Dening neonatal hypoglycaemia: A continuing debate

Win Tin
*
The James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK
Keywords:
Denition
Hypoglycaemia
Neonate
s u m m a r y
Hypoglycaemia is one of the most frequent metabolic problems in neonatal medicine, and maintaining
glucose homeostasis is one of the important physiological events during fetal-to-neonatal transition.
Although frequently observed transient low blood glucose concentrations in the majority of healthy
newborns are the reections of normal metabolic adaptation processes during this transition, there has
been a genuine concern that prolonged or recurrent low blood glucose levels may result in acute sys-
temic effects and long-term neurological and developmental consequences. Hence, it is not surprising
that neonatal hypoglycaemia remains one of the most important issues in our day-to-day practice and
that we also become obsessed with the numbers and values that we believe are a cut-off for its de-
nition. The aim of this article is to critically appraise some of the available evidence either to support or
refute the most widely accepted denition of neonatal hypoglycaemia (blood glucose concentration:
<2.6 mmol/l or 47 mg/dl), to highlight our knowledge gaps in dening neonatal hypoglycaemia, and to
address the important concept of using an operational threshold, rather than focusing too much on a
single blood glucose cut-off value, which is often applied to all newborn infants.
2013 Elsevier Ltd. All rights reserved.
1. Introduction
There has been much controversy about the numerical de-
nition of neonatal hypoglycaemia, a blood glucose concentration
below which would impose the risk of long-term neurological and
developmental consequences. However, there has also been a
widespread acceptance that a blood glucose level of <2.6 mmol/l
(47 mg/dl) should be used to dene neonatal hypoglycaemia over
the past 25 years, even if the newborn baby has no abnormal
clinical signs. In the 2006 systematic reviewof all the available data,
Boluyt et al. concluded that none of the 18 eligible studies they
identied provided a valid estimate of neonatal hypoglycaemia on
neurodevelopment [1].
It is widespread clinical practice to use bedside reagent test
strips to monitor glucose levels in the postnatal setting despite the
established knowledge that they may not provide reliable results,
and also that the variation of glucose levels is greatest at low
glucose concentrations [2,3]. The fact that low glucose levels
frequently observed in otherwise healthy newborn infants during
the early postnatal period are the reection of normal physiological
processes, and also that newborn infants have the ability to
compensate by producing other metabolic fuels including ketone
bodies (that cannot be measured readily as bedside tests) have
often been overlooked [4]. As a result, many newborn babies
are subjected to overdiagnosis, investigation, and treatment for
neonatal hypoglycaemia.
2. Blood glucose homeostasis during fetal to neonatal
transition
The detailed description of glucose metabolism during the
transition period of a newborn is not within the scope of this article,
but it is worth a brief review to highlight the fact that it is not
possible to identify a single cut off value of blood glucose that can
be applied to dene signicant neonatal hypoglycaemia for all
newborn infants with different conditions.
The fetus depends on the placental transfer of glucose and
other energy substrates (including ketones, free fatty acids, and
amino acids) for its metabolic demands and energy needs. The
normal lower limit of fetal glucose concentration is w3 mmol/l
(54 mg/dl) throughout gestation [5]. Following delivery and
clamping of the umbilical cord, the glucose supply from the
mother ceases abruptly and the glucose concentration in the
newborn decreases rapidly during the rst 4e6 h, from values
close to maternal levels to about 2.5 mmol/l (45 mg/dl) [6].
Effective glucose homeostasis during this transition is dependent
on several factors including a functioning glycogenolytic enzyme
system and adequate stores of glycogen, functioning gluconeo-
genic enzymes and an adequate supply of substrates (amino
acids, lactate, glycerols), and the production of glucose-regulating
* Tel.: 44 1642 854834; fax: 44 1642 854874.
E-mail address: win.tin@stees.nhs.uk.
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine
j ournal homepage: www. el sevi er. com/ l ocat e/ si ny
1744-165X/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.siny.2013.09.003
Seminars in Fetal & Neonatal Medicine 19 (2014) 27e32
hormones including insulin and glucagon. The normal adaptation
process also requires a change in the major energy source from
glucose to fat, from adipose tissue stores and milk feeds [4]. It has
also been shown that the brain is capable of using alternative
fuels such as ketone bodies and lactate for oxidative metabolism
[7,8]. Whereas the majority of newborns can get through this
adaptation process smoothly, some may have difculty, and may
need more time to respond to the low blood glucose concentra-
tions during this fetal-to-neonatal transition.
3. Approaches to dene neonatal hypoglycaemia
The late Marvin Cornblath and his six co-investigators with
expertise in the area of neonatal glucose homeostasis described
four different approaches to the denition of hypoglycaemia,
but they have also stressed that none of these has been satis-
factory [9].
3.1. Approach based on clinical manifestation
This approach is often misinterpreted because the clinical
manifestations (Box 1) are not unique to neonatal hypoglycaemia,
and can also be seen with other pathologic conditions (e.g. sepsis,
perinatal hypoxia/ischaemia). Cornblath et al. also emphasised that
in order to attribute such manifestations to hypoglycaemia,
Whipples Triad [10] (Box 2) must be fullled [11]. It is equally
important to emphasize that several newborns without any clinical
manifestations may well have low blood glucose, had this been
measured.
3.2. Approach based on epidemiological data
This approach is based on blood glucose concentrations
measured on normal newborns, and using the cut-off values of
more than two standard deviations below the mean as neonatal
hypoglycaemia. This approach has huge limitations, as the
measured blood glucose levels are likely to be inuenced by the
feeding practices as well as the varying attitudes and management
policies to low blood glucose measurements by the caregivers
(clinicians, nurses, midwives). This approach also overlooks the
physiological adaptations that most newborns can mount in
response to low blood glucose, and, more importantly, there is no
correlation between the clinical outcomes and the epidemiological
denition of neonatal hypoglycaemia.
3.3. Approach based on acute changes in physiological responses
This approach has been used in an attempt to dene neonatal
hypoglycaemia as the blood glucose level below which newborns
demonstrate counter-regulatory responses such as changes in
cerebral blood ow and hormonal responses [12], or abnormal-
ities in neurophysiological function [13]. Unfortunately, the data
for this physiological denition are limited and the correlation
between these observed changes and the meaningful develop-
mental outcome has not been established.
3.4. Approach based on neurologic and developmental outcomes
This is the approach that most caregivers would like to adopt,
but the data for this functional denition that correlates the
glucose concentration with adverse neurodevelopmental outcome
is still very limited, and confounded by the use of various cut-off
glucose levels as well as the duration and frequency of hypo-
glycaemia in different studies. Furthermore, most data from the
observational studies have failed to include non-hypoglycaemic
controls [14,15]. Boluyt et al. identied 18 observational studies
that correlate neonatal hypoglycaemia and neurodevelopmental
outcome, and stated that overall quality and methodology was
considered poor in 16 of them, and that there was a major clinical
and methodological heterogeneity of the other two high-quality
studies. They also stated that no studies provided a valid
estimate of the effect of neonatal hypoglycaemia on neuro-
development [1]. This statement remains unchanged by more
recently published evidence from a 15-year follow-up cohort of
preterm infants (<32 weeks of gestation) with frequent low blood
glucose measurements in the rst 10 days and their carefully
matched controls [16].
4. Evolution of the denition of neonatal hypoglycaemia and
its controversies
Hartmann and Jaudon reported their data in 1937, based on 286
neonates and infants who had clinical manifestations and low
blood glucose measurements. The authors dened hypoglycaemia
of different severities as follows:
mild: true blood glucose 2.2e2.8 mmol/l (40e50 mg/dl);
moderate: 1.1e2.2 mmol/l (20e40 mg/dl);
extreme: <1.1 mmol/l (20 mg/dl) [17].
In the rst edition of the Textbook of neonatology published in
1986, it was stated that Hypoglycaemia in the newborn period is
usually dened as a blood glucose concentration below 1.1 mmol/
l (20 mg/dl) during the rst 3 days in preterm or small-for-dates
neonates, and below 1.7 mmol/l (30 mg/dl) in term infants. It
was also stated that not all investigators agreed with this arbi-
trary denition, and that some had suggested that the lowest
acceptable limit should be 2.2 mmol/l (40 mg/dl) for all age
groups [18].
Box 1
Clinical manifestations frequently associated with neonatal
hypoglycaemia.
Altered level of consciousness
e Lethargy
e Irritability
e Abnormal cry
e Stupor
Feeding difculty
Hypotonia, oppiness
Tremors
Convulsions
Apnoeic (cyanotic) episodes
Hypothermia
Coma
Box 2
Whipples triad
1. A reliable low blood glucose measurement.
2. Clinical signs and symptoms consistent with
hypoglycaemia.
3. Resolution of clinical signs and symptoms after restoring
blood glucose to normal values.
W. Tin / Seminars in Fetal & Neonatal Medicine 19 (2014) 27e32 28
The numerical cut off value of the denition was widely
adopted as <2.6 mmol/l (47 mg/dl) from the late 1980s, inuenced
by an important publication in 1988 by Lucas et al. [19] that re-
ported serious impairment in motor and cognitive development at
18 months in babies with recurrent asymptomatic hypo-
glycaemia. This paper provided observational data derived from a
large multicentre feeding study [20] on 661 babies with birth
weight <1850 g, of whom 543 had a neurodevelopmental
assessment. The authors used statistical strategies to identify the
blood glucose value that would reliably predict an adverse
outcome, and found that using a value <2.6 mmol/l (47 mg/dl)
offered the greatest predictive power for poor developmental
outcome. They also reported that reduced developmental scores
were associated independently with the number of days on which
the level was below this cut-off value. The risk was doubled if
blood glucose <2.6 mmol/l (47 mg/dl) occurred on 3 days or more,
and increased by three-and-a-half times if it occurred on 5 days or
more [19].
This study involved >6800 blood glucose samples taken
weekly until discharge or until the baby weighed 2000 g (usually
up to the ninth week). In addition, samples were also taken daily
on all babies requiring intensive care until they were stable
(usually up to the second or third week). This method of blood
sampling is highly likely to produce a sampling bias e more
samples might be available for analysis in babies who seemed ill
and more immature, and thus might be at risk of suboptimal
outcome for reasons other than hypoglycaemia per se. Lucas
et al. stated in this original paper that the association between
modest hypoglycaemia and poor neurodevelopment reported
here might not be causal and might reect our failure to adjust
adequately for confounding factors [19]. The authors also
stressed in a letter published later about the difculty in proving
causation by the observational study, stating when such obser-
vations generate hypotheses or legitimate clinical concerns, this
should stimulate future studies [21]. However, most readers
(including the author of this paper, who was then a trainee) were
attracted only to the nal statement of the abstract e These data
suggest that, contrary to general belief, moderate hypoglycaemia
may have serious neurodevelopmental consequences and reap-
praisal of current management is urgently required [19] e and
perhaps turned the hypothesis into belief, adopting a blood
glucose value of <2.6 mmol/l (47 mg/dl) to dene neonatal
hypoglycaemia.
One other reason that had made an impact on the evolution of
this numerical denition was that the report by Lucas et al. was
soon followed by the publication of a paper reporting that auditory
and somatosensory evoked brain stem potentials in ve babies
were delayed or blocked when the blood glucose level fell to
<2.6 mmol/l (47 mg/dl) [13]. However, subsequent studies using
the same approach failed to support this nding [12,22,23].
Mindful of the need to conrmthe ndings by Lucas et al. [19], a
group of clinicians and nurses in the north of England (the Northern
Neonatal Nursing Initiative Trial Group) initiated an observational
study along with two other randomised trials [24,25]; all nested
into the prospective study of early neonatal care and neuro-
developmental outcome in preterm infants. This prospective study
included all 781 babies of <32 weeks of gestation, born in 1990 and
1991 to mothers residing in the north of England, and all the sur-
viving babies had their blood glucose levels measured (by glucose
oxidase assay) every morning at a xed time in the rst 10 days of
life. The results of additional glucose samples taken for other
clinical reasons at different times were also recorded.
All 566 children who were still alive at 2 years had detailed
clinical and developmental assessment [26] performed by a sin-
gle clinician, using the Grifths Scales for Mental Development
[27]. Forty-seven of the 566 children were identied as index
children with neonatal hypoglycaemia [blood glucose level of
<2.6 mmol/l (47 mg/dl) collected at a xed time on 3 days or
more during the rst 10 days], and their developmental outcome
ndings were individually matched with those found in control
children, who had never had such a low blood glucose level
documented. The controls were chosen from the same birth
cohort and matched, rst for the hospital of early care, then for
gestational age at birth, and then for birth weight. The protocol
for blood glucose sampling and for choosing control children
was strictly followed in order to avoid the risk of sampling bias
and other confounders described in other observational studies
[14,15]. No differences in developmental progress or in physical
disability were detected when full assessments were carried out
at 2 years of corrected age (Fig. 1) [28,29]. Nevertheless, the
120
100
80
60
40
20
0
General
Quotient
Locomotor Personal &
Social
Hearing &
Speech
Eye-Hand Co-
ordination
Performance
Griffiths
Development
Quotients
Index
Control
Fig. 1. Comparison of mean Grifths Development Quotients at 2 years of age between 47 index children and their matched controls. Scores appear higher than expected in both
groups because of the use of the assessment and scoring system before re-standardisation, and also because of correction for prematurity.
W. Tin / Seminars in Fetal & Neonatal Medicine 19 (2014) 27e32 29
parents agreed that these children would be assessed again in
their teens, since cognitive skills, academic potentials, and
behaviour (all of which could be potentially affected by low blood
glucose levels in neonatal period) cannot be assessed reliably in
children at 2 years of age.
All but two of the 47 index children and all the control chil-
dren were traced when they were about 15 years of age by a single
research psychologist, who was not aware of the child being either
the index or the control. Formal assessments were carried out on
psychometrics, literacy, numeracy, behaviour, and the adaptation to
daily living skills on all children who agreed and who were capable
of undertaking the tests. Once again, no differences were seen in
any outcome measures between the index children and their
matched counterparts (Fig. 2, Table 1). In short, this recently pub-
lished study that used methodology to minimise the risk of sam-
pling bias and to look at more meaningful long-term outcomes
found no evidence to support the belief that recurrent low blood
glucose <2.6 mmol/l [47 mg/dl] in the rst 10 days of life usually
poses a hazard to preterm babies [16].
5. Neonatal hypoglycaemia: The numerical denition or
operational threshold
In a recent article, Hawdon [30] stated that if neonatal hypo-
glycaemia continues in use as a short hand diagnostic term, it
should be accurately dened as a persistently low blood glucose
level, measured with an accurate device, in a baby at risk of
impaired metabolic adaptation but with no abnormal clinical signs;
or a single low blood glucose level in a baby presenting with
abnormal clinical signs. This denition is by far the most mean-
ingful denition described in the literature thus far. Considering the
differences in the underlying pathology, and the ability to mount
the metabolic and endocrine adaptations in response to low blood
glucose levels in the newborn during early transition, this deni-
tion also supported the viewpoint shared by several articles that
there is no single numerical cut-off value of blood glucose, or the
duration below this cut-off, that can be applied to all newborn in-
fants to predict long-term neurological and developmental prob-
lems [9,15,31,32].
0
20
40
60
80
100
Index
Control
WISC-III
Scores
Full Scale Verbal
Comprension
Perceptual
Organisation
Freedom from
Distraction
Processing
Speed
Fig. 2. Comparison of Wechsler Intelligence Scale for Children (WISC-III) at 15 years of age between 38 index children and their matched controls.
Table 1
Summary of assessments at 15 years of children who were found to have blood glucose of <2.6 mmol/l (47 mg/dl) on at least three of the rst 10 days of life and their matched
controls (who never had a low level documented) [16].
Measure No. of pairs Index [mean SD or n (%)] Control
a
[mean SD or n (%)] Mean paired
difference (95% CI)
Special education provision (10e15 years)
Extra help in mainstream school 46 3 (6.5%) 2 (4.3%) e
Attending special school 46 4 (8.7%) 4 (8.7%) e
Medications (10e15 years)
Medication for epilepsy 45 2 (4.5%) 2 (4.5%) e
Medication for behaviour problem 45 2 (4.4%) 4 (8.9%) e
Full psychometric assessment
Full scale IQ (WISC-III) 38 80.7 19.8 81.2 15.2 0.6 (8.3 to 7.2)
Reading (Wechsler WORD score) 36 91.1 18.3 90.2 15.9 0.9 (7.5 to 9.2)
Numeracy (Wechsler WOND score) 35 84.8 21.4 83.9 17.7 0.9 (7.5 to 9.4)
Behaviour (Total Achenbach score) 37 51.0 10.2 54.4 13.8 3.2 (9.3 to 2.9)
Adaptation to Daily Living (Vineland) 37 74.4 19.1 68.5 16.7 5.9 (2.8 to 14.7)
SD, standard deviation; CI, condence interval; WISC, Wechsler Intelligence Scale for Children; WORD, Wechsler Objective Reading Dimensions; WOND, Wechsler Objective
Numerical Dimensions.
a
Controls were matched in the order of: (i) for the unit where index child received care in the rst 2 weeks of life; (ii) gestation; (iii) birth weight.
W. Tin / Seminars in Fetal & Neonatal Medicine 19 (2014) 27e32 30
In view of the controversies related to the numerical denition,
a group of experts proposed the concept of operational thresholds
e the blood glucose thresholds for taking action [9] e that can be
used to develop protocols for screening and management of post-
natal glucose homeostasis in newborns at high risk of impaired
metabolic adaptation [15,33].
The suggested blood glucose operational threshold concentra-
tions at which clinicians should consider intervention are:
a single measurement of blood glucose <1 mmol/l (18 mg/dl);
blood glucose level <2 mmol/l (36 mg/dl), that remains below
the same value at the next measurement;
a single measurement of <2.5 mmol/l (45 mg/dl) in a newborn
with abnormal clinical signs.
The consensus expert opinion also highlighted the difference
between the operational threshold for taking action and the
higher therapeutic goal, aiming for blood glucose levels
>2.5 mmol/l (45 mg/dl), and to have a margin of safety in the
absence of any reliable data that correlate neonatal hypoglycaemia
with the neurodevelopmental outcome [9,30].
The use of operational threshold is far more pragmatic,
compared with being so obsessed with a single numerical value
[often <2.6 mmol/(47 mg/dl)] for all newborns, and should prevent
unnecessary investigations and interventions, including separation
of the baby and the mother [34].
6. Conclusion
It has been known for more than 50 years that low blood
glucose can cause neonatal seizures [35], and for more than 40
years that it can also cause permanent brain damage [36]. Much
progress has been made subsequently, in our understanding of
pathophysiology and altered glucose homeostasis in newborns;
and more recently neuroradiological studies have also helped us
to improve our understanding of variable neurological damage in
association with low blood glucose levels in newborn infants
[37,38]. Yet, there is no evidence to identify a specic blood
glucose level below which long-term damage occurs. The most
widely accepted lower limit of blood glucose, <2.6 mmol/l
(47 mg/dl), was derived from observational studies that at best
can only provide a hypothesis. Turning this hypothesis into a
belief may have trapped us in a clinical conundrum with a fear of
allegations of medical malpractice [39]. Perhaps, more impor-
tantly, many newborn babies (and their families) have also been
ensnared in such confusing conundrums, and subjected to
potentially harmful effects [34].
The time has come for all of us to accept our knowledge gaps in
dening neonatal hypoglycaemia [32], and to collaborate and
develop research agendas in accordance with our knowledge gaps.
Dame June Lloyd emphasized four conclusive statements in rela-
tion to the quest for rational denition of neonatal hypoglycaemia
in 1990 [31]: (i) eliminate the use of glucose sticks in the neonate;
(ii) discard the concept of cut-off blood glucose values; (iii) do a
proper prospective study comparing management regimens; and
(iv) encourage the basic scientists to study changes occurring with
development. Her words of wisdom remain entirely true 20 years
later.
Unfortunately, untoward long-term outcomes in infants with
one or two low blood glucose levels have become the grounds
for litigation and for alleged malpractice, even though the
causative relationship between the two is tenuous at best.
Marvin Cornblath et al [9].
Conict of interest statement
None declared.
Funding sources
None.
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Frequently observed transient low blood glucose con-
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There is no single cut-off blood glucose value that can be
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Establish normograms of postnatal blood glucose levels
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