
available source of glucose for the Estimates of the incidence of hypo- (50 mg/dL) if the rate of glucose
newborn in the first few hours post- glycemia in the newborn depend delivery to specific organs (eg, the
partum. However, it has been esti- both on the definition of the condi- brain) is less than the rate of glu-
mated that term infants have only tion and the methods by which cose utilization. No studies to date
enough hepatic glycogen to maintain blood glucose concentrations are have established an absolute blood
the glucose supply for about measured. The overall incidence has glucose concentration at which
10 hours. Therefore, other mecha- been estimated at 1 to 5 per 1,000 short- or long-term organ dysfunc-
nisms are required to maintain glu- live births, but it is higher in at-risk tion invariably occurs, although ani-
cose homeostasis. The high gluca- populations. For example, 8% of mal studies suggest that concentra-
gon:insulin ratio postpartum also large-for-gestational-age infants (pri- tions less than 1 mmol/L (,20 mg/
induces synthesis of the enzymes marily infants of diabetic mothers dL), if sustained over a number of
required for gluconeogenesis. With [IDMs]) and 15% of preterm infants hours, may be associated with inevi-
the combination of the release of and infants who have intrauterine table brain injury. Without specific
fatty acids stimulated by the high growth retardation (IUGR) have evidence to support an absolute
catecholamine concentrations that been reported as having hypoglyce- threshold value, no single blood glu-
leads to a marked increase in glyc- mia; the incidence in the entire pop- cose value can be used to define
erol availability and the availability ulation of “high-risk” infants may be physiologic hypoglycemia.
of free amino acids in the circula- as high as 30%. The definition of “normal” blood
tion, the infant becomes capable of glucose concentrations for a given
significant gluconeogenesis by 4 to population of newborns also
6 hours of life. However, enzyme LABORATORY DIAGNOSIS depends on the feeding practices in
activities do not reach adult levels The concentration of blood glucose that population. For example, the
until 1 to 2 weeks of age. at which the diagnosis of neonatal mean value for normal blood glu-
Basal glucose utilization rates in hypoglycemia should be made has cose concentrations in term infants
the newborn infant are 4 to 6 mg/kg been highly controversial. Hypogly- determined from studies 30 years
per minute, almost twice the weight- cemia in term infants has been ago was significantly lower than
specific rates in adults. During the defined as a blood glucose value of values determined in the past
first few hours of life, blood glucose less than 2.0 mmol/L (,35 mg/dL) 10 years. This is not because of a
concentrations fall from the fetal or as a plasma glucose value of less change in neonatal physiology, but
value, which reflects the mother’s than 2.2 mmol/L (,40 mg/dL). because pediatricians no longer fol-
blood glucose concentration, to as However, a recent survey of pedia- low the practice of withholding
low as 1.7 mmol/L (30 mg/dL) tricians in the United Kingdom dem- feedings from healthy newborns for
before the infant attains the meta- onstrated no consensus as to the a prolonged period after delivery.
bolic transition to independent glu- level of blood glucose that they con- Rather than reflecting “normal” neo-
cose production and establishes sidered “hypoglycemia”. They cited natal glucose homeostasis, these
postnatal glucose homeostasis. Until concentrations ranging from early values demonstrated the effects
an exogenous supply of substrate is 1 mmol/L (20 mg/dL) to 4 mmol/L of the interference of medical practi-
provided, either by enteral feedings (70 mg/dL) as the lower limit of tioners in the normal transition to
or administration of intravenous flu- normal. Further, definitions of hypo- postnatal metabolism. Similarly,
ids, hepatic glucose output serves as glycemia are based primarily on early data that demonstrated lower
the most significant source of glu- population studies of blood or blood glucose values in populations
cose to meet metabolic demands. To plasma glucose concentrations dur- of preterm infants compared with
maintain normal levels of hepatic ing the first 48 to 72 hours of life, term infants was interpreted errone-
glucose production, the infant must with hypoglycemia being defined as ously to mean that low-birthweight
have adequate stores of glycogen a blood glucose level more than infants tolerated hypoglycemia better
and gluconeogenic precursors 2 standard deviations below the pop- than normal-weight neonates. In
(eg, fatty acids, glycerol, amino ulation mean. Such definitions have fact, these data reflected failure of
acids, and lactate), appropriate con- only limited physiologic hepatic glucose production in pre-
centrations of the hepatic enzymes significance. term infants in response to an inade-
required for gluconeogenesis and Physiologically, hypoglycemia is quate supply of exogenous substrate.
glycogenolysis, and a normally func- present when glucose delivery is At that time, standard feeding prac-
tioning endocrine system. Absence inadequate to meet glucose demand tices had not been established for

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 ENDOCRINOLOGY
Hypoglycemia

this population, and reliable intrave- Reagent test strip results also are tachycardia or bradycardia; and neu-
nous (IV) nutrition was not avail- susceptible to variations in the tech- rologic findings, including jitteri-
able. Finally, the time at which the nique used to obtain the sample (eg, ness, lethargy, weak suck, tempera-
blood glucose concentration is mea- variability in the amount of blood ture instability, and seizures. Many
sured affects the value considered applied to the strip or contamination of these signs can result from other
“normal”; blood glucose concentra- of the sample by residual isopropyl common neonatal disorders, includ-
tions increase over the first 24 to alcohol on the skin). It has been ing sepsis, hypocalcemia, and intra-
48 hours of life in healthy term estimated that screening with cranial hemorrhage. Hypoglycemia
infants, probably as a result of both reagent strips will detect approxi- always must be considered in an
the increasing volume of enteral mately 85% of cases of hypoglyce- infant who exhibits one or more of
feeding and initiation of gluconeo- mia, although the false-positive rate these signs because untreated hypo-
genesis. Thus, a value that would be may be as high as 25%. Thus, to glycemia can have serious conse-
considered “low normal” at 3 hours ensure accurate detection of low quences, and the treatment is fast,
of life might be termed “hypoglyce- blood glucose concentrations, a con- relatively easy, and has limited side
mic” at 18 hours. firmatory sample should be sent to a effects. However, given current stan-
Making a firm diagnosis of hypo- central laboratory if a test strip dards for newborn care, most cases
glycemia is complicated further by value is consistent with hypoglyce- of hypoglycemia in the neonate are
the limitations of methods used to mia or if the test strip result is in diagnosed during routine screening
measure blood glucose concentra- the normal range but clinical find- of infants considered to be at risk
tions rapidly. Although the “gold ings raise the suspicion of but who appear physiologically nor-
standard” remains the hexokinase hypoglycemia. mal at the time of evaluation.
method used by many diagnostic
laboratories, this approach is imprac- CLINICAL PRESENTATION
tical as a screening tool because of Although hypoglycemia often is Etiology
the time required to process the classified as “symptomatic” or
sample and to perform the assay. “asymptomatic”, these terms actually PREMATURITY AND IUGR
Furthermore, if the sample is not reflect the presence or absence of The causes of neonatal hypoglyce-
transported rapidly to the laboratory physical signs that accompany a low mia can be categorized according to
and processed quickly, the glucose blood glucose concentration. A vari- associated disturbances in one or
will be metabolized by red blood ety of signs may be seen in cases of more of the processes required for
cells, thereby falsely decreasing the severe or prolonged hypoglycemia normal hepatic glucose production
glucose concentration. Placing the and in infants who have mild-to- that may lead to transient or pro-
specimen in a tube that contains a moderate hypoglycemia and are oth- longed episodes of hypoglycemia
glycolytic inhibitor such as sodium erwise physiologically stressed. (Table 1). Hepatic glycogen stores
fluoride can prevent this problem, Most findings are nonspecific and are limited in both preterm infants,
but such tubes are either not readily result from disturbances in one or who have not experienced the period
available or simply not used. more aspects of central nervous sys- of rapid glycogen accumulation dur-
Most nurseries use glucose oxi- tem function. These include abnor- ing late gestation, and small-for-
dase/peroxidase chromogen test mal respiratory patterns, such as gestational age (SGA) infants, who
strips to screen high-risk newborns tachypnea, apnea, or respiratory dis- have not had adequate substrate sup-
for low blood glucose concentra- tress; cardiovascular signs, such as ply available for glycogen synthesis,
tions. A drop of blood placed on the
reagent-impregnated paper strip for
the specified time will induce a
color change that correlates with TABLE 1. Etiologies of Neonatal Hypoglycemia
blood glucose concentration. The DURATION OF
actual blood glucose concentration ETIOLOGY HYPOGLYCEMIA
can be estimated by comparison
with a standard chart or determined Prematurity, intrauterine growth retardation Transient*
more precisely by “reading” the Asphyxia, hypothermia Transient
color of the strip with a reflectance
colorimeter that has been calibrated Sepsis Transient
using a standard solution. Although Infant of diabetic mother Transient
use of a reflectance colorimeter to
read the test strips improves preci- Erythroblastosis fetalis Transient
sion, multiple studies comparing
Exposure to beta-agonist tocolytics Transient
various methods have found that the
correlation between “real” blood Familial hyperinsulinism Prolonged
glucose values and values obtained
using test strips remains highly vari- Inborn errors of metabolism Prolonged
able. This is especially true at low *Generally <7 d duration.
blood glucose concentrations.

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 ENDOCRINOLOGY
Hypoglycemia

which puts these newborns at risk to alterations in hepatic enzyme gers more insulin secretion and
for hypoglycemia. IUGR due to pla- functions that impair glycogenolysis, upregulates the beta cells. Exchange
cental insufficiency with preserva- gluconeogenesis, or both. Hepatic transfusions may exacerbate the
tion of normal head size puts an function can be affected by a num- problem because transfused blood
added demand on the infant’s ber of endocrine and metabolic dis- usually is preserved with a combina-
already low glycogen stores because turbances, the most common being tion of dextrose and other agents.
of the increased brain-to-bodyweight hyperinsulinism. IDMs may have During the exchange, the infant
ratio. Postterm infants and infants of increased secretion of pancreatic receives a significant glucose load,
multiple gestations also may be at insulin because of exposure to with subsequent exaggerated insulin
risk because of the presence of rela- increased maternal glucose concen- response from the hyperplastic pan-
tive placental insufficiency. In addi- trations in utero. Placental glucose creas. At the end of the exchange,
tion to decreased glycogen availabil- transport is increased, leading to the rate of dextrose administration
ity, studies in preterm and IUGR fetal hyperglycemia, which in turn returns to baseline, but insulin levels
infants have found altered patterns stimulates secretion of insulin by the remain elevated, leading to further
of insulin secretion, substrate metab- fetal pancreas. IDMs also have hypoglycemia.
olism, and hormonal responses to exaggerated pancreatic insulin secre- Use of beta-agonist tocolytic
changes in blood glucose concentra- tion in response to a given glucose agents such as terbutaline also is
tion compared with appropriate-for- load compared with nonIDMs. Other associated with hyperinsulinemia in
gestational age (AGA) term infants. diabetes-induced alterations in the newborn, especially if the agent
Infants who have experienced maternal metabolism, such as was used for more than 2 weeks and
perinatal stress due to asphyxia or changes in serum amino acids, may was discontinued less than 1 week
hypothermia or who have increased play a role in the metabolic alter- prior to delivery. Affected infants
work of breathing due to respiratory ations found in IDMs. also appear to have reduced glyco-
distress may have “normal” glyco- After delivery, increased blood gen stores, which further aggravates
gen stores, but the amount of glyco- glucose concentrations no longer are the hyperinsulinemia and its effects
gen available may be inadequate to present, but the hyperinsulinemia on decreasing glucose
meet their increased requirement due persists, thus maintaining a high concentrations.
to higher-than-normal levels of glu- insulin:glucagon ratio postnatally.
cose utilization. Hypoglycemia may As a result, glycogenolysis and
occur in these infants once available lipolysis are inhibited, gluconeo- HYPERINSULINISM
glycogen has been used to meet the genic enzymes are not induced, and Hypoglycemia that persists for more
initial postnatal metabolic demands, hepatic glucose production remains than 5 to 7 days is uncommon and
particularly if there has been a at low levels in the face of decreas- most often is due to hyperinsulin-
period of hypoxemia with associated ing blood glucose concentrations. ism. Some infants who have IUGR
rapid consumption of glucose via Insulin also increases peripheral glu- or perinatal asphyxia demonstrate
anaerobic metabolism. cose utilization in insulin-sensitive hyperinsulinemia that may persist
It is uncommon for inadequate tissues such as skeletal muscle, con- for as long as 4 weeks, but such
levels of gluconeogenic precursors tributing to rapid depletion of avail- cases are relatively rare, and the
to be a limiting factor in hepatic able glucose. The combined effects underlying mechanism is unclear.
glucose production in the newborn of increased glucose utilization and Several types of congenital hyperin-
because even preterm infants appear inhibited hepatic glucose production sulinism have been described and
to have sufficient fatty acids, glyc- result in hypoglycemia, which may are said to be the most common
erol, amino acids, lactate, and pyru- persist for 24 to 72 hours before cause of hypoglycemia persisting
vate available. However, gluconeo- insulin secretion patterns normalize. beyond the first week of life.
genic enzymes are induced more The autosomal recessive form of
slowly in preterm infants. Further, congenital hyperinsulinism has been
production of ketone bodies is rela- ERYTHROBLASTOSIS FETALIS linked to a defect in the sulfonylurea
tively diminished in response to AND BETA-AGONIST TOCOLYTIC receptor or K1-ATP channel. A sin-
hypoglycemia. Term infants may AGENTS gle mutation on the short arm of
have augmented release of ketone Although maternal diabetes is the chromosome 11 has been described
bodies when blood glucose most common cause of hyperinsulin- in the Ashkenazi Jewish population,
decreases, but the concentrations of ism in the newborn, postnatal insulin but cases in other ethnic groups
ketones correlate poorly with the secretion may be abnormal due to have been associated with a number
degree of hypoglycemia. As a result, several other disorders. Infants who of other mutations in the same
the contribution of gluconeogenesis have erythroblastosis fetalis have region. An autosomal dominant form
to hepatic glucose production may increased levels of insulin and an of hyperinsulinemia also has been
be limited in some newborns. increase in the number of pancreatic described. The mutation(s) responsi-
beta cells. The mechanism for this ble for the autosomal dominant form
development is unclear, but one pos- of hyperinsulinism has not yet been
IDMS sibility is that glutathione released identified, but the disorder differs
Several groups of infants are at from hemolyzed red cells inactivates from the autosomal recessive form
increased risk for hypoglycemia due insulin in the circulation, which trig- in that it does not appear to result

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 ENDOCRINOLOGY
Hypoglycemia

from abnormal sulfonylurea receptor crine disorders, and inborn errors of sis, further contributing to a restora-
function. A syndrome of congenital metabolism should be investigated, tion of normal glucose homeostasis.
hyperinsulinemia and asymptomatic especially if the hypoglycemia is It is estimated that blood glucose
hyperammonemia associated with refractory to standard treatment. concentrations should increase by
mutations in the glutamate dehydro- Unfortunately, it often is difficult approximately 1.67 mmol/L (30 mg/
genase gene also has been described. to document hyperinsulinemia dL) within the first hour after a
Beckwith-Weidemann syndrome is because insulin levels must be feeding of 30 to 60 mL of standard
associated with hyperplasia of multi- drawn during episodes of hypogly- infant formula.
ple organs, including the pancreas, cemia to demonstrate the presence
with consequent increased insulin of inappropriate insulin secretion.
secretion. Rarely, hyperinsulinemia Levels of the binding protein for IV THERAPY
may result from localized islet cell insulin-like growth factor 1 (IGFBP- Infants whose blood glucose concen-
adenomas within an otherwise nor- 1) are decreased in the presence of trations normalize following an
mal pancreas. hyperinsulinemia, making measure- enteral feeding should continue to
ment of serum levels of IGFBP-1 have blood glucose concentrations
INBORN ERRORS OF useful in confirming the diagnosis of checked before each feeding for
METABOLISM hyperinsulinemia. Serum and urine 12 to 24 hours. If the postprandial
tests for specific metabolic and concentration is normal, but the
Inborn errors of metabolism may
endocrine disorders, such as serum value before the next feeding is
affect either the availability of glu-
amino acid profiles and measure- again in the hypoglycemic range,
coneogenic precursors or the func-
ment of cortisol and growth hor- enteral feeding should be considered
tion of the enzymes required for
mone levels, also may be necessary a failure, and the infant is a candi-
production of hepatic glucose. Meta-
to elucidate the etiology of neonatal date for IV therapy. Prompt provi-
bolic defects that may present with
hypoglycemia. sion of IV glucose in these circum-
hypoglycemia include some forms
stances will avoid repeated episodes
of glycogen storage disease, galac-
of preprandial hypoglycemia. This
tosemia, fatty acid oxidation defects,
Management may be important because follow-up
carnitine deficiency, several of the
The goals in treating the infant who studies of infants who have recur-
amino acidemias, hereditary fructose
has hypoglycemia are to normalize rent hypoglycemia indicate that mul-
intolerance (fructose-1,6-diphos-
blood glucose concentrations as tiple episodes of low blood glucose
phatase deficiency), and defects of
quickly as possible and to avoid concentrations are more likely to be
other gluconeogenic enzymes.
further episodes of hypoglycemia by associated with adverse neurodevel-
Finally, endocrine disorders such as
providing adequate substrate until opmental outcomes than a single
hypopituitarism and adrenal failure
normal glucose homeostasis can be episode.
also can result in hypoglycemia
established. The method chosen to IV therapy should be the first
because of the absence of the appro-
achieve this goal is a function of treatment modality used in symp-
priate hormonal response to hypo-
both the clinical status of the infant tomatic infants, infants unable to
glycemia and subsequent failure to
and the suspected etiology of the tolerate enteral feedings, and those
activate hepatic glucose production.
hypoglycemia. in whom the disturbance in glucose
However, these conditions are very
homeostasis is severe or is expected
rare and should be considered after
to last more than a few hours. The
ruling out more common etiologies. ENTERAL FEEDING latter category includes preterm
In term infants who have asymptom- infants, infants who have IUGR,
DETERMINING ETIOLOGY atic mild hypoglycemia, an initial infants of women who have poorly
Obtaining a careful perinatal history attempt at enteral feeding may be controlled diabetes, and infants who
is the first step in determining the successful in reaching target blood have underlying etiologies for hypo-
etiology of hypoglycemia in the glucose values. Although a prompt glycemia, such as sepsis, known or
newborn. The presence of risk fac- increase in blood glucose concentra- suspected inborn errors of metabo-
tors, such as abnormal results on a tions can be achieved following a lism or endocrine defects, or
maternal glucose tolerance test, feeding with a 5% dextrose and erythroblastosis.
maternal administration of drugs water solution, the dextrose is Administration of an initial bolus
associated with neonatal hypoglyce- metabolized rapidly, and hypoglyce- of 200 mg/kg of 10% dextrose and
mia, or prematurity, makes the diag- mia may recur before normal feed- water (2 mL/kg of D10W) should be
nosis relatively simple. Growth ings can be established. Use of a followed by continuous infusion of
parameters should be plotted to standard infant formula will provide dextrose calculated to deliver 5 to
establish if the infant is SGA, AGA, not only carbohydrate in the form of 8 mg/kg per minute of glucose (ie, a
or LGA. Sepsis should be suspected lactose but also protein and fat, rate equivalent to the glucose utili-
strongly in the term infant who has which are metabolized more slowly zation rate of a healthy infant). The
hypoglycemia but no other apparent and, therefore, will provide a sus- “mini-bolus” approach has been
risk factors. If hypoglycemia persists tained supply of substrate. Fat intake shown to return blood glucose con-
for more than 1 week, the possibili- also decreases cellular glucose centration to normal more rapidly
ties of hyperinsulinemia, other endo- uptake and stimulates gluconeogene- than a constant infusion alone. The

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 ENDOCRINOLOGY
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“mini-bolus” dose also is designed studies have shown that the pancre- caregivers must be prepared to man-
to avoid overshooting the desired atic insulin response to galactose is age hypoglycemia when it recurs.
glucose concentration. By limiting less than the response to an equiva- Preterm infants and infants who
the amount of glucose given as a lent amount of glucose. When a nor- have IUGR have limited glycogen
bolus, it is possible to avoid induc- mal blood glucose concentration has stores and are unlikely to experience
ing iatrogenic hyperglycemia, which been established and the requirement an increase in blood glucose concen-
might stimulate excess insulin secre- for IV glucose has been stable for tration following administration of
tion and induce rebound hypoglyce- 12 to 24 hours, the infant can be glucagon. An initial dose of
mia. The blood glucose concentra- weaned from this therapy by mea- 30 mcg/kg may produce a response
tion should be checked suring preprandial blood glucose in some infants, but those who have
approximately 30 minutes after the concentrations and decreasing the hyperinsulinemia may require a
bolus, then every 1 to 2 hours until infusion rate by 10% to 20% each 10-fold higher dose to overcome the
stable and in the normal range. If a time the blood glucose is greater effects of high circulating insulin
subsequent value falls in the hypo- than 2.8 to 3.4 mmol/L (.50 to levels and stimulate glycogenolysis.
glycemic range, the bolus should be 60 mg/dL). Failure to tolerate wean- Administration of glucagon is most
repeated and the infusion rate ing from IV glucose indicates the useful in those infants who have
increased by 10% to 15%. It is not presence of a pervasive disorder, severe hypoglycemia as a temporiz-
uncommon for infants who have such as a metabolic defect or idio- ing measure until stable IV access
transient or sustained hyperinsulin- pathic hyperinsulinemia, and should can be obtained (eg, while awaiting
emia to require as much as 12 to prompt further evaluation. the arrival of a transport team).
15 mg/kg per minute of IV glucose Several other agents may be valu-
to maintain normoglycemia. In such able for management of infants in
cases, it may be necessary to place OTHER AGENTS whom the diagnosis of hyperinsulin-
an umbilical venous catheter or a Several other agents have been used emia is confirmed and who remain
peripheral central venous catheter to treat refractory hypoglycemia, persistently hypoglycemic in spite of
(so-called PIC line) to allow admin- most often encountered in one of the administration of IV glucose at
istration of IV solutions with dex- hyperinsulinemic states (Table 2). 15 to 20 mg/kg per minute. Diazox-
trose concentrations greater than Corticosteroids (hydrocortisone, 5 to ide at a dose of 5 mg/kg every
12.5%. 15 mg/kg per day in two to three 8 hours will inhibit pancreatic insu-
Unless there are concerns about divided doses, or prednisone, lin secretion. Somatostatin or its
fluid overload or the ability to toler- 2 mg/kg per day) are associated long-acting analogue octreotide also
ate enteral nutrition, infants requir- with decreased peripheral glucose inhibits insulin release as well as
ing IV therapy for hypoglycemia utilization and increased blood glu- growth hormone and glucagon
should be permitted to continue cose concentrations, but they have a secretion and is used most often
feedings. There are several benefits variety of other metabolic effects preoperatively in infants requiring
to this practice. First, it will allow that must be considered. Administra- pancreatectomy for refractory hypo-
an easier transition from a parenteral tion of corticosteroids as an adjunct glycemia and hyperinsulinemia. Sub-
to an enteral source of carbohydrate to IV glucose may be useful when total (95%) or near-complete pancre-
once blood glucose concentrations glucose requirements are greater atectomy may be required to
have stabilized. Second, providing than 15 mg/kg per minute. manage cases of hyperinsulinemia
some carbohydrate as galactose (one Glucagon will produce a rapid due to gene mutations or islet cell
of the sugars that comprise lactose) rise in blood glucose in infants who adenomas. However, hypoglycemia
may be useful in IDMs and other have adequate glycogen stores, but recurs in up to 33% of surgically
infants who have hyperinsulinemia; this is only a transient effect, and treated patients, and 40% to 60%

TABLE 2. Adjunct Therapies for Hypoglycemia

THERAPY EFFECT DOSAGE
Corticosteroids Decrease peripheral glucose Hydrocortisone 5 to 15 mg/kg per day
utilization or
Prednisone 2 mg/kg per day
Glucagon Stimulates glycogenolysis 30 mcg/kg if normal insulin
300 mcg/kg if increased insulin
Diazoxide Inhibits insulin secretion 15 mg/kg per day
Somatostatin (long-acting: Inhibits insulin and growth 5 to 10 mcg/kg every 6 to 8 h
octreotide acetate) hormone release
Pancreatectomy Decreases insulin secretion —

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 ENDOCRINOLOGY
Hypoglycemia

develop diabetes mellitus later in a means of maintaining delivery of in the synaptic cleft, most likely due
life. cerebral glucose. In preterm new- to a combination of increased gluta-
borns, such changes in cerebral mate release from presynaptic neu-
blood flow may predispose to intra- rons and decreased adenosine
Consequences of ventricular hemorrhage and may 59-triphophate (ATP)-dependent glu-
Hypoglycemia tamate uptake by glial cells. Gluta-
have little effect on neuronal glu-
cose supply because transfer of glu- mate binds to postsynaptic receptors,
HYPOGLYCEMIC BRAIN INJURY triggering release of second messen-
cose across the blood-brain barrier
Although hypoglycemia is associ- gers via the metabotropic glutamate
depends on the activity of the glu-
ated with a number of physiologic receptors and changes in transmem-
cose transporters on the vascular
changes, the most profound effects brane ion fluxes via the ionotropic
are seen in the brain, where glucose endothelium and cell membranes.
glutamate receptors. Although there
is the major substrate for energy Glucose transporter levels are
are several types of ionotropic
metabolism and both local energy decreased in the fetus and newborn
receptors, the N-methyl-D-aspartate
stores and the supply of alternate compared with older infants and
(NMDA)-type glutamate receptor,
substrates are limited. Severe hypo- may be rate-limiting for cerebral which is associated with an ion
glycemia in the newborn is associ- glucose uptake. channel that transports sodium and
ated with selective neuronal necrosis If glucose supply to the brain is calcium into the cell and potassium
in multiple brain regions, including not maintained, there may be a out of the cell, predominates in
the superficial cortex, dentate gyrus, decrease in cerebral electrical activ-immature brain. In all species stud-
hippocampus, and caudate-putamen. ity, membrane breakdown with ied, including humans, the number
The initiating events in hypoglyce- release of free fatty acids, and of functional NMDA receptors
mic encephalopathy still are not altered amino acid metabolism, increases during brain development,
understood completely, but brain including increased production of subsequently decreasing to adult
injury appears to result from a num- glutamate. Glutamate, which is one levels.
ber of processes that are initiated of the excitatory amino acid neuro- The increased number of NMDA
when blood glucose concentrations transmitters found only in the cen- receptors in the late fetal and early
decrease (Figure). A moderate tral nervous system, is believed to newborn periods most likely reflects
reduction in blood glucose concen- play a major role in the pathophysi- the role of the receptor as one of the
tration is associated with compensa- ology of hypoglycemic brain injury. primary mediators of long-term
tory increases in cerebral blood flow Hypoglycemia is associated with potentiation, a process that is associ-
that have been assumed to represent increased glutamate concentrations ated with synaptogenesis and mem-
ory formation. NMDA
receptor activity also
may be involved in
regulating the process
of apoptosis, or pro-
grammed cell death,
via changes in cyto-
plasmic and nuclear
calcium concentrations.
In the human fetus, the
third trimester of fetal
development and early
neonatal period are
characterized by active
formation and modifi-
cation of synaptic con-
nections and arboriza-
tion of dendrites
associated with
increased NMDA
receptors. Thus, nor-
mal levels of NMDA
receptor activity are
critical to the develop-
ment of the immature
brain. However, excess
FIGURE. Proposed mechanism for the pathogenesis of hypoglycemic brain injury in the newborn. activation of NMDA
ATP 5 adenosine 59-triphosphate; PCr 5 phosphocreatine. Used with permission of Ross Products receptors by glutamate
Division, Abbott Laboratories Inc., Columbus, OH 43216. From Semin Neonat Nutr Metab. 1997; increases cytoplasmic
4, Ross Products Division, Abbott Laboratories Inc. concentrations of

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 ENDOCRINOLOGY
Hypoglycemia

sodium and calcium to levels that Hypoglycemia also could exacer- complicate acute management sig-
exceed the capacity of neuronal bate brain injury during periods of nificantly. Prompt, rapid normaliza-
homeostatic mechanisms, thereby cerebral hypoxia in immature brain. tion of low blood glucose concentra-
altering transmembrane ion gradi- As in hypoglycemia, cerebral tions is required to minimize the
ents. Hypoglycemia specifically hypoxia is associated with depletion hormonal and metabolic derange-
increases the sensitivity of NMDA of high-energy phosphates, increased ments. If a normal blood glucose
receptors to activation by glutamate, extracellular glutamate concentra- concentration can be achieved in a
which may result in a lower thresh- tions, activation of ionotropic gluta- timely manner, the acute effects of a
old for glutamate-induced excitotox- mate receptors, and increased intra- single episode of hypoglycemia can
icity. During hypoglycemia, energy- cellular sodium and calcium. In be minimized.
dependent mechanisms for restoring addition, anaerobic glycolysis during The long-term effects of neonatal
normal transmembrane gradients of hypoxia accelerates depletion of glu- hypoglycemia remain controversial.
sodium and calcium cannot operate cose in the brain. Thus, the combi- Repeated episodes of symptomatic
because of the depletion of ATP and nation of hypoglycemia and hypoxia hypoglycemia, as are seen in infants
phosphocreatine associated with might be expected to act synergisti- who have persistent hyperinsulinism,
hypoglycemia. Excess calcium cally in producing neuronal injury. have been associated with selective
influx activates cellular phospho- Although hypoglycemia appears to neuronal necrosis and long-term
lipases and proteases, alters mito- be neuroprotective during cerebral impairment of cognitive and motor
chondrial metabolism, triggers free ischemia in adults, studies in imma- function. Early studies also reported
radical formation, changes patterns ture animals have demonstrated that poor neurodevelopmental outcomes
of synaptic transmission, and even- concurrent hypoglycemia exacer- in IDMs. However, more recent data
tually may result in selective neuro- bates hypoxic-ischemic brain injury, suggest that hypoglycemia alone
nal necrosis. possibly by accelerating depletion of does not alter long-term outcome in
There is increasing evidence that high-energy phosphates. Hypoglyce- IDMs; rather, adverse outcomes
specific changes in mitochondrial mia also abolishes hypoxic vasodila- were related to the presence of con-
function may play a significant role tation of cerebral blood vessels, thus genital anomalies.
in the early events leading to hypo- impairing compensatory mechanisms Very few data are available
glycemic encephalopathy. Decreased that might otherwise improve oxygen regarding the long-term outcome in
fluxes of substrate through the tri- delivery to the brain during periods of the vast majority of hypoglycemic
carboxylic acid cycle results in hypoxemia. Although further investi- infants who have asymptomatic
decreased availability of reducing gation is necessary, these results indi- hypoglycemia that is detected on
equivalents in mitochondria. As a cate that maintenance of normoglyce- routine screening and is treated
result, there is incomplete reduction mia is especially critical in infants at promptly. Studies in normal adults
of molecular oxygen within mito- risk for episodes of hypoxemia, such have shown that cognitive function
chondria and increased formation of as those who have significant respira- is impaired during mild insulin-
oxygen free radicals, which damage tory distress. induced hypoglycemia (blood glu-
both mitochondrial membranes and cose values , 3.4 mmol/L
mitochondrial DNA. Fragmentation [,60 mg/dL]). Adult diabetics who
of mitochondrial DNA interferes CLINICAL CONSEQUENCES have a history of recurrent episodes
with synthesis of electron transport The physiologic disturbances associ- of hypoglycemia have been found to
chain enzymes, such as subunits of ated with acute hypoglycemia in the have persistent cognitive deficits as
cytochrome oxidase and nicotin- newborn result in a stress response, well as mild cortical atrophy, find-
amide adenine dinucleotide with release of catecholamines and ings that have not been observed in
(NADH)-dehydrogenase that are glucagon and subsequent lipolysis diabetics who have not experienced
coded for by the mitochondrial and glycogenolysis in an attempt to significant hypoglycemia.
genome. Thus, the ability of the cell increase substrate availability for Most studies in newborns,
to restore ATP levels is impaired. normal metabolic processes. Thus, although unavoidably limited in
Local depletion of high-energy even in asymptomatic hypoglycemia, scope, have failed to demonstrate
phosphates as well as changes in the there are significant short-term any long-term sequelae in term
mitochondrial membranes lead to effects on the infant that may result infants who have experienced brief
decreased sequestration of calcium in depletion of endogenous sub- episodes of hypoglycemia. Changes
by the mitochondria as cytoplasmic strate, leaving the infant unprepared in brainstem auditory evoked
calcium. Mitochondrial dysfunction to handle subsequent physiologic responses (BAERs) were reported in
also may contribute directly to neu- stress. In term infants, a brief period several infants (1 to 5 d old) during
ronal necrosis by initiating the pro- of increased sympathetic activity episodes of hypoglycemia of
cess of apoptosis. Recent studies and altered hepatic metabolism usu- unspecified etiology. Abnormal
have indicated that release of cyto- ally is tolerated well. However, in BAERs were detected at blood glu-
chrome c from mitochondria is the preterm or SGA infant, the cose concentrations ranging from
required to activate the enzymes that added physiologic stress associated 0.7 to 2.5 mmol/L (12 to 45 mg/dL),
trigger apoptosis and that cyto- with a low blood glucose concentra- and in two infants they remained
chrome c is released as oxidative tion may be sufficient to precipitate abnormal for several hours after glu-
phosphorylation fails. cardiorespiratory instability and cose had been administered. How-

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 ENDOCRINOLOGY
Hypoglycemia

ever, no long-term follow-up was mon among newborns. Awareness of infants, maintaining blood glucose
reported on these infants. A second risk factors that predispose infants to concentrations well above the
study, which analyzed factors affect- hypoglycemia allows for screening threshold for hypoglycemia may
ing outcome at 18 months of age in of those at risk so that clinically improve neurologic outcome. Fur-
a cohort of preterm infants, found undetectable hypoglycemia can be ther studies are necessary to deter-
that those who had at least one treated promptly, thereby preventing mine the consequences of hypogly-
blood glucose value less than the development of severe or symp- cemia in term infants.
2.6 mmol/L (46 mg/dL) on 5 or tomatic hypoglycemia, which is
more days had significantly lower associated with adverse outcomes.
scores on standardized tests of men- However, management of high-risk
tal and motor development and a infants is complicated by the lack of SUGGESTED READING
threefold higher incidence of cere- a consensus on the blood glucose Aynsley-Green A. Glucose, the brain, and the
bral palsy than those who had fewer value that constitutes hypoglycemia pediatric endocrinologist. Horm Res.
episodes of hypoglycemia or those as well as the inaccuracies in meth- 1996;46:8 –25
who had experienced a single epi- ods used to measure blood glucose Kalhan S, Saker F. Metabolic and endocrine
disorders, part one: disorders of carbohy-
sode of more severe hypoglycemia. values. A further unresolved issue is drate metabolism. In: Fanaroff AA, Martin
The differences remained significant whether asymptomatic hypoglycemia RJ, eds. Neonatal-Perinatal Medicine:
when other risk factors such as birth- is associated with permanent effects Diseases of the Fetus and Newborn. 6th
weight and intraventricular hemor- on brain function in the newborn. ed. St. Louis, Mo: Mosby-Year Book Inc;
rhage were accounted for. Thus, there No conclusive studies demonstrate 1997
is evidence to suggest that mild-to- long-term effects of asymptomatic Stanley CA. Hyperinsulinism in infants and
children. Pediatr Clin North Am.
moderate hypoglycemia may affect hypoglycemia in term infants, but it 1997;44:363–374
outcome, at least in high-risk infants. is likely that hypoglycemia contrib- Williams AF. Hypoglycemia in the Newborn:
utes to abnormal neurodevelopmen- A Review. WHO Publications #5778, 1997
tal outcome in infants who have
Conclusion other risk factors for brain injury,
Disturbances of glucose homeostasis such as prematurity or hypoxic-
that result in hypoglycemia are com- ischemic brain injury. In these

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 Neonatal Hypoglycemia
Jane E. McGowan
Pediatrics in Review 1999;20;e6
DOI: 10.1542/pir.20-7-e6

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 Neonatal Hypoglycemia
Jane E. McGowan
Pediatrics in Review 1999;20;e6
DOI: 10.1542/pir.20-7-e6

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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Illinois, 60143. Copyright © 1999 by the American Academy of Pediatrics. All rights reserved.
Print ISSN: 0191-9601.

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