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BLOOD GLUCOSE

Blood glucose levels in infancy – clinical

significance and accurate measurement
A low blood glucose in a newborn baby is not an uncommon finding, but some controversy
remains regarding the definition and clinical significance of neonatal hypoglycaemia. This article
describes how application of data from clinical research studies assists our understanding of
neonatal metabolic adaptation, and which babies are at risk of the sequelae of hypoglycaemia.
In addition the more rare, but more significant, occurrence of hypoglycaemia in older infants is
discussed. The mechanisms of development of hyperglycaemia in infants are also described.
Finally, the requirement for accurate measurement of blood glucose levels is reinforced.

Jane M. Hawdon The clinical significance of low and

MA, MBBS, PhD, MRCP, FRCPCH, Consultant high blood glucose levels
Neonatologist, University College London
Hospitals, Clinical Lead North Central
Traditionally, a baby who has lower than
London Perinatal Network normal blood glucose levels has been
considered to have hypoglycaemia.
Hypoglycaemia in infancy has been
recognised for many years, and is more
commonly described in the neonatal
period1,2. At the same time, there has been
much controversy regarding the definition
of the condition and its clinical
significance3,4. It is well known that severe
and prolonged hypoglycaemia may cause
brain injury. Anxieties regarding the effects FIGURE 1 Babies with co-existing
complications must have blood glucose levels
of neonatal hypoglycaemia on the brain
monitored.
were heightened by papers that had studied
Keywords
particular patient groups, eg preterm responses, such as the increased availability
hypoglycaemia; hyperglycaemia; babies5,6. These anxieties resulted in what of alternative fuels. It has been suggested
metabolic adaptation; ketone bodies; may have been over-aggressive manage- that some cases of sudden infant death are
blood glucose measurement ment of some babies, resulting in the result of severe hypoglycaemia resulting
Key points separation of babies from their mothers from inborn errors of metabolism, but this
and the consequent impact on the estab- is likely to be an extremely rare cause of
Hawdon J.M. (2005) Blood glucose levels
lishment of breast feeding. Subsequent this tragic event7.
in infancy – clinical significance and
work has demonstrated that most infants Until the advent of neonatal intensive
accurate measurement. Infant 1(1): 24-27.
1. Healthy term babies adapt to the
are protected from the neurological effects care, hyperglycaemia was a rare phenom-
physiological fall in blood glucose of hypoglycaemia by mounting protective enon. However, it is now commonly seen
concentration. responses, eg increased availability of in the increasing numbers of extremely
2. However, preterm or sick babies may alternative fuels to glucose for the brain. low-birthweight infants who are cared for
fail in this adaptation and hypo- The most abundant alternative fuels, in our neonatal units. In addition, a small
glycaemia should be detected and especially in the early neonatal period, are number of infants present with classical
treated. ketone bodies, produced by the oxidation diabetes mellitus, or have transient
3. In older infants, hypoglycaemia is more of fatty acids4,5. hyperglycaemia in response to stress when
commonly a marker for serious under- Hypoglycaemia is a less common very unwell. In the neonate it is rare for
lying disorders so that in addition to occurrence in the older infant and as such hyperglycaemia to be associated with
treating hypoglycaemia the underlying usually has a pathological underlying cause osmolar diuresis, ketosis or hyperosmolar
disorder should be investigated. brain injury, but infants presenting with
and must be taken seriously. There have
4. Hyperglycaemia is not physiological at classical diabetes mellitus may become
been fewer studies of the effects of
any age and the underlying cause
hypoglycaemia on the brain in older dehydrated and hyperosmolar.
should be investigated and treated.
infants, and whether there are protective The following groups of babies are at

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risk of having blood glucose levels which

are too high or too low, and must have
blood glucose levels monitored especially
when there are abnormal clinical signs:
1. Babies cared for on neonatal units or
paediatric wards who have known co-
existing clinical complications such as
extreme prematurity, previous hypoxia-
ischaemia, infection – low blood glucose
concentrations indicate that energy
provision (intravenous or enteral) should
be increased and monitoring should be
continued to assess the effects of changes in
management (FIGURE 1). High blood
FIGURE 2 Infants with septicaemia are at risk of hypoglycaemia and hyperglycaemia.
glucose concentration may arise from Photograph courtesy of Meningitis Research Foundation.
injudicious high glucose infusion rates
which must be adjusted, or may be an early carried out alongside the support and previously well infant. The older infant
marker of infection, uncontrolled pain or optimisation of breast feeding. Many of the who is metabolically stressed is more likely
other stress which causes metabolic babies in this group will mount protective to present with hyperglycaemia (see below)
disturbance and thus should alert responses and will tolerate low-normal (FIGURE 2).
attending staff to carry out further blood glucose levels. Therefore, there must ■ Rarely, moderately preterm neonates
investigations. be experienced clinical assessment as well (34-36 weeks’ gestation) or those who have
2. A baby (neonate or infant) presenting as glucose monitoring, to indicate when experienced intrauterine growth
unexpectedly with any acute illness, additional measures, such as tube feeds retardation may exhaust their counter-
especially with abnormal neurological with breast milk (preferably) or formula (if regulatory response if milk intake is
signs – measurement of blood glucose necessary) are required to maintain energy insufficient, and present with significant
concentration is important to identify levels. This is far preferable to a blanket hypoglycaemia.
hypoglycaemia as either the cause or an policy of formula supplementation of ■ Inborn errors of metabolism – defects
association of the collapse, and to guide breast feeds in this group. of fatty acid oxidation are the most
subsequent intravenous fluid manage- In summary, the accurate measurement common inborn errors of metabolism to
ment. Unexpected hypoglycaemia should of blood glucose concentration is essential present with hypoglycaemia in infancy.
alert clinicians to an inborn error of for the prevention of severe and prolonged The severity of this group of conditions is
metabolism or endocrine disorder (see hypoglycaemia and hyperglycaemia in at heightened by the failure of alternative fuel
below) and appropriate blood and urine risk groups, for the diagnosis of underlying (ketone body) production. Other conditions
samples should be taken immediately, as it disorders in sick infants, and in guiding that may present with hypoglycaemia in
is often difficult to diagnose metabolic feeding and fluid prescriptions for small, infancy are glycogen storage disorders and
conditions in such infants at times when vulnerable or sick infants. fructose-1, 6-biphosphatase deficiency.
they are unstressed and normoglycaemic. These disorders usually require to be
Finally, high blood glucose concentrations
Pathophysiology of hypoglycaemia ‘unmasked’ by the baby entering a
are commonly associated with the stress and hyperglycaemia catabolic state. Therefore they most
response in older infants, or may represent The preceding section highlighting ‘at risk’ commonly present in the neonatal period,
the onset of classical diabetes mellitus infants refers to some of the underlying or during intercurrent illness, or when the
presenting with typical clinical signs in causes of blood glucose disturbances. This baby commences sleeping through the
infancy. section now provides more detail regarding night. Details of investigations for these
3. Newborn babies of diabetic mothers underlying mechanisms of hypoglycaemia conditions are to be found in standard
when there has been poor diabetic control in and hyperglycaemia. neonatal and paediatric textbooks.
pregnancy – these babies may have high ■ Endocrine disorders – infants are
insulin levels persisting in the first few days Hypoglycaemia dependent on counter-regulatory
after birth which will result in Insufficient glucose supply with failure of hormones to mount the metabolic
hypoglycaemia with, in addition, impaired alternative fuel production responses to hypoglycaemia. The most
protective alternative fuel responses. ■ Very preterm or very sick (eg septi- common endocrine deficiency that
4. Neonates of macrosomic appearance – caemia, hypoxia-ischaemia) neonates due presents with hypoglycaemia in infancy is
in the absence of diabetes in pregnancy. to immaturity and dysfunction of enzyme adrenal insufficiency which may arise from
These babies may have intrinsic pancre- systems and exhaustion of fuel stores (eg primary adrenal dysfunction (eg congenital
atic dysfunction causing hyperinsulinism liver glycogen and fat in adipose tissue). adrenal hyperplasia), or as a result of
and usually present with clinical signs of Hypoglycaemia may also be found in older abnormal control of adrenal function by
hypoglycaemia as alternative fuel infants who are severely unwell (eg the pituitary, as in pituitary insufficiency.
production is also impaired. septicaemia) and should always be ruled Again, it is often only possible to confirm
5. Moderately preterm or growth retarded out, but is less common as counter- this diagnosis on samples taken during
neonates – blood glucose monitoring is regulation is more robust in the older, hypoglycaemia or other stress.

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Excessive glucose utilisation blood glucose level is considered to

■ The baby of a diabetic mother be harmful, the presence of clinical
after poor diabetic control in signs or associated complications,
pregnancy. Fortunately it is now the group of infants studied, and
rare for such babies to be severely the consideration of protective
affected as improved maternal responses. Most of these criteria
management prevents the fetus have never been adequately
(and therefore neonate) becoming addressed by previously published
hyperinsulinaemic. If hyperin- definitions, despite the extensive
sulinism does occur, the babies are literature regarding the numerical
invariably of macrosomic definition of neonatal
appearance and the circulating hypoglycaemia, which has been
insulin levels fall within a few days succinctly summarised by Halamek
of birth, the condition is self et al19:
limiting. However, hyperinsulinism “As of 1997 no consensus exists
causes both hypoglycaemia and in the normal newborn nursery,
failure to produce alternative fuels. NICU, or the courtroom as to the
Therefore, the baby is completely definition of hypoglycaemia in the
dependent upon glucose and neonate.”
glucose requirements are high. This paucity of data has resulted
There is a consensus view that in a pragmatic approach to
babies who present with significant hypoglycaemia recently proposed
hyperinsulinism should receive milk by a group of clinicians that is
intake or glucose infusion adequate FIGURE 3 Collecting blood using a heel incision device. based on thresholds for
to maintain blood glucose levels intervention rather than attempts
Photograph courtesy of LDH UK Ltd.
above 3mmol/L4. to define hypoglycaemia as a single
■ Neonatal hyperinsulinism. ■ Insulin resistance. This occurs as a
numerical term4. This group
This may arise from diffuse pancreatic suggested that, for infants who are at risk
result of the endocrine stress response, for
dysfunction (previously termed of neurological sequelae by virtue of their
example during severe illness or surgery,
nesidioblastosis), or a localised insulinoma especially if without adequate analgesia, or inability to mount protective responses
so that excessive quantities of insulin are (see above), intervention to raise blood
as a result of trauma, including
secreted, even when blood glucose levels glucose should be considered if two
submersion11-16. High circulating levels of
are low. Hyperinsulinism is also associated consecutive blood glucose levels, in a baby
cortisol and catecholamines (adrenaline
with some congenital syndromes eg with no abnormal clinical signs, are below
and noradrenaline) have the reverse action
Beckwith Weidemann syndrome. 2mmol/L (measured using accurate device)
to insulin, rendering the baby insulin
Hyperinsulinism in these conditions is or a single blood glucose level is below
resistant and catabolic, and in addition the
usually more prolonged and severe than in latter directly suppress insulin release. High 1mmol/L. Regardless of the blood glucose
the infant of the diabetic mother and concentration, neurological signs in
glucose levels may be the earliest indication
requires treatment in specialist centres. If association with low blood glucose levels
of deterioration in a baby’s condition and
diagnosed and treated promptly and should prompt investigations to establish a
are associated with a worse prognosis14,15.
adequately, hypoglycaemic brain injury firm diagnosis of hypoglycaemia and its
■ Excessive glucose administration. The
may be avoided8. underlying cause, and the institution of
extremely preterm neonate is very sensitive
■ Accidental or non-accidental admin- to excessive glucose administration,
urgent treatment. The group recom-
istration of insulin or oral hypoglycaemic mended maintenance of blood glucose
especially if glucose infusion rates exceed
agents. This must be considered if a baby levels above 3mmol/L if hyperinsulinism is
10mg/kg/min (equivalent to >144 ml 10%
presents with severe and unexplained suspected or identified.
dextrose/kg/day) or are increased rapidly
hypoglycaemia, and if suspected, Although there can be no single
to this level. There is also a risk in older
appropriate child protection processes defining values for hypoglycaemia and
infants that injudicious glucose
must be employed. hyperglycaemia, most clinicians caring for
administration will result in inefficient
small, sick or unstable neonates aim to
Hyperglycaemia glucose utilisation, hyperglycaemia and
maintain blood glucose levels above 2-
hyperosmolar states17,18.
■ Insulin insufficiency. It is rare for 3mmol/L and below 10-15mmol/L. For
classical diabetes mellitus to present in the Definitions and accurate blood glucose older infants, where low blood glucose
under-5 age group, and therefore this very measurement levels are more likely to have a more
rarely presents in infancy9. When diabetes Ideally, definition of hypoglycaemia and serious underlying cause, clinicians usually
mellitus occurs in the neonatal period, hyperglycaemia should include the aim to maintain blood glucose levels
usually as a result of underlying genetic following details – blood glucose above 3mmol/L.
abnormalities, this may be transient (with concentration considered to be the Adhering to a range of optimal blood
increased risk of later type 2 diabetes) or minimum or maximum safe level, the glucose values necessitates accuracy of
permanent10. length of time beyond which the abnormal monitoring as management may be

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changed if blood glucose measurements Summary 124: 547-51.

12. Chambliss C.R., Anand K.J. Pain management in the
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1mmol/L at either end of the optimal clinical signs, not ‘stand alone’ diagnoses. 9: 246-53.
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to over treatment or under treatment be impaired for a variety of underlying the infant under six kilograms. Perfusion 1997; 12:
which may in turn harm the baby. 303-0 8.
reasons, and it is essential that the cause of 14. Graf W.D., Cummings P., Quan L., Brutocao D.
Differences in measurement arise when hypoglycaemia or hyperglycaemia is Predicting outcome in pediatric submersion victims.
comparing plasma and whole blood considered and treated, rather than blindly Ann Emerg Med 1995; 26: 312-19.
measurements of glucose, even using treating the abnormal blood glucose value 15. Menon G., Anand K.J., McIntosh N. Practical
accurate laboratory methods20. This alone. In general terms, hypoglycaemia approach to analgesia and sedation in the neonatal
intensive care unit. Semin Perinatol 1998; 22: 417-
difference is greater at high haematocrit (ie may be avoided and treated by identifying 24.
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