Hipoglicemia OMS

WHO/CHD/97.
1
WHO/MSM/97.1
Distr.: GENERAL
Hypoglycaemia of the Newborn
Review of the Literature
World Health Organization
Geneva
1997
World Health Organization 1997
This document is not a formal publication of the World Health Organization
(WHO! and all rights are reserved b" the Organization# The document ma"!
ho$ever! be freel" revie$ed! abstracted! reproduced or translated! in part or in
$hole! but not for sale or for use in con%unction $ith commercial purposes#
The vie$s e&pressed in documents b" named authors are solel" the
responsibilit" of those authors#
i
Contents
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0c3no$ledgements#################################################################################################################27
Acknowledgements
ii
This revie$ has been compiled b" 0nthon" 4# Williams! +5hil! 4-15! /enior 6ecturer 7
1onsultant in 8eonatal 5aediatrics! /t# George9s Hospital :edical /chool! 6ondon! ;<#
The follo$ing e&perts commented on the draft document and provided valuable suggestions=
5rofessor 0nna 0lis"ahbana (/chool of :edicine! 5ad%ad%aran ;niversit"! >andung! 5rofessor
0# 0"nsle"?Green ((nstitute of 1hild Health! 6ondon! +r 0nthon" 1ostello ((nstitute of 1hild
Health! 6ondon! +r 0rmida 4ernandes (6o3man"a Tila3 :unicipal :edical 1ollege! >omba"!
+r @ane Ha$don (;niversit" 1ollege Hospital! 6ondon! 5rofessor W#W# Ha" (;niversit" of
1olorado Health /ciences 1enter! 1olorado! +r @ane .# :cGo$an (;niversit" of 5enns"lvania!
5hiladelphia! +r 0# :ehta (8ine$ells Hospital and :edical /chool! +undee! +r :# Ward 5latt
(The -o"al Aictoria (nfirmar"! 8e$castle! and +r /#8# Aani (>#@# :edical 1ollege and 1ivil
Hospital! 0hmedabad#
3
Recommendtions !or "re#ention nd Mn$ement
Recommendations for Prevention and Management
1# .arl" and e&clusive breastfeeding is safe to meet the nutritional needs of health" term
ne$borns $orld$ide#
'# Health" term ne$borns $ho are breastfeeding on demand need not have their blood
glucose routinel" chec3ed and need no supplementar" foods or fluids#
*# Health" term ne$borns do not develop Bs"mptomaticB h"pogl"caemia as a result of
simple underfeeding# (f an infant develops signs suggesting h"pogl"caemia (see point 17!
loo3 for an underl"ing condition# +etection and treatment of the cause is as important as
correction of the blood glucose level#
)# Thermal protection (the maintenance of normal bod" temperature in addition to
breastfeeding is necessar" to prevent h"pogl"caemia#
2# >reastfeeding should be initiated as soon as an infant is read"! preferabl" $ithin 1 hour of
birth# (mmediatel" after birth the bab" should be dried and held against the motherCs chest
$ith s3in?to?s3in contact to provide $armth and to facilitate the initiation of
breastfeeding#
D# >reastfeeding should continue on demand# Health" term ne$borns sho$ signs of
readiness to feed $hen the" are hungr"! but the interval bet$een feeds varies
considerabl"! particularl" in the first fe$ da"s of life# There is no evidence that long
interfeed intervals adversel" affect health" ne$borns $ho are 3ept $arm and $ho are
breastfed $hen the" sho$ signs of hunger# 0n infant $ho sho$s no signs of hunger or is
un$illing to feed should be e&amined to e&clude underl"ing illness#
7# 8e$borns at ris3 of h"pogl"caemia include those $ho are preterm andEor small for
gestational age (/G0! those $ho suffered intrapartum asph"&ia or $ho are sic3! and
those born to diabetic mothers#
,# (n ne$borns at ris3! h"pogl"caemia is most li3el" to occur in the first ') hours of life! as
the infant adapts to e&trauterine life# H"pogl"caemia $hich presents after the first da" of
life! or $hich persists or recurs! does not necessaril" indicate inadeFuate feeding# (t ma"
indicate underl"ing disease such as infection! or a $ide range of other conditions (see
Table * of main document# -eference should be made to standard te&ts#
9# 4or ne$borns at ris3! breastmil3 is the safest and nutritionall" most appropriate food#
Ho$ever it ma" need to be supplemented $ith specific nutrients for some ver" lo$ birth
$eight infants#
%
H&'o$(&cemi o! t)e Ne*+orn
1G# 0t?ris3 ne$borns $ho have a gestational age of *' $ee3s or more or $ho $eigh more
than 12GG g at birth! ma" be able to breastfeed sufficientl" to satisf" their nutritional needs
(but see also point 1'# (f health"! the" should be given the opportunit" to breastfeed
$ithin 1 hour of birth li3e term babies#
11# 0t?ris3 ne$borns able to suc3le sufficientl" should continue to breastfeed $hen the"
sho$ signs of hunger# Ho$ever! the" should not be allo$ed to $ait more than * hours
bet$een feeds# 8ormal bod" temperature should be carefull" maintained#
1'# 0t?ris3 ne$borns not able to suc3le adeFuatel" and obtain all the mil3 that the" need
from the breast! but $ell enough for oral feeds! can be fed e&pressed breastmil3 (.>:!
or if necessar" an appropriate breastmil3 substitute! b" cup or b" gavage (orogastric or
nasogastric tube feeding# 4eeds should commence $ithin * hours of birth! and should
continue at least * hourl" thereafter#
[-eference should be made to Hstandard te&tsI for details of the feeding of ne$borns $ho are less than *'
$ee3s gestational age! or $ho are ver" lo$ birth $eight! $ho are sic3 or born to diabetic mothers! or $ho
are unable to feed enterall"]
1*# 4or ne$borns at ris3! the blood glucose concentration should be measured at around )?D
hours after birth! before a feed! if reliable laborator" measurements are available#
:easurements using glucose?o&idase based reagent paper strips have poor sensitivit" and
specificit" in ne$borns! and should not be relied upon as an alternative#
1)# 4or ne$borns at ris3 who do not show abnormal clinical signs (Bas"mptomaticB! the
blood glucose concentration should preferabl" be maintained at or above '#D mmol l
?1

()7 mg E1GG ml#
(f the blood glucose concentration is belo$ '#D mmol l
?1
=
The infant should be fed# This can be a breastfeed if the infant can suc3le
adeFuatel"# (f not! .>: or an appropriate breastmil3 substitute can be given b"
cup or gavage#
The blood glucose measurement should be repeated preferabl" after 1 hour and
certainl" before the ne&t feed * hours later# (f it is still belo$ '#D mmol l
?1
!
treatment $ith intravenous glucose should be considered#
(f facilities for administering intravenous glucose are not readil" available! a
supplementar" feed should be given b" cup or gavage#
>reastfeeding should continue#
12# (f reliable laborator" measurements of blood glucose are not available! ne$borns at ris3
should be 3ept $arm and breastfed# (f breastfeeding is not possible the" should be given
supplements of .>: or an appropriate breastmil3 substitute b" cup or gavage at least
ever" * hours# The infant should continue to breastfeed as much as he or she is able#
1D# (f a ne$born is un$ell or sho$s signs of h"pogl"caemia= apnoea! c"anosis! %itteriness! or
convulsions (Bs"mptomatic h"pogl"caemiaB! the above guidelines are superseded# >lood
glucose should be measured urgentl"! and if it is belo$ '#D mmol l
?1
! intravenous glucose
should be administered as soon as possible#
,
Recommendtions !or "re#ention nd Mn$ement
17# 4or management of Bs"mptomatic h"pogl"caemia!B $hen intravenous treatment is
indicated and feasible! give 1GJ glucose intravenousl"# :onitor the blood glucose! and
ad%ust the rate of infusion accordingl"# 1ontinue normal feeding as soon as possible#
1,# (f reliable blood glucose measurement is not possible! intravenous glucose should be
reserved for the treatment of ma%or complications associated $ith h"pogl"caemia (e#g#
convulsions and for situations in $hich enteral feeds are contra?indicated# .nteral
treatment is other$ise preferable#
4urther details about the above procedures $ill be found in the main document ?
Hypoglycaemia of the Newborn: Review of the Literature (WHO/H!/"#$%&
( WHO/'('/"#$%&$
efinition of terms
!"clusive breastfeeding# 0n infant is given no food or drin3! including $ater! other than
breastmil3! (e&cept an" medicinal drops or s"rups $hich ma" be indicated#
Preterm# >orn before *7 completed $ee3s of gestation#
$mall for gestational age %$&A'# >irth $eight belo$ the lG
th
percentile for infants of the same
gestational age in the same population#
(ery low birth weight# >irth $eight less than 12GG grams#
-
!"ecutive $ummary
1# The term Bh"pogl"caemiaB refers to a lo$ blood glucose concentration# 8eonatal
h"pogl"caemia is not a medical condition in itself! but a feature of illness or of failure to
adapt from the fetal state of continuous transplacental glucose consumption to the
e&trauterine pattern of intermittent nutrient suppl"# (t is more li3el" to occur in conditions
$here infants become cold! or $here initiation of feeding is dela"ed#
'# :etabolic adaptation at birth involves mobilisation of gl"cogen reserves (glycogenoly)i)!
hepatic s"nthesis of glucose from other substrates (gluconeogene)i)! and production of
alternative cerebral fuels such as 3etone bodies# The processes $hich ensure availabilit"
of glucose and other fuels are collectivel" described as counterregulation# The" are
activated principall" b" glucagon and adrenaline# The concentration of glucose in the
blood is onl" one piece in a comple& metabolic %igsa$ and cannot be interpreted in
isolation#
%$ection )*)+ $ection ,*)'
*# 0 Bnormal rangeB for blood glucose values in the ne$born has not been properl" defined#
Aalues are influenced b" birth $eight! gestational age! feeding method and postnatal age#
4e$ studies have been made of breastfed infants and the" do not define feeding patterns
or mil3 inta3e# %$ection -*.'
)# There is controvers" over the definition of a BsafeB blood glucose concentration! i#e# a
value belo$ $hich there is ris3 of long?term neurodevelopmental impairment#
H"pogl"caemia associated $ith abnormal clinical signs ()ymptomatic hypoglycaemia has
a poor short? and long?term outcome but evidence of ris3 in the absence of clinical signs
(a)ymptomatic hypoglycaemia& is inconclusive# This is to be e&pected as maintenance of
cerebral function depends as much on abilit" to mobilise alternative fuels (e#g# 3etones as
on blood glucose concentration# %Chapter .+ Chapter ,'
2# (t follo$s that the anticipated maturit" of the counterregulator" response and the
presence or absence of s"mptoms are as influential as the blood glucose concentration in
deciding $hether to treat# 0 rigid definition of h"pogl"caemia relevant to all clinical
situations cannot be made#
D# There is no evidence that lo$ blood glucose concentrations among health" breastfed term
babies are detrimental to outcome# Health" term babies $ho are breastfed on demand
reFuire no food or drin3 other than breastmil3# %$ection /*)*.'
7# 0ll infants should be fed as soon as possible after birth# Those $ho are health" and
mature enough to suc3le should be offered a breastfeed# There is some evidence that
breastmil3 promotes 3etogenesis more vigorousl" than formula# %$ection )*,'
,# /creening for h"pogl"caemia using glucose?o&idase based reagent strips has poor
sensitivit" and specificit"# (t is preferable to ma3e occasional pre?feed laborator"
measurements of blood glucose in infants at ris3# /creening health"! breastfed! term
infants for h"pogl"caemia is furthermore inappropriate because a normal range of blood
glucose values has not been defined# %$ection -*.+ $ection 0*.*/'
7
E.ec/ti#e S/mmr&
9# /ome evidence suggests that preterm babies and babies $ho are small for gestational age
sho$ a constrained counterregulator" response to h"pogl"caemia# +etection and
treatment of h"pogl"caemia in these groups is therefore important# Other groups of
infants at ris3 of earl" h"pogl"caemia are those $ho are infected! $ho have suffered
intrapartum asph"&ia and $ho are infants of diabetic mothers# /upplementar" feeding
ma" be reFuired both to prevent and treat h"pogl"caemia in these groups# H"pogl"caemia
$hich recurs or persists longer than ),?7' hours of age suggests an underl"ing medical
condition (e#g# inborn error of metabolism or endocrine disorder# %$ection )*,+
Chapter /+ Chapter 1'
1G# (nfants at ris3 of h"pogl"caemia and $ho are mature enough to suc3le should be
breastfed on demand# 0 blood glucose estimation should be made before a feed at around
)?D hours of age# 1urrent evidence suggests that supplementar" feeding should be
considered if the value falls belo$ '#D mmol l
?1
though there is no conclusive evidence
that brief e&posure to lo$er levels is harmful in as"mptomatic infants# 0 blood glucose
measurement should be repeated 1 hour after feeding# (f the blood glucose value still lies
belo$ '#D mmol l
?1
! treatment $ith an intravenous glucose infusion is necessar"# %$ection
/*)+ $ection 1*.'
11# (nfants too immature to suc3le should be given supplementar" feeds either b" cup or b"
gavage# >reastmil3 or formula is preferable to de&trose $ater as it has greater energ"
densit" and contains fat $hich promotes 3etogenesis and reduces glucose o&idation# The
volume of mil3 administered should be DG ml 3g
?1
d
?1
on the first da"! 9G ml 3g
?1
d
?1
on the
second da"! 1'G ml 3g
?1
d
?1
on the third and 12G ml 3g
?1
d
?1
on the fourth# (nfants in stable
condition $ithout respirator" distress ma" tolerate larger volumes! starting $ith
1GG ml 3g
?1
d
?1
on the first da"# >lood glucose concentration should be measured at )?D
hours of age# %$ection /*)'
1'# /ic3 infants $ho have clinical features $hich contraindicate enteral feeding (e#g
cardiorespirator" instabilit"K abdominal distension should receive an intravenous infusion
of 1GJ de&trose! commencing at DG ml 3g
?1
d
?1
# This Fuantit" of glucose () mg 3g
?1
min
?1

$ill maintain normogl"caemia in the ma%orit" of infants of appropriate $eight for
gestational age# The infusion rate should be ad%usted according to blood glucose
concentration# %$ection /*)+ $ection 1*.'
1*# /creening and supplementar" feeding are inappropriate for infants $ho are health" but
large for gestational age! unless 3no$n to be infants of diabetic mothers# %$ection 0*,+
$ection 0*-+ $ection /*)*0'
0
Review of the Literature
.* H2$34R2CAL 5AC6&R47N
The term Bh"pogl"caemiaB refers to a reduction in the glucose concentration of
circulating blood# (t is almost a centur" since it $as first described in children and
over fift" "ears since it $as recognised in ne$born and older infants (Hartmann 7
@audon! 19*7# Given the numerous advances $hich have since occurred in the
care of ne$born infants it is surprising that so much controvers" still surrounds
the definition! significance and management of neonatal h"pogl"caemia#
5arado&icall"! technological developments in the form of bedside glucose
monitoring have e&acerbated rather than eased the problem b" facilitating
screening for an ill?characterised clinical entit"#
.*. Patterns of hypoglycaemia
The vulnerabilit" of premature infants and those of diabetic mothers to
h"pogl"caemia $as recognised earl" in the histor" of neonatal medicine (e#g#
:iller 7 -oss! 19)GK 8orval! 192GK :cLuarrie! 192)K 4arFuhar! 192)# The
transient nature of h"pogl"caemia and apparent infreFuenc" of clinical
manifestations led man" to assume that lo$ blood glucose concentrations among
these groups $ere innocuous and Bph"siologicalB! in contrast to h"pogl"caemia
caused b" metabolic and endocrine disease# Ho$ever! in 1929 1ornblath et al
described eight! '?da" old infants born to mothers $ith pre?eclamptic to&aemia in
$hom s"mptoms (apnoea! c"anosis! coma and convulsions $ere associated $ith
reduced blood glucose concentrations (1?') mg dl
?1
1
# The" described a clinical
response to the infusion of intravenous glucose and dre$ attention to the Bself?
limited but Fuite refractor"B course of h"pogl"caemia# The outcome of this small
group of infants $as poor# 4ive $ere normal $hen follo$ed?up at t$o $ee3s to
eleven months but one died and t$o had persisting neurological abnormalities#
4urther descriptions of neurological seFuelae associated $ith )ymptomatic
hypoglycaemia (i#e# that associated $ith clinical signs
'
$hich resolve at increased
blood glucose concentration in the ne$born follo$ed#
1oncern arose that h"pogl"caemia without associated clinical signs
'
(a)ymptomatic hypoglycaemia might also lead to neurodevelopmental seFuelae#
This led to an attempt to define h"pogl"caemia statisticall" as a blood glucose
concentration more than ' standard deviations belo$ the mean for populations of
$ell full?term and lo$ birth $eight infants# This! and the introduction in the earl"
197GCs of reagent strip glucose assa"s (e#g# !e*tro)ti*
T:
for cotside screening of
ne$borns at ris3! led to clinical classifications of neonatal h"pogl"caemia (e#g#
4luge! 197)K Gutberlet 7 1ornblath! 1972# Gutberlet 7 1ornblath estimated the
1
1, mg dl
?1
M 1 mmol l
?1
glucose#
''
(t is technicall" incorrect to spea3 of Bs"mptomsB in the conte&t of an infant because
the term describes changes reported b" a patient# The term BsignsB more accuratel"
describes clinical observations# -eference to Bas"mptomaticB and Bs"mptomaticB
h"pogl"caemia has nevertheless been preserved throughout the manuscript as these
terms have become $idel" adopted in the literature#
9
Historic( 1c2$ro/nd
prevalence of h"pogl"caemia (defined as serum glucose concentration
N*G mg 1GG ml
?1
as )#) per 1GGG total inborn live births! 12#2 per 1GGG lo$ birth
$eight infants# 6ubchenco 7 >ard (1971 arrived at much higher estimates=
11#)J of all nurser" admissions and 'G#*J of those premature or lo$ birth
$eight had blood sugar N*G mg 1GG ml
?1
if screened before feeding at D hours of
age#
.stimating the e&act freFuenc" of as"mptomatic h"pogl"caemia obviousl" begs
the Fuestion of numerical definition# This is addressed in /ection ) but it is $orth
noting at this %uncture that transitional h"pogl"caemia is a common problem
observed in both industrialised and less?developed countries# 4ormal studies in the
latter are fe$# Ho$ever! 0nderson et al (199* observed that *,J of
uncomplicated term infants born in <athmandu! 8epal sho$ed a blood glucose
concentration of N'#D mmol l
?1
during the first 2G hours of life# 0n approach
aimed first at the prevention of h"pogl"caemia! second at its reliable detection in
ne$borns at ris3 and third at appropriate treatment $hich $ill not be deleterious
to breastfeeding is thus of global importance#
.*) 8$ymptomatic8 and 8asymptomatic8 hypoglycaemia
+espite clinical characterisation of neonatal h"pogl"caemia on the basis of blood
glucose concentration! controvers" e&isted as to $hether h"pogl"caemia!
particularl" in the absence of clinical signs! cau)e+ or $as merel" a))ociate+ with
neurodevelopmental seFuelae# 6ong?term neurological seFuelae $ere identified in
up to *2J of those $ith s"mptomatic h"pogl"caemia and 'GJ of those $ith
as"mptomatic h"pogl"caemia (Ha$orth 7 Aid"asagar! 1971K Ha$orth 7 :c-ae!
19D2K though others could find no relationship (Griffiths 7 >r"ant! 1971#
(n a large retrospective case?control stud" <oivisto (197' and colleagues
follo$ed 121 cases of neonatal h"pogl"caemia (defined as a blood glucose
concentration of N*G mg dl
?1
for up to four "ears# The control series consisted of
2D concurrentl" treated as"mptomatic ne$borns $ith no h"pogl"caemia or
neonatal disease# 8inet"?four per cent of DD as"mptomatic h"pogl"caemia
sub%ects and 92J of controls $ere classified as developmentall" normal at follo$?
up# 0mong the ,2 $ho had suffered s"mptomatic h"pogl"caemia! onl" 2GJ of
those presenting $ith convulsions (, infants and ,,J of those $ith non?
convulsive s"mptoms $ere developmentall" normal# This stud" therefore
identified no important neurodevelopmental abnormalities in infants $ith
a)ymptomatic h"pogl"caemia# The authors stressed the tendenc" of s"mptomatic
h"pogl"caemia to present later in the clinical course than as"mptomatic# /imilar
conclusions $ere dra$n in a recentl" published (ndian follo$?up stud" of 1G7
cases of as"mptomatic or s"mptomatic neonatal h"pogl"caemia (/ingh et al!
1991#
5ildes et al (197) studied the effect of treatment on prognosis in a prospective
stud" of *9 cases# )1 controls $ere selected in the first $ee3 of life! matched as
far as possible for se&! $eight! gestation! ethnic group! mode of deliver"!
condition at birth! serum chemistr" and birth date# 0t follo$?up
(2 to 7 "ears of age BadeFuatel" treatedB h"pogl"caemia $as the )ole identifiable
factor associated $ith neurological seFuelae in onl" t$o cases# ;nfortunatel"!
despite strenuous efforts to match cases and controls prospectivel"! there $as a
13
stri3ing difference in the number of small for gestational age infants (cases 7'#'J!
controls ',#,J# This emphasises the $ea3ness of case?control methodolog" in
stud"ing $hether h"pogl"caemia itself affects outcome or is merel" a pro&" for
other ris3 factors# /inclair (1ornblath et al 199G has recentl" pointed out that all
studies to date have been too fla$ed to demonstrate definitive correlation
bet$een h"pogl"caemia and developmental outcome# 0 randomised intervention
stud" seems li3el" to be the onl" means of stud"ing this problem adeFuatel"#
.*, Neonatal hypoglycaemia# current problems
(ymptomatic hypoglycaemia is associated $ith a ris3 of long?term
neurodevelopmental seFuelae but evidence for a causative lin3 is $ea3#
1ontrovers" persists about the significance of a)ymptomatic hypoglycaemia for
several reasons# 4irst! glucose is onl" one of several brain fuels! and health" term
infants capable of mounting a counterregulator" response (/ection ' seem
unli3el" to develop seFuelae if as"mptomatic# 0 corollar" is that preterm infants
and infants that are small for gestational age (/G0 ma" be at greater ris3 of
seFuelae (6ucas et al! 19,, because of metabolic immaturit" (/ection '#
/econd! it seems li3el" that infants $ho develop s"mptomatic h"pogl"caemia
$ere h"pogl"caemic but as"mptomatic at an earlier stage of their clinical course#
-igorous! dichotomous classification of s"mptomatic and as"mptomatic
h"pogl"caemia is thus philosophicall" difficult#
11
G(/cose Homeostsis nd Met+o(ic Ad'ttion t 1irt)
)* &L7C4$! H4M!4$3A$2$ AN M!3A54L2C AAP3A324N A3 52R3H
)*. 3he fetal nutritional and metabolic environment
Glucose! amino acids and lactate are the principal energ" substrates during fetal
life! glucose alone providing about half the total energ" reFuirement# Glucose
crosses the placenta b" facilitated diffusion along a concentration gradient
bet$een maternal and fetal plasma! fetal plasma glucose concentrations being 7G?
,GJ of those in maternal venous plasma# 8et fetal glucose consumption is highl"
dependent upon both the maternal blood glucose concentration and the placental
concentration gradient but on average appro&imates 7 g 3g fetal $eight
?1
d
?1
(2 mg 3g
?1
min
?1
! $hich is close to the rate of endogenous glucose production
after birth# .nz"me s"stems involved in gluconeogenesis and gl"cogenol"sis are
present in the fetal liver! but remain inactive unless provo3ed b" e&treme maternal
starvation# Weight for $eight! fetal liver contains about three times more
gl"cogen than adult liver and hepatic gl"cogen stores at birth comprise about 1J
of the neonateCs energ" reserves at birth#
The rate of placental fatt" acid transport varies bet$een species in proportion to
adiposit" of the ne$born# 4at o&idation is believed Fuantitativel" less important
than amino acidEglucose o&idation! and rates of 3etone bod" production are lo$
during fetal life (Ha"! 1991# The fetal endocrine milieu is dominated b" insulin#
(nsulin does not cross the placenta! fetal secretion being influenced b"
concentrations of both glucose and amino acids in fetal plasma# The fetal insulin
a&is is therefore independent of the motherCs# The ?cells of the fetal pancreas
become responsive to glucose relativel" late in gestation and ?cell mass increases
mar3edl" in the last trimester of pregnanc"# (t has been speculated that this ma"
be a critical developmental period at $hich substrate provision programme)
pancreatic islet development irreversibl" influencing the metabolic response to
glucose in later life and predisposing to certain patterns of adult disease (Hales 7
>ar3er! 199'# (nsulin promotes anabolism in the fetus b" stimulating upta3e of
glucose into muscle and adipose tissue (Table 1# Thus the last trimester of
pregnanc" is a period of rapid fetal gro$th! particularl" deposition of fat in
adipose tissue# (n this $a"! energ" stores are laid do$n in preparation for birth#
3able .
Metabolic effects of insulin
(O indicates stimulation! ? indicates inhibition
Glucose upta3e into muscle
Glucose upta3e into adipose tissue
-elease of amino acids from muscle
-elease of fatt" acids from adipose tissue
Gluconeogenesis
<etogenesis
O
O
?
?
?
?
)*) 3he regulation of blood glucose concentration after birth
14
8ormall" blood glucose concentration is regulated $ithin a much narro$er range
than other metabolic fuels! var"ing onl" t$o to three?fold# >" comparison 3etone
bod" and non?esterified fatt" acid concentrations ma" var" ten to one hundred?
fold under different ph"siological conditions# This tight control of blood glucose
concentration during both the fed (or po)tpran+ial and fasted (or
po)tab)orptive states is accomplished b" balancing the utilisation of glucose in
tissues $ith endogenous glucose production# The liver is the principal site of
endogenous glucose production! though after prolonged fasting up to 1GJ of
circulating glucose ma" originate in the 3idne"# Glucose is produced b" gl"cogen
brea3do$n (glycogenoly)i) or is s"nthesised from gl"cerol! lactate! p"ruvate and
glucogenic amino acid precursors! of $hich alanine is Fuantitativel" most
important# The general term used to describe the processes b" $hich the bod"
ma3es glucose available in the fasted state is counterregulation#
'#'#1 ,lycogen metaboli)m# Gl"cogen ma" be s"nthesised either directl" from glucose
or indirectl" from other precursors such as lactate! p"ruvate and gl"cerol# The
balance bet$een gl"cogen s"nthesis and brea3do$n is determined b" the relative
activities of gl"cogen s"nthase and phosphor"lase respectivel"# 0 protein 3inase!
activated b" increased c0:5 concentrations in the hepatoc"te! simultaneousl"
activates hepatic phosphor"lase and inactivates gl"cogen s"nthase# Thus! a rise in
hepatoc"te c0:5 levels stimulates gl"cogen brea3do$nK a fall stimulates
gl"cogen s"nthesis#
1hanges in hepatoc"te c0:5 levels are effected b" the hormones $hich regulate
glucose metabolism# These fall into t$o groups= in)ulin and the so?called
counterregulatory hormone) (Tables 1 7 '#
3able )
Counterregulatory hormones
Glucagon
1atecholamines
1ortisol
Gro$th hormone
(nsulin is secreted in response to a rise in blood glucose concentrations#
Hepatoc"te c0:5 levels fall in the presence of insulin! thereb" stimulating
gl"cogen s"nthesis# The principal counterregulator" hormones are glucagon and
adrenaline# >oth increase hepatoc"te c0:5 levels and favour gl"cogen
brea3do$n# 0drenaline also promotes release of glucogenic substrates (lactate
and alanine from peripheral tissues through stimulation of peripheral ?receptors#
'#'#' ,luconeogene)i)# Glucose is s"nthesized from lactate or p"ruvate (some of $hich
is derived from alanine essentiall" b" the reversal of the gl"col"tic path$a"#
1ertain regulator" steps are sub%ect to substrate andEor endocrine activation and
inhibition# The" are= p"ruvate deh"drogenase! p"ruvate carbo&"lase!
phosphoenolp"ruvate carbo&"3inase (5.51<! p"ruvate 3inase and
fructose?1!D?biphosphatase# The precise details of activationEinhibition at each of
13
these steps are complicated (for revie$ see Gerich! 199* but for the purpose of
this discussion it is sufficient to note that the overall effect of insulin is to
inhibit gluconeogenesis9 whilst glucagon directly activates it# 0part from the
insulinEglucagon ratio! intracellular accumulation of precursors (e#g# p"ruvate!
acet"l 1o0 concentration and 80+HE80+
O
ratio are regulator" influences# 4at
and fatt" acids are not themselves converted to glucose# Ho$ever! fat o&idation
promotes gluconeogenesis b" increasing intracellular acet"l 1o0 concentration
and 80+HE80+
O
ratio# 0drenaline indirectl" stimulates gluconeogenesis b"
stimulating peripheral mobilisation of non?esterified fatt" acids from adipose
tissue and their subseFuent o&idation in the liver# 5lasma adrenaline
concentrations immediatel" after birth are higher than at an" other time of life!
inductive proof of this hormoneCs 3e" role in perinatal metabolic and cardio?
respirator" adaptation#
'#'#* -eripheral gluco)e utili)ation# :ost tissues! including brain! ta3e up glucose in
proportion to the concentration gradient across the cell membrane! but in muscle!
adipose tissue! and liver the process is insulin sensitive# (ntracellular glucose is
phosphor"lated to glucose?D?phosphate (GD5 through the action of he&o3inase#
When cells o&idise fat c"toplasmic glucose?D?phosphate (GD5 concentrations
increase! inhibiting he&o3inase and reducing the cellCs abilit" to BtrapB glucose b"
phosphor"lation# Thus provision of fat both reduces glucose upta3e into cells and
favours gluconeogenesis in the liver#
'#'#) .urnover of gluco)e: the balance between pro+uction an+ utili)ation# (n recent
"ears it has been possible to measure rates of glucose production in
ne$born infants using stable (non?radioactive isotopes of glucose labelled $ith
deuterium (
'
H or
1*
1 (D!D
'
H
'
glucose! 1?
1*
1 glucose and ;?
1*
1 glucose#
.&periments $ith
'
H tracers "ield estimates of glucose production about 12J
higher than those obtained $ith
1*
1 tracers! as some
1*
1 is rec"cled through the
1ori c"cle# ;sing D!D
'
H
'
glucose! >ier et al (1977 estimated the rate of glucose
production in infants over 1 da" old as )#*?,#2 mg 3g
?1
min
?1
# (n contrast!
<alhan et al (197D obtained a figure of *#,?)#9 mg 3g
?1
min
?1
using 1?
1*
1
glucose in ' hour old infants# Gluconeogenesis is certainl" demonstrable on the
second da" of life in health" term ne$borns# +enne 7 <alhan (19,D used
+?P;?
1*
1Q?glucose to measure glucose production rates on the second da" of life
in infants starved for 9 hours# The" estimated the proportion of glucose
manufactured from re?c"cled glucose (measured from
1*
1?1 enrichment as
appro&imatel" *DJ or 1#,7 G#7) mg 3g
?1
min
?1
of the total glucose production rate
of 2#G' G#)1 mg 3g
?1
min
?1
#
/ubseFuent studies using D!D
'
H
'
glucose have found comparable glucose
production rates in appropriate $eight for gestational age (0G0 preterm and
term infants (mean s#d#= *#2 G#) mg 3g
?1
min
?1
and *#2 G#* mg 3g
?1
min
?1
respectivel"# (n the same e&periment small for gestational age (/G0 infants
sho$ed higher rates of glucose production ()#* 1#G mg 3g
?1
min
?1
# (t has been
suggested that this reflects the higher brain= bod" mass ratio of /G0 babies
(<alhan et al! 19,D and that glucose reFuirements correlate more closel" $ith
brain than bod" $eight (>ier et al! 1977#
(nfusion of glucose into adults suppresses endogenous glucose production both
through a direct effect of glucose concentration and through enhancement of
1%
insulin secretion (see '#'#' above# The same phenomenon has been observed in
normal ne$born infants though the degree of suppression is ver" variable and less
mar3ed in sic3! stressed infants! particularl" those $ho are ver" preterm (1o$ett
et al 19,*K /unehag et al! 199)# This probabl" demonstrates variable e&pression
of the counterregulator" response in h"pogl"caemic and stressed ne$borns#
'#'#2 (ummary# :oment?to?moment endocrine control of blood glucose concentration
is achieved through the opposing actions of insulin and glucagon# 0drenaline
BboostsB the counterregulator" response during stress# Other hormones act
permissivel"K cortisol has little! short?term! direct effect on blood glucose
concentrations but the effect of glucagon is reduced in cortisol deficienc"#
/ubstrate concentrations directl" affect the rate at $hich gluconeogenesis
proceeds# 0dministration of glucose suppresses gluconeogenesis $hereas it is
activated b" lactate! p"ruvate and glucogenic amino acids# (ncreased o&idation of
non?esterified fatt" acids facilitates gluconeogenesis indirectl" in the liver b"
increasing acet"l 1o0 and 80+H concentrations# (t also reduces peripheral
glucose reFuirements#
)*, Metabolic events at birth# the role of insulin and substrates other than glucose
/n)ulin# 0t birth the ne$born must s$itch abruptl" from a state of net glucose
upta3e and gl"cogen s"nthesis to one of independent glucose production# The
maintenance of normogl"caemia depends upon adeFuac" of gl"cogen stores!
maturation of gl"cogenol"tic and gluconeogenic path$a"s! and an integrated
endocrine response# The endocrine events believed to trigger the release of
glucose and the mobilisation of fat from peripheral stores are an increase in
adrenaline secretion and a rapid fall in the insulin= glucagon ratio during the first
fe$ hours of life! attributed to both a fall in the plasma insulin concentration and a
surge in glucagon concentration (<torza et al! 19,2# Whether insulin
concentration does actuall" fall is still debated# Ha$don et al (199' $ere unable
to confirm this in a cross?sectional stud" of health" term and preterm neonates of
appropriate $eight for gestation# 0 methodological problem is the cross reaction
bet$een insulin! proinsulin! and other propeptides in radioimmunoassa"s# ;sing
highl" specific assa"s Ha$don et al (1992 found that insulin= glucose ratios
remain high in health" preterm infants $hilst proinsulin and *'?** split proinsulin
account for *)?7GJ of the total insulinEinsulin pro?peptide concentration# Health"
term infants have not been studied to date# :uch remains to be learnt about the
maturation of insulin and insulin pro?peptide secretion in the neonatal period and
its relevance to metabolic regulation#
'etabolic )ub)trate)$ +ata on metabolic substrate concentrations during earl"
postnatal adaptation in the human ne$born are relativel" fe$ and man" date from
the era in $hich earl" starvation $as fashionable and feeding (usuall" $ith
formula $as postponed for hours or da"s after birth (>eard et al0 19DDK :elichar
et al! 19D7K 5ersson 7 Gentz! 19DDK /tanle" et al! 1979K 0nda" et al! 19,1#
5rincipal findings of these studies $ere! first! that blood glucose concentration
falls $ith the duration of starvation and! second! that the concentrations of other
metabolic substrates (free fatt" acids! 3etone bodies and gl"cerol rise as blood
glucose concentration falls#
1,
4or e&ample! >eard et al (19DD alternatel" allocated term and preterm infants to
an Bearl" feedingB group (fed $ith formula from D hours of age and a group
fasted for 7' hours# :ean blood glucose concentration at 7' hours $as )G mg dl
?1
('#' mmol l
?1
in the fasted term infants! as compared to D, mg dl
?1
(*#, mmol l
?1

in the Bearl"?fedB group# 2,J of the fasted premature infants had a blood glucose
concentration of N'2 mg dl
?1
(1#) mmol l
?1
b" 7' hours of age! as compared to
onl" )J (1 infant among the earl"?fed groupK though no complications $ere
noted# The fasted group also sho$ed a reduced increment in blood glucose
concentration on in%ection of glucagon and adrenaline! suggesting a relative
reduction in their gl"cogen stores# 4ree fatt" acid concentrations nevertheless rose
in the fasted infants and over 2GJ of the fasted health" premature infants sho$ed
3etonuria b" ),?7' hours of age# 5ersson 7 Gentz (19DD similarl" noted
increases in free fatt" acid! gl"cerol and 3etone bod" levels among fasted term
infants# The highest values $ere noted in babies $ith the lo$est blood glucose
concentrations# (ncreases in the concentration of glucogenic precursors (alanine
and lactate and 3etone bod" concentrations $ith starvation at this time of life are
nevertheless smaller than those in older children $ith similarl" lo$ glucose levels
(/tanle" et al! 1979K 0nda" et al! 19,1# :oreover it is important to emphasise
that the BprematureB babies of thirt" "ears ago $ere probabl" more mature as a
group than preterm infants of toda" $hose adaptive capacit" ma" be even less
$ell developed#
:ore recentl" Ha$don et al (199' conducted a cross?sectional stud" of whole
bloo+ glucose concentration among 12D health" term babies# This $or3 is of
importance for man" reasons# 4irstl"! infants $ere +eman+1fe+# /econdl"!
breastfed babies $ere studied ()DJ of the sample# Thirdl"! metabolic substrates
other than glucose (gl"cerol! lactate! p"ruvate! alanine! non?esterified fatt" acids!
3etone bodies $ere measured# 4inall"! infants $ere studied throughout the first
$ee3 and not onl" in the first eight hours (/tanle" et al! 1979 to three da"s
(>eard et al! 19DDK 0nda" et al! 19,1# (t $as sho$n convincingl" that although
health" term breastfed babies had significantl" lo$er blood glucose concentrations
than those $ho $ere bottle?fed (breastfed= mean *#D mmol l
?1
! range 1#2?2#* mmol
l
?1
K bottle?fed= mean )#G mmol l
?1
! range '#2?D#' mmol l
?1
! their 3etone bod"
concentrations $ere elevated in response# 0 statisticall" significant negative
correlation bet$een PlogQ 3etone bod" and blood glucose concentration $as
measured at '?* da"s of age! but not $ithin the first ') hours or after * da"s#
6ucas et al (19,1 also found breastfed babies to have significantl" higher 3etone
bod" concentrations than formula?fed babies studied on the si&th da" of life#
/n )ummary! blood glucose concentration falls in babies $ho are not fed# >ut
health" term babies of appropriate $eight for gestation (0G0 mobilise
alternative metabolic substrates (free fatt" acids and 3etone bodies in response#
>reastfed babies as a group have lo$er blood glucose concentrations (referred to
later as Bsuc3ling h"pogl"caemiaB and higher 3etone bod" levels than those $ho
are bottle?fed# (t is not clear $hether this reflects specific promotion of
3etogenesis (e#g# b" breastmil3 fat or another mil3 component! or $hether it is
simpl" the result of differences in blood glucose concentrations and postprandial
increments in plasma insulin concentration#
)*- Abnormal glucose homeostasis
1-
'#)#1 -reterm babie)# (t has been ac3no$ledged for man" "ears that blood glucose
concentrations of preterm infants tend to be lo$er than those of term infants# This
$as considered Bph"siologicalB though there is no evidence that preterm infants
are more resistant to the effects of h"pogl"caemia than term infants#
-easons for the preterm infantCs propensit" to h"pogl"caemia are man"# 4irst!
energ" reserves at birth! both as liver gl"cogen and fat! are greatl" reduced#
+ifferences in fat content are particularl" importantK fat accounts for onl" 'J of
bod" $eight at ', $ee3s of gestation but about 1DJ at term# 0lthough fat is not
itself convertible to glucose! mobilisation and o&idation of fat reduces glucose
upta3e and o&idation (/ection '#'#*#
/econd! recent evidence indicates that preterm infants sho$ plasma insulin
concentrations greater than those of term infants $hen related to plasma glucose
concentration# (t appears that the elevated insulin= glucose ratio and relative
immaturit" of 3etogenesis persist for some months after birth (+eshpande et al!
199)# This phenomenon is une&plained though it is possible that the greater
protein inta3e of preterm infants! necessar" to match their faster gro$th potential!
is an insulinogenic stimulus# (t has been 3no$n for some "ears that insulin
secretion in term infants (as reflected b" 1?peptide e&cretion is modified b"
dietar" protein inta3e and related to plasma valine= gl"cine ratio (Ginsburg et al!
19,2#
Third! it is li3el" that gluconeogenic path$a"s are less mature than in term infants#
4or e&ample! e&pression of microsomal glucose?D?phosphatase $as reduced in
liver necrops" samples obtained from preterm infants up to 1 "ear of age and
ranging bet$een ')?*D $ee3s of gestation at birth# This enz"me catal"ses the
final step of both gl"cogenol"sis and gluconeogenesis (Hume 7 >urchell! 199*#
Given the increased ris3 of h"pogl"caemia associated $ith preterm birth! some
recent research has focused on the adeFuac" of the counterregulator" response#
Ha$don et al (199* studied D' clinicall" stable preterm babies (median gestation
*1 $ee3s! range '2?*D $ee3sK median birth $eight 17DG g! range ,*G?*'G* g#
8on?esterified fatt" acid and 3etone bod" concentrations of preterm infants $ere
significantl" lo$er than those of term infants# :oreover! preterm infants $ith lo$
blood glucose levels did not sho$ increased 3etone bod" concentrations as did
infants born at term# The range of gestational age in this stud" is remar3able# 0t
*D $ee3s of gestation a dramatic increase in 3etogenic potential appeared! but
this cross?sectional observational stud" does not ma3e clear $hether this is a
developmental event! or $hether it simpl" reflects differences in the clinical
management of babies N*D $ee3s of gestation# (t ma" be recalled (see /ection
'#* that >eard et al (19DD observed 3etonuria in over 2GJ of premature infants
after prolonged fasting (),?7' hours# Ho$ever! blood 3etone concentrations
$ere not measured#
/n )ummary! preterm infants sho$ an increased incidence of h"pogl"caemia and a
reduced capacit" to mobilise alternative metabolic fuels# 4rom the point of vie$
of managing breastfeeding in mildl" preterm infants (*'?*D $ee3s gestation!
more data on maturation of the counterregulator" response are reFuired if
e&cessive intervention is to be avoided#
17
'#)#' (mall for ge)tational age ((,2& infant)# This group has long been recognised to
be at increased ris3 of neonatal h"pogl"caemia (1ornblath et al! 1929# :ore
recentl" h"pogl"caemia has been detected during fetal life among infants small for
gestational age at birth# 4actors $hich ma" account for this include a high
brain=bod" mass ratio ($ith corresponding increase in glucose consumption!
reduced fat stores! failure of counterregulation (including dela"ed maturation of
gluconeogenesis and h"perinsulinism#
<alhan et al (19,D noted /G0 infants in the basal (fasting state on the first
da" of life to have significantl" higher rates of endogenous glucose production
()#'2 G#9, mg 3g
?1
min
?1
than appropriate $eight for gestational age (0G0
infants (*#2* G#*' mg 3g
?1
min
?1
K p NG#G*# (t $as suggested that this reflected the
greater brain $eight of /G0 infants relative to 0G0 infants# /everal studies have
sho$n that /G0 infants! $hen compared to 0G0 infants! have increased plasma
concentrations of glucogenic substrate (6indblad! 197GK 6indblad et al 197GK
Ha"mond et al! 197)K :est"an et al! 1972# 0mongst the glucogenic substrates!
alanine and lactate levels particularl" $ere increased# When alanine is infused into
/G0 infants it disappears more slo$l" than in normal! 0G0 full?term ne$borns
(:est"an et al! 1972 and has less effect on blood glucose concentrations (/ann
et al! 197,# These changes are most mar3ed in the earl" hours of life! and it has
been suggested that the" reflect a dela" in the maturation of glucogenic path$a"s!
in particular the induction of phosphoenolp"ruvate carbo&"3inase (5.51<
(Ha"mond et al! 197)# Ha$don 7 Ward 5latt (199*! in a longitudinal stud" of
** /G0 infants throughout the first postnatal $ee3! found that increased blood
levels of lactate and other total gluconeogenic substrates persisted until the fourth
postnatal da" in preterm /G0 infants but fell $ithin the first ') hours in term
/G0 infants thereafter being lower than those of 0G0 infants# This seems
consistent $ith the h"pothesis that elevated concentrations of gluconeogenic
substrates reflect dela"ed maturation of gluconeogenic path$a"s in /G0 infants!
particularl" those born preterm#
0t birth! 3etone bod" concentrations of /G0 and 0G0 infants do not appear to
differK though b" ') hours of age (Ha"mond et al! 197)! and throughout the first
postnatal $ee3 (Ha$don 7 Ward 5latt! 199* 3etone bod" levels of both term
and preterm /G0 infants remain lo$ relative to those seen in 0G0 infants at
eFuivalent blood glucose concentrations# Whether this reflects an inabilit" of the
/G0 infant to mount a 3etogenic response! or %ust more aggressive attention to
nutritional management and prevention of h"pogl"caemia among the infants
studied! is open to debate# (n the studies of Ha$don 7 Ward 5latt (199* fe$er
/G0 than 0G0 infants had a blood glucose concentration N* mmol l
?1
#
There is some evidence that /G0 infants $ith abnormal metabolic adaptation are
those in $hom +oppler studies identif" abnormal end diastolic flo$ velocities
(.+A in the umbilical arter"# Ha$don et al (199' found that a group of 11
fetuses $ith absent .+A sho$ed lo$er blood glucose and free fatt" acid
concentrations in the first si& hours of life than a group of 1) control /G0 infants
$ith normal .+A# (n this small stud"! the group $ith absent .+A had lo$er
mean birth $eight (12'2 g! range DD,?'G'G g v)$ 19G* g! ,29?''9D gK though
the difference did not attain statistical significance (p M G#GD2#
10
.ndocrine adaptation in /G0 babies has also been studied b" several authors#
:ost have sho$n no differences bet$een 0G0 and /G0 infants in insulin and
glucagon concentrations! though the range seen in both populations is $ide#
8evertheless )ome /G0 babies appear to have both high plasma insulin
concentrations and high glucose reFuirements! consistent $ith h"perinsulinism
(6e+une! 197'K 1ollins 7 6eonard! 19,)K 1ollins et al! 199G# 0 prospective
stud" of /G0 infants admitted to a single neonatal unit over one "ear found that
1G of '7 became h"pogl"caemic and that half of them had inappropriatel" high
plasma insulin concentration at the time of h"pogl"caemia (1ollins et al! 199G#
0lthough the assa" used did not discriminate insulin from its propeptides! and
hence ma" have overestimated the BtrueB insulin concentration (Ha$don et al!
1992! lo$ plasma free fatt" acid concentrations and high glucose reFuirements
(e&ceeding 1G mg 3g
?1
min
?1
in t$o infants provided functional evidence of
h"perinsulinism#
/ome of the babies also sho$ed lo$ plasma glucagon concentrations! raising the
possibilit" that failure of the glucagon surge after birth pla"s as great a part in the
aetiolog" of h"pogl"caemia in /G0 infants as does h"perinsulinism (:ehta!
1991# :est"an et al (197D studied this possibilit" b" infusing glucagon into
normogl"caemic and h"pogl"caemic /G0 infants# Onl" the former group
responded b" sho$ing a reduction in concentration of glucogenic amino acids# (t
$as suggested that /G0 infants ma" sho$ glucagon resistance (see /ection
7#*#1#
'#)#* (tre)) hypoglycaemia# H"pogl"caemia ma" be present in a number of neonatal
conditions associated $ith severe stress# The most common are sepsis and
perinatal asph"&ia! but it is also seen in congenital heart disease (heart failure and
severe c"anotic heart disease and neonatal cold in%ur" $ith fat necrosis#
0lthough the catecholamine response to stress is a central feature of
counterregulation! peripheral circulator" failure in sepsis and asph"&ia ma" lead to
both reduced mobilisation of substrate from the peripher" and accumulation of
lactate in the presence of anaerobic gl"col"sis# This leads to e&haustion of liver
gl"cogen and reduced capacit" for gluconeogenesis $hich ma" be compounded
b" ano&ic liver in%ur"# H"perinsulinism and increased insulin sensitivit" ma" also
be present in these circumstances#
'#)#) .ran)ient hyperin)ulini)m# H"pogl"caemia associated $ith transient
h"perinsulinism is seen most commonl" among infants born to diabetic mothers# (t
is also seen in infants affected b" er"throblastosis fetalis# (atrogenic factors!
including the use of glucose infusions in labour and maternal administration of
s"mpathomimetics! ma" give rise to maternal h"pergl"caemia and associated
fetal h"perinsulinism# 6ess commonl"! h"perinsulinism is associated $ith the rare
>ec3$ith?Wiedemann s"ndrome or ma" be idiopathic#
The macrosomic infant of the diabetic mother ((+: has a characteristic habitus#
Whereas the infant $ho is simpl" large for dates has proportionate increases in
both brain size and abdominal circumference! the macrosomic (+: has increased
muscle! fat and liver mass as might be predicted from the 3no$n effects of insulin
(Table 1# Thus! in fetal life the (+: has an increase in abdominal circumference=
head circumference ratio (4raser! 199)# 4or man" "ears fetal h"perinsulinism has
been ascribed to maternal! and conseFuent fetal! h"pergl"caemia (5edersen et al!
19
192)# :ore recentl" it has been speculated that other factors! including amino
acid concentrations! must operate as mid?trimester human pancreatic tissue sho$s
little insulin response to glucose concentration in vitro (:ilner et al! 197'# The
ris3 of h"pogl"caemia in the neonatal period (4arFuhar! 192D ma" be reduced b"
careful control of maternal blood glucose concentration during pregnanc" but is
still greater in (+: of appropriate $eight for gestational age than in the normal
neonatal population# H"perinsulinism leads to reduced concentrations of free fatt"
acids and 3etone bodies in association $ith h"pogl"caemia! $hich reflects both an
increased rate of glucose upta3e and a reduced rate of glucose production
(<alhan et al! 1977# 0 reduced postnatal glucagon surge appears to accompan"
the h"perinsulinism (Williams et al! 1979#
/ome aspects of obstetric management ma" result in transient h"perinsulinism and
h"pogl"caemia among other$ise normal infants# 6ucas et al (19,G found that
intravenous infusion of R1G g glucose h
?1
during labour $as associated $ith
significantl" increased cord blood insulin concentration# /ubseFuent randomised
trials investigating the effect on blood glucose concentrations and incidence of
h"pogl"caemia in the ne$born have been revie$ed b" +iGiacomo 7 Ha" (199'#
When mothers $ere infused $ith R'2 g glucose h
?1
in the ' hours prior to
deliver" there $as a 17J mean increase (92J 1( 2! *G in the incidence of
h"pogl"caemia (blood glucose N'#' mmol l
?1
# >lood glucose in the bab" $as a
mean G#, mmol l
?1
(92J 1( G#2! 1#1 lo$er at ' hours of age than in babies born
to mothers $ho had received no glucose# The difference at 1 hour of age $as not
statisticall" significant# /maller differences in ' hour blood glucose
concentrations $ere also apparent in the bab" even $hen N'2 g glucose h
?1
had
been infused (mean G#) mmol l
?1
! 92J 1( G! G#,! though the incidence of
h"pogl"caemia $as not significantl" different (mean odds ratio '#D! 92J 1( G#D1!
11#*)#
>oth prolonged oral (.pstein et al! 1979! and short?term intravenous!
administration of ?agonists (5rociano" 7 5inheiro! 19,' used to suppress
preterm labour have been associated $ith increased cord plasma insulin
concentrations# This ma" be the result of both transplacental passage of the drug
and the presence of h"pergl"caemia in the mother (Thomas et al! 1977#
.pstein et al (1979 noted transient h"pogl"caemia in the bab"! but @ouppila et al
(19,G noted an increa)e in the bab"Cs blood glucose concentration $hen
fenoterol $as administered briefl" to suppress uterine contractions before
caesarian section#
'#)#2 -er)i)tent hyperin)ulini)m0 en+ocrine +i)or+er) an+ inborn error) of
metaboli)m# 8eonatal h"pogl"caemia $hich persists or recurs after the first fe$
da"s of life should raise the diagnostic possibilit" of an endocrine disorder or
inborn error of metabolism (Table *#
0mong the more common endocrine disorders are adrenocortical insufficienc"!
h"popituitarism! and the B>?cell d"sregulation s"ndromeB (nesidioblastosis# The
first t$o ma" be associated $ith abnormalities of the e&ternal genitalia# /epto?
optic d"splasia ma" also be associated $ith h"popituitarism# (nfants $ith organic
h"perinsulinism have a habitus resembling the (+: in the absence of features of
gestational diabetes mellitus in the mother# (nfants $ith congenital or acFuired
glucagon deficienc" also sho$ severe and protracted h"pogl"caemia (Aidnes 7
43
O"saeter 1977! <ollee et al 197,! Gotlin 7 /ilver 197G! illustrating $ell the
importance of this hormone in perinatal adaptation#
(nborn errors of metabolism $hich ma" present as h"pogl"caemia in the neonatal
period include gl"cogen storage diseases! defects of ?o&idation (dicarbo&"lic
aciduria! defects of gluconeogenesis (e#g fructose?1!D?diphosphatase deficienc"!
and some defects of amino acid metabolism#
The diagnosis and treatment of these conditions is be"ond the scope of this $or3!
and the reader is! therefore! referred to recent revie$ articles (/audubra" et al!
199GK 0"nsle"?Green! 1991K 4ernandes 7 >erger! 199*K 1ornblath 7 /ch$artz!
199*#
41
3able ,
Causes of recurrent and persistent neonatal hypoglycaemia
(1ornblath 7 /ch$artz! 199*
!ndocrine deficiency
H"popituitarism
Gro$th hormone deficienc"
Glucagon deficienc"
1ortisol deficienc" E01TH unresponsiveness
Hyperinsulinism
>ec3$ith?Wiedemann s"ndrome
> cell d"sregulation s"ndrome
isorders of carbohydrate metabolism
Gl"cogen storage disease T"pe (
4ructose intolerance
Galactosaemia
Gl"cogen s"nthase deficienc"
4ructose?1!D?diphosphatase deficienc"
isorders of amino acid metabolism
:aple s"rup urine disease
5ropionic acidaemia
:eth"lmalonic acidaemia
T"rosinaemia
*?h"dro&" *?meth"lglutar"l 1o0 l"ase deficienc"
isorders of fatty acid metabolism
:edium chain ac"l 1o0 deh"drogenase deficienc"
6ong chain ac"l 1o0 deh"drogenase deficienc"
44
,* !::!C3$ 4: H;P4&L;CA!M2A 4N 3H! C!N3RAL N!R(47$ $;$3!M
+espite the lac3 of clinical evidence in human infants that h"pogl"caemia is
cau)al in inducing seFuelae of s"mptomatic h"pogl"caemia (/ection1! evidence
from animal studies and po)t mortem studies of human infants indicate that severe
and prolonged h"pogl"caemia can be correlated $ith particular neuroanatomical
patterns of brain damage# (n recent "ears much has also been learnt about the
e&citoto&ic mechanisms $hich lead to in%ur" in h"pogl"caemia#
,*. Pathology of brain damage associated with hypoglycaemia
The cerebral corte&! hippocampus! and caudate nucleus are the regions principall"
affected b" e&perimentall"?induced h"pogl"caemia sufficient to create an
isoelectric ..G# This differs from the distribution of h"po&icEischaemic damageK
the dentate g"rus is particularl" rarel" affected b" ischaemia but characteristicall"
damaged in h"pogl"caemia# >rain stem and posterior fossa structures are least
affected b" h"pogl"caemia (revie$ed b" 0uer 7 /ies%o! 19,,K 0uer 7 /ies%o!
199*#
(t is no$ clear that neuronal death attributable to h"pogl"caemia is not simpl" the
result of metabolic attrition but an active e*citoto*ic process# .lectron
microscop" reveals the a&on?sparing! dendritic lesion characteristic of this
process# ;nderstanding the nature of the cellular in%ur" has potential importance
in the prevention of h"pogl"caemic brain damage for pre?treatment $ith
n1 meth"l?d?aspartate (N:+0 antagonist drugs (notabl" dizocilpine maleate has
been found protective in both cell culture and animal models (revie$ed b"
5apagapiou 7 0uer! 199GK 0uer 7 /ies%o! 199*#
,*) Cerebral defences in hypoglycaemia
2lternative )ub)trate)$ H"pogl"caemia reduces cerebral glucose consumption in
ne$born animals $ithout a commensurate reduction in cerebral o&"gen
consumption# This suggests that alternative metabolic fuels are utilised# The
primar" candidates are lactate and 3etone bodies# 6actate reverses stupor
associated $ith insulin induced h"pogl"caemia in suc3ling?$eaning mice
(Thurston et al! 19,* and has been sho$n to serve as a cerebral fuel in other
species of ne$born animals (Soung et al! 1991# (nsulin?induced h"pogl"caemia
(blood glucose NG#2 mmol l
?1
in ne$born dogs $as accompanied b" a more than
2GJ fall in cerebral metabolic rate for glucose (1:-
gluc
! and a more than 12?fold
rise in cerebral metabolic rate for lactate (1:-
lac
$hich became the predominant
metabolic fuel in this h"po3etonaemic situation (Hernandez et al! 19,G# -ecent
studies in h"pogl"caemic! diabetic! human adults have also demonstrated that the
brain consumes lactate (0miel! 199)# 6actic acidosis is believed to be protective
during the profound and protracted episodes of h"pogl"caemia observed in
infants $ith gl"cogen storage disease T"pe?( (glucose?D?phosphatase deficienc"
(4ernandes et al! 19,)#
The ne$bornCs capacit" to promote 3etogenesis in the face of Bsuc3ling
h"pogl"caemiaB has been described previousl" (/ection '#*# 8e$born term
infants rapidl" increase 3etone bod" flu& to rates observed in adults! but onl" after
several da"s of fasting! flu& (i#e# rate of 3etone bod" turnover being correlated
$ith plasma 3etone bod" concentration (>ougneres et al! 19,D# 4urthermore!
43
E!!ects o! H&'o$(&cemi on t)e Centr( Ner#o/s S&stem
free fatt" acid! gl"cerol (5ersson 7 Gentz! 19DD and 3etone bod" concentrations
(Ha$don et al! 199' are inversel" related to blood glucose concentration#
.&tensive evidence from animal species (+ombro$s3i et al! 19,9K 8ehlig et al!
199*! including primates (6evits3" et al! 1977! demonstrates that 3etone bodies
are important cerebral energ" substrates# O$en et al (19D7 first demonstrated
that the human brain consumes 3etones# The" catheterised the cerebral vessels of
three adults and found that 3etone bodies became the predominant cerebral fuel
$ith prolonged (2?D $ee3s starvation# /imilar catheterisation studies in infants
(mean age 2 months undergoing elective surger" demonstrated higher rates of
3etone bod" upta3e than those measured in adults (/ettergren et al! 197D#
.nz"me s"stems necessar" for the metabolism of 3etones are present in human
fetal brain (5atel et al! 1972 and upta3e of 3etone bodies has been demonstrated
in perfused brain obtained from fetuses aborted at 1'?'1 $ee3s of gestation
(0dam et al! 1972# <raus et al (197) studied the cerebral arteriovenous
difference (0A in 3etone bod" concentration among 11 preterm and ' term
ne$borns fasted for D hours# 0A and 3etone bod" concentration $ere positivel"
correlated $ith cerebral upta3e of 3etone bodies! accounting for around 1GJ of
overall brain energ" balance# (n these studies there $as net cerebral pro+uction of
lactate and p"ruvate! suggesting that 3etone bodies are more important than
lactate as an alternative cerebral fuel to glucose#
erebral bloo+ flow# (n full"?gro$n animals local cerebral blood flo$ (61>4 is
$ell matched to the local cerebral metabolic rate for glucose (1:-
gluc
# (n
ne$born dogs total cerebral blood flo$ $as conserved even at blood glucose
concentrations NG#2 mmol l
?1
(Hernandez et al! 19,G# Ho$ever! the
developmental time course of the mechanisms responsible ma" var" from species
to species (revie$ed b" 8ehlig! 199* and e&trapolation to human neonates must
be cautious# 5r"ds et al (19,,! 199G identified increased plasma adrenaline
concentrations and cerebral blood flo$ (measured using
1**
Te in preterm infants
$hose blood glucose fell belo$ 1#7 mmol l
?1
# (n further studies a fall in cerebral
blood volume (measured using near infra?red spectroscop" accompanied
restoration of normal blood glucose concentration in h"pogl"caemic preterm
infants (/3ov 7 5r"ds! 199'# The authors speculated that the speed of change
reflects the e&istence of a cerebral blood glucose BsensorB $hich maintains
cerebral glucose suppl" b" recruitment of underperfused capillaries#
,*, $ummary
H"pogl"caemic brain damage differs from ischaemic brain damage in both the
distribution and the mechanism of cellular in%ur"# The ne$born sho$s adaptive
responses to h"pogl"caemia $hich ma" be protective to cerebral metabolism#
These responses include an increase in cerebral blood flo$ and the use of
alternative metabolic substrates! particularl" 3etone bodies and lactate# (ncreasing
understanding of the mechanism of h"pogl"caemic brain in%ur" indicates that
N:+0 antagonists ma" have a future clinical role in cerebral protection#
4%
-* !:2N2324N 4: H;P4&L;CA!M2A
1onfusion about the definition of Bneonatal h"pogl"caemiaB $as $ell documented
b" <oh et al (19,, $ho surve"ed paediatric te&tboo3s and the opinion of
consultant paediatricians in the ;nited <ingdom (Table )# /ubseFuent revie$
articles have restated the controvers" (1ornblath et al! 199GK 0"nsle"?Green!
1991K Ward 5latt! 1991K Ward 5latt 7 Ha$don! 199*K /ch$artz! 1991K
1ornblath 7 /ch$artz! 199*#
3able -
$ome definitions of neonatal hypoglycaemia
Te&tboo3s 5aediatricians
Term 0G0
5reterm or /G0
N 1#7 (N 1#G ? '#2
N 1#1 (N 1#G ? '#2
N '#G ( N 1#G ? N )#G
N 1#1 ( N 1#G ? N )#G
Table sho$s modal value (range in parentheses for blood glucose concentration (mmol l
?1
defined as neonatal
h"pogl"caemia b" paediatric te&tboo3s or practising paediatricians (<oh et al! 19,,#
0pproaches to defining abnormall" lo$ blood glucose concentration have
included= statistical ()#1! metabolic ()#'! neuroph"siological ()#*!
neurodevelopmental ()#)#
-*. $tatistical definition
(n general terms a Blo$B value for an" normall" distributed biochemical variable is
defined as a value belo$ ' standard deviations from the mean for a health"
population# ;nfortunatel" this approach has man" problems $here blood glucose
is concerned#
4irst! the result is dependent upon the source of the blood sample! the assa"
method! and $hether blood or plasma glucose concentration is determined# These
aspects are discussed further in 1hapter 2# /econd! earl" feeding schedules have a
prominent effect on blood glucose concentrations but have changed a great deal
since earl" studies (1ornblath 7 -eisner! 19D2K 1hance 7 >o$er! 19DDK
6ubchenco 7 >ard! 1971K 4luge! 197)# .ven no$ the" var" greatl" from
hospital to hospital and fe$ breastfed infants have been studied (Ha$don et al!
199'K 0nderson et al! 199*# Third! there is a problem in defining $hat is meant
b" a Bnormal health" term bab"B in this conte&tK in one stud" (/e&son! 19,) 7'J
of inborn babies had one or more of the Bris3 factorsB for h"pogl"caemia set out
b" 1ornblath 7 /ch$artz (197D# 4ourth! there is an ethical dilemma over
longitudinal blood sampling of health" babies simpl" to define a BnormalB
biochemical range# Thus the onl" available data for breastfed babies are cross?
sectional (Ha$don et al! 199'#
1ornblath 7 -eisner (19D2 first published data on blood glucose concentrations
in normal ne$borns# The" found that 92J of values among term infants $ere
R*G mg dl
?1
and 9,#)J of values in BprematureB infants R'G mg dl
?1
# The"
4,
De!inition o! H&'o$(&cemi
defined h"pogl"caemia in Bfull?sizeB term infants as a blood glucose value belo$
*G mg dl
?1
in the first ), hours and belo$ )G?2G mg dl
?1
after ), hours of age#
/G0 babies $ere not considered as a specific group# H"pogl"caemia among lo$
birth $eight babies $as defined as N'G mg dl
?1
# These values dominated opinion
over the management of neonatal h"pogl"caemia for man" "ears# 4urthermore!
the acceptance of a lo$er threshold concentration for smaller babies has onl" been
challenged relativel" recentl"#
.arl" feeding $as commonl" discouraged in the era of this stud" (1ornblath 7
-eisner! 19D2# /rinivasan et al (19,D have more recentl" published pla)ma
3
glucose concentrations of *)) health" full?term! appropriate $eight for
gestational age (0G0 infants# :ean and 92J confidence intervals (92J 1(
$ere calculated from a mi&ture of serial and cross?sectional data# The lo$er
estimate of 92J 1( for cord samples $as *#* mmol l
?1
! falling to 1#) mmol l
?1
('D
mg dl
?1
at one hour of age# 0fter t$o hours it e&ceeded '#* mmol l
?1
()' mg dl
?1
#
The applicabilit" of even these data to the normal! breastfed! ne$born bab" is
Fuestionable for the earl" care of the infants studied is described as follo$s=
B0ll neonates $ere admitted to an observation nurser" $here $eight!
temperature and other vital signs $ere recorded# The infant $as placed under
a servo?controlled radiant $armer to maintain s3in temperature at *D#2
o
1#
/3in care and bath $ere given after stabilisation of core temperature# 0ll
infants $ere fed 'G caloriesEoz formula at * to ) hours of ageK after feeding!
the infants $ere transferred to their respective nurseries and fed ever" )
hoursK 1G?12J of the infants $ere breastfed#B
Hec3 7 .renburg (19,7 made longitudinal measurements of serum glucose
concentration in D) breastfed and 2G bottle?fed term infants during the first ),
hours of life# >oth groups appear to have been fed first at ' hours of age and then
at BscheduledB *?) hour intervals# 0n unspecified number of the breastfed infants
$ere given $ater or formula supplements (though not before blood sampling#
4ifth centile blood glucose concentrations for the combined breastfed and bottle?
fed groups $ere lo$est at D?1' hours of age (1#9 mmol l
?1
! rising to '#7 mmol l
?1
at ), hours# Aalues N'#' mmol l
?1
$ere obtained in 1DJ of the sample studied#
(nterestingl" the mean serum glucose concentration of bottle?fed babies $as
G#'' mmol l
?1
lower than that of the breastfed at 2?D hours of age# This statisticall"
significant difference ma" have been attributable to higher postprandial insulin
levels in the bottle?fed babies (6ucas et al! 19,1#
+ata published b" Ha$don et al (199' have been discussed in a previous section
('#*# These authors measured cross?sectionall" a number of metabolic substrates!
not %ust glucose! among health"! term! demand?breastfed and bottle?fed infants#
The paper provides limited information about the management of breastfeeding in
the infants studied! stating onl" that the infants $ere Bdemand?fedB# 8o
supplements of $ater or formula $ere given (@: Ha$don! personal
communication# Wide variation in both blood glucose concentrations and those
of other substrates prompted the authors to highlight a final problem in defining
hypoglycaemia for the purpose of clinical management=
3
;suall" 12?'GJ higher than blood glucose concentrations#
/ection 2#1#2#
4-
B###factors other than absolute blood glucose concentration are important in the
neonatal period and! $hile guidelines are important for clinical management!
rigid definitions Pof h"pogl"caemiaQ are inadeFuate and should be avoided#
The influence of gestational age! feeding practices and counterregulator"
abilit"#####must be considered in the interpretation of neonatal metabolic
data#B
/n )ummary! changing care practices account for the $ide variet" of threshold
plasma and blood glucose concentrations used in the past to define
Bh"pogl"caemiaB statisticall"# There are ver" fe$ data on breastfed babies# :ore
recent studies of the part pla"ed b" substrates other than glucose in perinatal
metabolic adaptation suggest that the Fuest to identif" a BsafeB blood glucose
level b" defining a BnormalB range is not appropriate#
-*) Metabolic definition
(f glucose is vie$ed as the primar" metabolic fuel! does the glucose concentration
at $hich the counterregulator" response becomes activated indicate a BsafeB
valueU 0t present such a figure cannot be identified from the limited published
dataK fe$ studies have measured concentrations of metabolic substrates other than
glucose and variabilit" in the concentration of some! for e&ample 3etone bodies!
appears even greater than that of glucose#
:etabolic studies nevertheless ma3e one essential point about the definition of
h"pogl"caemia# 1ounterregulator" responses differ significantl" bet$een term and
preterm infants (Ha$don et al! 199'! suggesting that the threshold for a BsafeB
blood glucose concentration in the preterm infant is higher than that for a term
infant and not lo$er as implied b" earlier data (1ornblath 7 -eisner! 19D2#
-*, Neurophysiological definition
(f the ultimate goal of identif"ing and treating h"pogl"caemia is the maintenance
of normal cerebral metabolism! can a threshold blood glucose concentration
associated $ith disturbed neuroph"siological function be identifiedU
<oh et al (19,, studied latenc" of the auditor" evo3ed response $aveform
(0.5Cs among 17 children! some of $hom $ere spontaneousl" h"pogl"caemic
$hilst others $ere undergoing insulin?induced h"pogl"caemia stress testing#
0bnormalities $ere identified in some $hen blood glucose concentration fell
belo$ '#D mmol l
?1
but generalisation to the health" ne$born is ver" difficult for
t$o reasons# 4irst! onl" five of the sub%ects $ere ne$born babies# /econd! the
infants $ere relativel" h"po3etonaemic and conseFuentl" deprived of alternative
cerebral fuels (/ection *#* unli3e the health" breastfed infant# (t is also important
to note that the electroph"siological abnormalities identified $ere not permanent#
Others have failed to observe an effect of h"pogl"caemia on 0.5Cs in the
ne$born (Greisen 7 5r"ds! 19,9# 4urthermore! 5r"ds et al (19,, $ere unable
to identif" abnormalities of either the amplitude?integrated ..G signal or of single
flash visual evo3ed potentials (A.5Cs among nine h"pogl"caemic preterm infants
(mean gestational age *G#, $ee3s! range 'D?*) $ee3s# >lood glucose
concentrations at the time of stud" ranged from NG#2 mmol l
?1
(five infants to 1#2
mmol l
?1
#
47
De!inition o! H&'o$(&cemi
/n )ummary! current published evidence correlating neuroph"siological
disturbance $ith blood glucose concentration is eFuivocal and based on too fe$
observations to set a BsafeB threshold for either term or preterm infants#
-*- Neurodevelopmental definition
The ma%orit" of studies e&amining neurodevelopmental prognosis after
s"mptomatic or as"mptomatic h"pogl"caemia have compared control sub%ects
$ith infants in $hom blood glucose concentration fell belo$ a defined value
(/ection 1#'# ;sing a different approach 6ucas et al (19,, correlated plasma
glucose concentration $ith outcome in a large stud" of DD1 preterm infants
$eighing N1,2G g at birth# >a"le" motor and mental developmental scores
ascertained blindl" at 1, months of age $ere regressed upon lo$est recorded
glucose concentrations bet$een G#2 and )#G mmol l
?1
ad%usting for se&! gestational
age! birth $eight! da"s of ventilation and other identifiable perinatal and social
ris3 factors# :a&imum regression coefficient for plasma glucose concentration
and >a"le" scores $as observed at a threshold value of '#2 mmol l
?1
but no
correlation $ith outcome $as evident for plasma glucose concentrations R)#G
mmol l
?1
# /cores $ere also significantl" correlated $ith logarithm of number of
da"s on $hich plasma glucose levels N'#D mmol l
?1
$ere recorded# 4reFuent
BmoderateB h"pogl"caemia (plasma glucose N'#D mmol l
?1
$as more strongl"
associated $ith developmental deficit than more severe but less freFuent
h"pogl"caemia# 6arge differences $ere seen bet$een eugl"caemic infants and
those in $hom plasma glucose fell belo$ '#D mmol l
?1
on five or more! not
necessaril" consecutive! da"s# :ean (/. scores in these respective groups for the
>a"le" motor developmental inde& $ere 9D#1 (1#* v ,)#) (*#' (pNG#GG1 and
1G'#G (1#2 v ,2#D (*#7 (p NG#GG2 for mental development# 4urthermore! the
ris3 of neurodevelopmental impairment (defined as cerebral pals" or >a"le"
motorEmental development score N7G for infants $hose plasma glucose fell
belo$ '#D mmol l
?1
on five da"s or more $as *#2 (92J 1( 1#*?9#)! pNG#G'
relative to the ris3 for those in $hom h"pogl"caemia $as not recorded#
This stud" is notable for its large sample size and unparalleled statistical po$er#
8evertheless! it has a number of limitations as a guide to BsafeB plasma glucose
concentrations# 4irst! it applies onl" to preterm infants and there is increasing
evidence that the immature counterregulator" response of this group might ma3e
them more vulnerable to effects of h"pogl"caemia (/ection '#)#1# /econd! it is
important to reiterate (/ection 1#* that evidence of an association bet$een
h"pogl"caemia and neurodevelopmental outcome in studies of this t"pe ma" not
reflect causation# H"pogl"caemia ma" merel" have acted as a pro&" for other
unidentified ris3 factors not entered into the multiple regression model# (t cannot
be assumed that maintenance of a plasma glucose concentration R'#2 mmol l
?1
$ould have prevented neurodevelopmental seFuelae#
-*0 $ummary
There are insufficient data to define a normal range for blood glucose values in
health" term breastfed babies# The fe$ studies $hich have e&amined this problem
have not given detailed descriptions of breastfeeding management# .ven if a
normal range of blood glucose concentrations could be set it $ould not establish a
40
threshold blood glucose level at $hich to initiate treatment in the as"mptomatic
term bab"! because concentrations of alternative cerebral fuels (particularl"
3etone bodies! fatt" acids and lactate remain un3no$n# Glucose concentration is
onl" one piece in a comple& metabolic %igsa$ and its significance cannot be
determined in isolation#
(n the case of s"mptomatic term babies and preterm babies there is more room for
caution# 6imited data suggest both that 3etogenesis is constrained in preterm
infants (/ection '#)K /ection )#' and that presence of a plasma glucose
concentration N'#D mmol l
?1
in this group is associated $ith adverse
neurodevelopmental outcome (/ection )#)# The neurodevelopmental outcome of
s"mptomatic term babies $ith h"pogl"caemia is also $orse than in those $ho are
as"mptomatic# Whilst these associations are not evidence of a causative lin3! it
seems $ise to adopt a cautious approach in the presence of s"mptoms and rapidl"
institute treatment to increase the blood glucose concentration regardless of a
measured value! as no definite threshold can be set#
49
Screenin$
0* $CR!!N2N&
The development of reagent strip blood glucose tests in the 197GCs facilitated the
practice of screening for h"pogl"caemia in ne$born infants# Ho$ reliable are
these tests! and ho$ %ustifiable is screeningU
0*. Methods for measuring blood<plasma glucose concentration
2#1#1 Re+uctiometric metho+)# Traditional methods for measurement of blood glucose
depended on the reducing propert" of glucose# 0n e&ample is the ferric"anide
method $hich can be adapted for use on an 0utoanal"ser# These methods
measure total reducing sugar concentrations# The difference bet$een total
reducing sugar and glucose concentrations is generall" unimportant at high
glucose concentrations but becomes clinicall" significant at lo$ blood glucose
concentrations# 0 preliminar" sample dial"sis step in the full" automated
ferric"anide method circumvents this problem# .nz"matic methods (>ergme"er!
197) have largel" superseded reductiometric methods in clinical practice $here
precise measurement of blood or plasma glucose concentrations is reFuired#
2#1#' ,luco)e o*i+a)e metho+# Glucose o&idase catal"ses the o&idation of glucose to
"ield glucuronic acid and h"drogen pero&ide# The concentration of h"drogen
pero&ide liberated is measured using a pero&idase step coupled to a coloured
o&"gen acceptor or an electrode (>ergme"er! 197)# These reactions form the
basis of both reagent strip and benchtop glucose electrode methods# The
limitations of these s"stems are described in more detail belo$ (/ections 2#1#D!
2#1#7#
2#1#* He*o4ina)e metho+# He&o3inase catal"ses the phosphor"lation of glucose b"
0T5# Glucose?D?phosphate is then reduced b" glucose deh"drogenase "ielding
80+5HEH
O
$hich can be measured using a suitable spectrophotometric indicator
s"stem# This method is precise and highl" specific for glucose (>ergme"er! 197)#
2#1#) -reci)ion an+ )ource) of error in the +etermination of bloo+ 5 pla)ma gluco)e
concentration)# -eFuirements for the ideal method for measurement of glucose
concentrations in clinical practice are= accurac"! precision! and rapid processing of
small samples $ithout the need for preparator" steps# The method must also be
sufficientl" simple for medical and nursing personnel to underta3e it $ithout
e&tensive training in laborator" s3ills# :ethods developed and used most
e&tensivel" in the last t$o decades for cotside monitoring of blood and plasma
glucose concentrations include paper reagent strips and glucose electrodes# >oth
depend on the glucose o&idase reaction (/ection 2#1#'# 0nother more recentl"
developed method (the Hemo1ue photometer! /ection 2#1#, emplo"s glucose
deh"drogenase to reduce 80+ but measures indicator colour change b"
transmission spectrophotometr" rather than the reflectance technolog" emplo"ed
$ith paper strip methods#
2#1#2 -ropertie) of the )ample an+ )ource) of error# 0rterial blood has a slightl" higher
glucose concentration than venous# The magnitude of this difference varies $ith
tissue glucose demands and $ill be greatest under anaerobic conditions# 1apillar"
sampling is unreliable if peripheral blood flo$ is reduced# /amples must be al$a"s
be free?flo$ing as sFueezing the heel causes haemol"sis $hich interferes $ith the
33
assa" unless deproteinisation is performed (see belo$# 1ontamination b" alcohol
used for s3in preparation leads to erroneousl" high values (Grazaitis 7 /e&son
19,GK Togari et al0 19,7# The sample should either be anal"sed immediatel" or
deproteinised (for e&ample using perchloric acid and chilled# Gl"col"sis
other$ise continues# 1ommerciall" available sodium fluoride coated tubes do not
al$a"s ensure a fluoride concentration sufficient to inhibit gl"col"sis (@oosten et
al0 1991#
One of the greatest problems $ith neonatal samples is that haematocrit ma" var"
from N)G to R7GJ# -ed cells contain less $ater than an eFuivalent volume of
plasma (though the glucose concentration in red cell $ater is the same as that in
the plasma# 5lasma glucose concentration is therefore higher than that of $hole
blood! on average b" about 1,J (0"nsle"?Green! 1991# 4urthermore! all
methods emplo"ing paper reagent strips are sub%ect to an intrinsic haematocrit
biasK the higher the haematocrit value! the lo$er the result# 5ossible reasons
include discolouration of the test?pad and resistance to $iping or $ashing before
reading# 0lso the higher sample viscosit" impedes diffusion of plasma into the
test?pad of the strip# 5reparation of a plasma sample! e#g# in a heparinised micro?
haematocrit tube! overcomes this problem (<aplan et al0 19,9#
>ilirubin! uric acid! and haemol"sis also interfere $ith glucose o&idase?pero&idase
based strip methods# >ilirubin inhibits both steps of the assa" leading to falsel"
lo$ values (4o& 7 -edstone 197D# Haemol"sis also produces falsel" lo$ values#
This ma" be attributable to presence of haemoglobin or to release of reduced
glutathione $hich competes $ith the chromogen for h"drogen pero&ide released
in the assa"# (nterference b" haemol"sates! uric acid! and bilirubin can be
prevented b" deproteinisation of the sample#
2#1#D -aper )trip)# These $ere initiall" developed for monitoring blood glucose
concentration in diabetes and not intended for detection of h"pogl"caemia# 1are
must be ta3en to avoid contamination b" alcohol s3in?cleansers! to cover the
$hole surface of the test?pad! and to time the reaction precisel" before $iping the
strip# .ven $hen these precautions are adopted! all tend to under?estimate
s"stematicall" the mean of a series of measurements in the range of glucose
concentrations relevant to the diagnosis of neonatal h"pogl"caemia (N'#D mmol l
?
1
K appro& N 2G mg dl
?1
and are imprecise! t"picall" giving values onl" to $ithin
G#2 mmol l
?1
even $hen coupled $ith a reflectance metering s"stem (e#g
Reflolu*#
/everal commerciall" available s"stems are available and have been evaluated for
neonatal use including !e*tro)ti* (0mes 1o# (1hantler et al! 19D7K Wil3ins 7
<alra! 19,'! 6'1te)t1glycemie %177 (Wil3ins 7 <alra! 19,'K -e"nolds 7
+avies! 199*K 0nderson et al0 199*! and hem)trip b, (>oehringer :annheim
(Holtrop et al! 199GK <aplan et al! 19,9# :ost studies have compared methods
using linear correlation anal"sis (e#g <aplan et al! 19,9K Wil3ins 7 <alra! 19,'K
5erelman et al! 19,'K Hererra 7 Hsiang! 19,*K Ha" 7 Osberg! 19,*K 6in et al!
19,9K Hameed et al! 1992 but a more informative means of comparing t$o
methods of measurement is to plot the difference bet$een results obtained b"
each method against the average of the t$o (>land 7 0ltman! 19,D# This
describes more clearl" inaccurac" ()y)tematic difference bet$een methods and
imprecision (ran+om variation of results about the mean#
31
Screenin$
4our studies have e&amined the problem in this $a"# One (0"nsle"?Green! 1991
compared blood glucose measurements made using the 6' glycemie %177 strip
and Reflolu* reflectance meter $ith autoanal"ser measurements across the range
of blood glucose concentrations G#,?'#, mmol l
?1
# The 92J confidence limits
(precision across this range appro&imated G#2 mmol l
?1
! and there $as a small
s"stematic difference of G#G2 mmol l
?1
at all concentrations# 0nderson et al (199*
compared 6' strip $ith the 8ellow (pring) /n)trument) glucose electrode
s"stem# 6' glycemie te)t gave results on average G#*7 mmol l
?1
lo$er than those
obtained $ith the glucose electrode in the range of concentrations 1?2 mmol l
?1
#
1onfidence limits $ere not given#
0 third stud" (-e"nolds 7 +avies! 199* e&amined the effectiveness of paper
strip s"stems in screening for neonatal h"pogl"caemia (see 2#' belo$! defined as
a blood glucose concentration of N'#G mmol l
?1
detected at the cotside $ith the
6' glycemie %177 te)t (Table 2# The 9o+a4 :4tachem s"stem $as used as a
comparative laborator" reference# :ean 6' glycemie te)t values understimated
mean 9o+a4 :4tachem values b" as much as 1#2 mmol l
?1
at a 6' glucose
concentration of 1 mmol l
?1
but $ere comparable at *#2 mmol l
?1
# 0t all
concentrations there $as a $ide scatter of results! such that the laborator" blood
glucose at a 6' value of '#G mmol l
?1
could have been bet$een 1#) and
)#* mmol l
?1
on 92J of occasions# Hameed et al (1992 similarl" compared
venous and capillar" sample 6'?test reflectance estimates $ith laborator" values
obtained b" the he&o3inase techniFue and observed a tendenc" for the mean
6'1 test value to underestimate $ith a $ide scatter of individual values (92J 1(
appro&imatel" V 1#D mmol l
?1
#
/n )ummary! reagent strip methods are prone to man" errors $hen used to screen
for neonatal h"pogl"caemia# The mean of a series of measurements ma" be
underestimated b" as much as G#2?1#G mmol l
?1
# Conse=uently9 treatment
should not be initiated on the basis of results obtained with these tests alone*
2#1#7 ,luco)e electro+e )y)tem)# One stud" (1onrad et al! 19,9 e&amined the
reliabilit" of a glucose electrode based anal"ser (S/( (8ellow (pring)
/n)trument)! :odel '*0 used b" nurses in a clinical setting# The device measures
plasma glucose concentration on a $hole blood uncentrifuged '2l sample# 0n in
vitro stud" found good linear agreement (r M G#99 over the range G?1GG mg dl
?1
(G ? 2#D mmol l
?1
bet$een S/( results and those obtained using a laborator"
glucose o&idase method# The regression eFuation $as=
S/( blood glucose (mg dl
?1
M G#92 laborator" value O G#7D mg dl
?1
#
/tandard error of the estimate (nM)9 $as *#G mg dl
?1
(G#17 mmol l
?1
! significantl"
better than agreement obtained bet$een S/( and reagent strip methods
(,lucometer //0 hem)trip b,0 !e*tro)ti*0 ,luco)ti* for $hich standard error of
the estimate ranged bet$een 12?'G mg dl
?1
# (nterference from bilirubin is
negligible at concentrations encountered in practice! and sample haematocrit does
not affect the assa"# 4ull" automated s"stems are available but e&pensive (appro&
W12!GGG compared to reflectance meters# Once purchased! the running costs of
the S/( eFuate closel" to the cost of disposable reagent strips#
34
2#1#, Other be+)i+e )y)tem)$ The Hemoue ?glucose photometer (Hemo1ue 26!
0ngelholm! /$eden is an optical method measuring $hole blood glucose on
small (2l samples utilising disposable cuvettes# >lood is haemol"sed in the
cuvette and 80+H formed b" enz"matic glucose o&idation reduces
meth"lthiazol"ldiphen"l tetrazolium to produce a formazan d"e! the concentration
of $hich is determined spectrophotometricall"# Onl" one stud" has evaluated
application to neonatal samples (Aadsadi 7 @acobs! 199*# 4urthermore! its
reliabilit" for detection of h"pogl"caemia cannot be established because too fe$
observations $ere in the range of importance (N* mmol l
?1
and results $ere
e&pressed onl" in terms of statistical correlation rather than limits of agreement
(see comments in /ection 2#1#7# :oreover! the cost per test is high $hen
compared $ith reagent strip or electrode s"stems# 1uvette storage temperature
and room temperature variation can introduce errors! though these are more
significant at high than at lo$ glucose concentrations# 0 recent stud" (.llis et al!
199D conducted in 8epal found that Haemoue tended to overestimate blood
glucose concentrations of neonatal samples and $as unsuitable for the detection
of h"pogl"caemia (N' mmol l
?1
#
0*) !ffectiveness of screening based on reagent strip methods
Table 2 summarises data on the effectiveness of screening from t$o published
studies# 0 positive predictive value (55A of G#1, or G#2' implies that a reagent
strip measurement predicted true h"pogl"caemia (i#e# confirmed b" laborator"
measurement on onl" 1, or 2'J of occasions# The discrepanc" bet$een studies
in estimated positive predictive value probabl" reflects different incidence of
h"pogl"caemia# (n one (Holtrop et al0 199G the proportion of true positives $as
'1J of all tests! in the other (-e"nolds 7 +avies! 199* it $as N1GJ# (n general!
the lo$er the incidence of a condition! the greater the li3elihood of a false positive
diagnosis being made b" a screening test and the poorer its positive predictive
value (Hall 7 :ichel! 1992# /ensitivit" and specificit" values are unaffected b"
the incidence of a condition and estimates in these t$o studies! of ,'J and ,DJ
for sensitivit"! and 7GJ and 7,J for specificit"! $ere comparable# ;sing an
average specificit" value of 7)J it can be calculated that appro&imatel" 1 in )
normogl"caemic babies tested $ould have been erroneousl" classified as
h"pogl"caemic# 0 third stud" (Ho et al! 1991K not sho$n in Table 2 using 6'1
te)t ,lycemie ;<1=<< and the Reflolu* meter gave similar estimates= sensitivit"
,,J and specificit" ,1J#
33
Screenin$
3able 0
!ffectiveness of screening for
neonatal hypoglycaemia using reagent strip methods
+efinition= N'#G mmol l
?1
N1#9 mmol l
?1
/ensitivit" ,'J ,DJ
/pecificit" 7GJ 7,J
5ositive predictive value G#1, G#2'
8egative predictive value G#9, G#92
H"pogl"caemia defined as N'#G mmol l
?1
using 6' glycemie /Reflolu* s"stem (-e"nolds 7 +avies!
199* or as N1#9 mmol l
?1
using hem)trip 6, $ith visual matching (Holtrop et al0 199G#
/ensitivit" M true positives E Ptrue positives O false negativesQ
/pecificit" M true negatives E Ptrue negatives O false positivesQ
5ositive predictive value M true positives E Ptrue positives O false positivesQ
8egative predictive value M true negatives E Ptrue negatives O false negativesQ
(n summar"! these studies sho$ that reagent strip screening detects onl" about
,2J of true cases of h"pogl"caemia and 72J of babies trul" normogl"caemic#
Thus! reagent strip tests are unsuitable for diagnosing neonatal
hypoglycaemia and should not be used* Less fre=uent but more accurate
laboratory or ward>based glucose electrode measurements among babies at
risk are preferable (/ection D#
0*, 2ncidence of hypoglycaemia
.stimates of the incidence of h"pogl"caemia clearl" var" $ith the definition
chosen! the population studied (postnatal age! gestation! $eight for gestational
age! and the pattern of care#
/e&son (19,) e&amined the effect of the diagnostic threshold for h"pogl"caemia
on incidence of the condition among '*' ne$born babies born to lo$?ris3
mothers in the ;/0# 8o information about feeding regimens $as given# 7'J
(1D, had one or more ris3 factors for h"pogl"caemia as defined b" 1ornblath 7
/ch$artz (197D# !e*tro)ti* $ere used to screen for h"pogl"caemia! a practice
li3el" to overestimate the true incidence (/ection 2#1#DK /ection 2#'! though lo$
values $ere confirmed b" laborator" anal"sis# H"pogl"caemia $as defined as a
bloo+ glucose value of N'#' mmol l
?1
(N)G mg dl
?1
# 8one of the D) infants
$ithout a ris3 factor $as h"pogl"caemic $hen tested at the age of 2 hours (before
the first feed! but ',#DJ of the 1D, infants $ith a ris3 factor became
h"pogl"caemic $ithin the first 1' hours of life# The mean blood glucose of the
h"pogl"caemic infants $as 1#2 mmol l
?1
(range G?'#1 mmol l
?1
and the mean age
at diagnosis *#) hours (range G#2?1' hours# The overall incidence of
h"pogl"caemia in the $hole sample of '*' babies $as 'G#DJ but it is difficult to
set this in conte&t as no data $ere given on birth $eight or gestational age#
8evertheless! had the definition proposed b" 1ornblath et al (N1#7 mmol l
?1
been
used! onl" ,#1J $ould have been labelled h"pogl"caemic#
3%
Holtrop (199* studied the incidence of h"pogl"caemia in 6G0 and /G0
0merican ne$borns! identified as having birth $eight R9G
th
or N1G
th
centile
respectivel"# The definition of h"pogl"caemia chosen $as that suggested b"
/rinivasan et al (19,D= a )erum glucose concentration of N*2 mg dl
?1
at N* hours
of age! N)G mg dl
?1
at *?') hours of age and N)2 mg dl
?1
at R') hours of age#
H"pogl"caemia $as detected in ,#1J (')E'9, of 6G0 infants and 1)#7J
(*GE'G) of /G0 infants# (n all but * /G0 infants it occurred in the first 1G hours
of life# 0lthough data on mean birth $eight and gestation $ere given! no
information about feeding regimens $as presented#
0 >ritish stud" of 1D) /G0 babies detected h"pogl"caemia (defined as
+e&trosti& value N1#) mmol l
?1
in onl" *E1G) $ith birth $eight R'#* centile and
DEDG $ith birth $eight N'#* centile# Onl" one of the 9 infants $as s"mptomatic!
being described as B%itter"B# Ha$don et al (199'! revie$ing the literature! Fuote
incidences of Bh"pogl"caemiaB
)
in term infants ranging bet$een G and ,J and
bet$een * and 12J in preterm infants#
(nformation on the incidence of neonatal h"pogl"caemia in developing countries is
ver" limited# 0nderson et al (199* conducted a cross?sectional stud" of ''D
full?term! uncomplicated ne$borns in a hospital in <athmandu! 8epal#
H"pogl"caemia! defined as a bloo+ glucose value of N'#D mmol l
?1
during the first
2G hours of life (<oh et al! 19,,! $as present in *,J# /even per cent had a
blood glucose concentration N'#G mmol l
?1
# 6o$ birth $eight and h"pothermia
$ere associated $ith h"pogl"caemia $hich $as present in 22J of those $eighing
N'2GG g! and *' J of those R'2GG g# /imilarl"! 27J of those $ith a rectal
temperature of N*2#2
O
1 at the time of sampling $ere h"pogl"caemic compared to
*'J of those $ho $ere not# :ore than half the babies studied received prelacteal
feeds (sugar $ater and man" mothers dela"ed initiation of breastfeeding for over
') hours! discarding colostrum# The authors speculated reasonabl" that these
$ere important aetiological factors but did not see3 s"stematicall" to correlate
these practices $ith h"pogl"caemia in their stud"#
0*- $ummary# is screening for hypoglycaemia necessary?
The term BscreeningB is used here to denote scheduled measurement of blood
glucose in as"mptomatic infants
.erm infant)# /creening for h"pogl"caemia in health" term infants is fla$ed for
t$o principal reasons# 4irst! no diagnostic blood glucose concentration can be set
(/ection )# /econd! no reliable cotside methodolog" is available= reagent strip
methods greatl" overestimate the true freFuenc" of h"pogl"caemia in this
population (/ection 2#' and are li3el" to lead to unnecessar" investigation and
treatment#
-reterm infant)# 6imited available data give cause for concern that infants
N*7 $ee3s gestation have an immature counterregulator" response to
h"pogl"caemia (/ection '#*! /ection '#)# (t seems desirable in this group to
maintain plasma glucose concentration R'#D mmol l
?1
(6ucas et al0 19,,# (n
) )
H"pogl"caemia defined as N*G mg dl
?1
(1#D mmol l
?1
in term infants N), hours old!
N)G mg dl
?1
if over ), hours old# H"pogl"caemia in preterm infants defined as
N'G mg dl
?1
(1#1 mmol l
?1
#
3,
Screenin$
achieving this aim! prevention (/ection D b" earl" enteral feeding (or provision of
intravenous glucose for those unable to feed is more important than freFuent
blood glucose testing# +ail" or t$ice dail" laborator" measurements are
preferable to freFuent but inaccurate reagent strip measurements# The" should be
sufficient in most cases to tailor feeding regimens to the individual infantCs
reFuirement#
(mall for ge)tational age ((,2& infant)# 1are should be ta3en in the diagnosis of
/G0 (see /ection D#'#*# This group is ver" heterogeneous and not all are at ris3
of h"pogl"caemia# Those N*rd percentile (birth $eight N' /+ from the mean for
gestation (@ones 7 -oberton! 19,DK 1ornblath 7 /ch$artz! 199*! and those
$ho are disproportionate (increased head circumference= bod" $eight ratio or
$ith abnormal umbilical arter" +oppler flo$ velocit" profiles in fetal life
(Ha$don et al! 199'! are probabl" most vulnerable# 5ol"c"thaemia is an
additional ris3 factor $hich is easil" e&cluded (/ection D#1# .&cessivel" freFuent
blood sampling is not necessar" to identif" those at ris3# -eliable laborator"
measurements of cord blood glucose and blood glucose at )?D hours of age
(before the second feed are preferable (Ha$don 7 Ward 5latt! 199*#
Large for ge)tational age (L,2& term infant)# -are infants $ith organic
h"perinsulinism are t"picall" large at birth! and this association has led to
screening of infants $hose birth $eight e&ceeds the 9G
th
percentile for gestational
age# Occasionall" 6G0 is associated $ith hitherto undetected maternal
gestational diabetes# >ut the ma%orit" of 6G0 infants are simpl" large! normal
health" infants (see /ection '#)#)# 0s in 0G0 infants (Ha$don et al! 199'!
blood glucose concentrations ma" fall belo$ ' mmol l
?1
in this group! usuall"
$ithin the first , hours of life (Holtrop! 199*# There is no evidence that transient
h"pogl"caemia in this group is detrimental to outcome# 1onseFuentl"! reagent?
strip screening! supplementar" feeding and treatment of transient! mild
h"pogl"caemia in the absence of s"mptoms are inappropriate#
/nfant) of +iabetic mother)# :ost of these infants displa" transient
h"perinsulinism and are conseFuentl" at ris3 of h"po3etonaemic h"pogl"caemia#
/creening should be underta3en for at least the first ') hours of life and the blood
glucose concentration maintained at R'#D mmol l
?1
# Testing ma" be discontinued
once satisfactor" blood glucose concentrations are maintained $ithout
supplementar" feeds or intravenous therap"#
3-
/* PR!(!N324N
/*. Peripartum factors
D#1#1 /ntrapartum factor)$ 0lthough man" intrapartum factors predisposing to neonatal
h"pogl"caemia are unavoidable (e#g# ?s"mpathomimetics to suppress preterm
labour! caesarean section some are avoidable# One such is e&cessive maternal
glucose infusion during labour# -estriction to N1G g h
?1
should not have a
significant effect on either the cord blood insulin concentration or the incidence of
h"pogl"caemia (/ection '#)#)#
D#1#' :arly po)tpartum management# The bab" should be dried immediatel" to reduce
evaporative heat loss $hich increases energ" demands# /3in?to?s3in contact
bet$een the mother and her bab" as soon as possible after deliver" are important
in the maintenance of core temperature (van den >osch 7 >ullough! 199G# .arl"
enteral feeding should have the highest priorit" in health" infants! $hether term or
preterm (/mallpeice 7 +avies! 19D)K Wharton 7 >o$er! 19D2#
D#1#* Neonatal ri)4 factor)# /ection '#) discussed factors $hich increase the ris3 of
neonatal h"pogl"caemia# 4eeding regimens for categories of babies at ris3 are
suggested belo$ (/ection D#'# 5ol"c"thaemia (pac3ed cell volume! or 51A! of
RG#D2 ma" be associated $ith h"pogl"caemia in some babies! particularl" those
$ho are small for gestational age and infants of diabetic mothers# The
management of neonatal pol"c"thamia is controversialK some authorities (Glader
7 8aiman! 1991 recommend partial dilutional e&change $ith 2J albumin in
infants $ho are Bs"mptomaticB (including those $ho are h"pogl"caemic but there
is no consistent evidence of short? or long?term benefit in those $ho are $ell
(+o"le 7 Xipurs3"! 199'#
/*) :eeding regimens
The most effective method of preventing h"pogl"caemia is feeding $ith mil3 as
soon as possible after deliver"# 5rolonged fasting is associated $ith a progressive
fall in mean blood glucose in both term and preterm infants and in those
appropriate or small for gestational age (>eard et al! 19DD# >reastmil3 is
preferred to formula because it appears to promote 3etogenesis (Ha$don et al!
199'# 4urthermore! there is some evidence that earl" blood glucose values in
term babies fed formula are lo$er than those in babies breastfed (Hec3 7
.renburg! 19,7# This ma" reflect the insulinogenic effect of protein in formula
(6ucas et al! 19,1 (/ection )#1#
.erm infant)# There is no %ustification for giving health" term infants 1GJ
de&trose $ater or an" other form of prelacteal feeds# 0lthough the practice $as
once routine! particularl" in 8orth 0merican nurseries! it is outdated# +e&trose
$ater is of lo$er energ" densit" than mil3 $hich contains fat# The practice of
feeding de&trose $ater presumabl" arose through concern about aspiration of the
first feed but there is no evidence that aspiration of colostrum is an" more harmful
than aspiration of de&trose or $ater#
(n some parts of the $orld! notabl" the (ndian sub?continent! prelacteal feeding
and $ithholding of colostrum is common# (n an (ndian 1ouncil of :edical
-esearch collaborative stud" of infant feeding! onl" *'J of mothers suc3led their
37
"re#ention
bab" $ithin the first ') hours and onl" 1*J in the first , hours# /event"?one per
cent of mothers offered an alternative to breastmil3! such as hone" or sugar $ater
(0nderson et al! 199*# /uch practices seem ver" li3el" to increase the incidence
of neonatal h"pogl"caemia though no intervention studies appear to have
documented this#
D#'#' -reterm infant)# (t is over thirt" "ears since t$o >ritish studies documented that
Bearl"B feeding $ith e&pressed breastmil3 reduced the incidence of h"pogl"caemia
(blood glucose N'G mg dl
?1
in preterm infants (/mallpeice 7 +avies! 19D)K
Wharton 7 >o$er! 19D2# (n the 19)GCs and 192GCs preterm infants $ere starved
for the first ') hours of life in order to reduce the incidence of aspiration#
/mallpeice 7 +avies (19D) sho$ed that nasogastric tube feeding of small infants
(birth $eight 1?' 3g using graded volumes of mil3 $as safe and reduced the
freFuenc" of h"pogl"caemia! %aundice and deh"dration $hen compared $ith
historical controls# The feeding schedule the" adopted! commencing $ith
DG ml 3g
?1
d
?1
and increasing dail" in steps of *G ml 3g
?1
d
?1
to 12G ml 3g
?1
d
?1
on the
fourth da" of life! is still $idel" recommended in standard neonatal te&ts though
has never been s"stematicall" evaluated# Wharton 7 >o$er (19D2 found that this
practice halved the incidence of as"mptomatic h"pogl"caemia (immediate?fed
group 2E))K late?fed group 1GE2) and abolished s"mptomatic h"pogl"caemia
(GE)) immediate?fedK )E2) late?fed though $as associated $ith an increased ris3
of mortalit"! often associated $ith aspiration#
0n alternative ma" be to provide 1GG ml 3g
?1
d
?1
on the first da"! 72 ml 3g
?1
d
?1
on
the second and 2G ml 3g
?1
d
?1
on the third as the volume of breastmil3 obtained b"
suc3ling increases (@: Ha$don! : Ward 5lattK personal communications! 199D#
1oncern about the relationship bet$een high earl" feed volume and necrotising
enterocolitis ma" be un%ustified! being based on case?control data (0nderson 7
<liegman! 1991K :c<eo$n et al! 199' and retrospectivel" controlled studies
(>ro$n 7 /$eet! 197,K Goldman! 19,G# (t $as not supported b" a single! small
randomised controlled trial (>oo3 et al! 197D# /tudies e&amining feed volume
moreover have not adeFuatel" controlled for the protective effect of human mil3
(6ucas 7 1ole! 199GK >eeb" 7 @effer"! 199'#
Preterm infants with features of respiratory distress (tach"pnoea! grunting!
recession should not be enterall" fed but should be treated $ith intravenous
glucose (see /ection D#) until respirator" rate begins to fall# 4eeding tubes should
al$a"s be passed via the mouth in infants recovering from respirator" distress as
nasogastric tubes increase air$a" impedance and ma" precipitate apnoea (/toc3s!
19,G# 0lternativel" infants ma" be cup?fed (6ang et al! 199)# (nitiall"! small
aliFuots of feed should be offered hourl" and intervals increased to *?hourl" as
tolerated#
Healthy preterm infants ,)>,/ weeks of gestation# /ustained coordination of
suc3ling and s$allo$ing is present from about *' $ee3s of gestation (-ennie!
199' and man" such infants ma" be allo$ed an opportunit" to suc3le# The abilit"
of small babies to feed at the breast is often underestimated# 5earce 7 >uchanan
(1979 reported that 1' of 17 ver" lo$ birth $eight babies consecutivel" admitted
to a neonatal unit started breastfeeding at a mean $eight of 1#*') V G#G99 3g
(mean! /+ and a mean age of 11 da"s# Ten $ere full" breastfed at a mean age of
'7 da"s $hen the" $eighed 1#DGG V G#1*9 3g#
30
The breast should be offered as soon as possible after birth and at *?hourl"
intervals thereafter# There is little point in persisting if the infant is sleep"!
undemanding and un$illing to attach or suc3le# Total reFuirements ma" not be
obtained directl" and supplementar" feeds should be given after breastfeeds
during the earl" da"s of life# The volume of supplement should be reduced as
suc3ling improves and birth $eight is regained (see guidelines in D#'#' above#
4eeds should be offered b" cup or gavage in preference to a bottle# .&pressed
breastmil3 is the food of choice but formula is preferable to de&trose $ater if it is
not available#
Healthy preterm infants under ,) weeks of gestation# The ma%orit" of these
$ill not suc3le effectivel" and reFuire gavage feeding though cup?feeding is
possible from *G $ee3s of gestation (6ang et al! 199)# (f reFuired! a gastric tube
should be passed orall" and not nasall" (/toc3s! 19,G# On the first da" a volume
of DG ml 3g
?1
d
?1
divided into hourl" aliFuots should be given# (f facilities for
intravenous therap" are available! a 1GJ glucose infusion should be initiated as
soon as possible after birth /ection D#)# 0bsolute contraindications to feeding
include bile?stained gastric aspirate and abdominal distension! most commonl"
attributable to ileus# 4eeds should be stopped and intravenous 1GJ glucose
infusion commenced (or parenteral nutrition $hen available# .nteral feeding ma"
be recommenced $hen signs resolve! assuming that necrotising enterocolitis
(8.1 has been e&cluded# 8.1 and other conditions associated $ith ileus (e#g#
sepsis! respirator" disease should be treated according to standard te&ts#
:ost infants N', $ee3s of gestation sho$ immature patterns of bo$el motilit"
though earl" feeding has been sho$n to hasten adaptation to the pattern seen in
more mature babies (>issett et al! 19,9# 0 randomised controlled stud" of babies
N1,2G g birth $eight found human mil3 feeds more rapidl" tolerated than formula
feeds (6ucas! 19,7#
Management of the mother# (f the bab" is unable to suc3le! mothers should
e&press their breastmil3 as soon as possible after deliver" and continue at least *?
hourl" even at night# 0ll mil3 e&pressed should be given to the bab"# (f the bab" is
capable of suc3ling but appears unable to obtain hisEher total reFuirements the
mother should e&press after each feed# /3in?to?s3in contact (B3angaroo careB
has been sho$n in a randomised controlled stud" to increase the duration of
lactation among mothers of ver" small preterm infants (Whitela$ et al! 19,,#
D#'#* (mall for ge)tational age ((,2& infant)
2dentifying $&A babies# ;suall" /G0 babies are defined as those $hose birth
$eight is belo$ the 1G
th
centile for gestational age# This crude classification
ignores the strong effect of maternal height and $eight on birth $eight# There is a
difference of appro&imatel" 2GG g bet$een the mean birth $eights at term of
babies born to mothers of ) feet 1G inches or 2 feet 1G inches# (f the e&tremes of
mid?pregnanc" $eight are also ta3en into account! the difference approaches 1 3g
(0ltman 7 1oles! 19,G# 0 stud" of >ritish babies (Gardosi et al! 199'
estimated that ',J of infants conventionall" classified as /G0 $ere of
appropriate $eight $hen maternal race! height! $eight! and parit" $ere ta3en into
account# /imilarl"! ')J of babies conventionall" classified as appropriate $eight
for gestational age (0G0 $ere trul" /G0# (deall"! birth $eight should be
ad%usted at least for the effect of maternal height! parit" and mid?pregnanc"
$eight (0ltman 7 1oles! 19,G before babies are labelled /G0#
39
"re#ention
0s the endogenous glucose production rate and glucose reFuirements correlate
more closel" $ith brain $eight than bod" $eight! the /G0 babies at greatest ris3
of h"pogl"caemia are probabl" those of disproportionate appearance $ith high
O41E:01 (head circumference= mid?arm circumference or O41Ebod" $eight
ratio# ;nfortunatel" there are insufficient data at present to establish a sufficientl"
precise threshold identif"ing an at?ris3 population# :oreover the calculation of
such an inde& from t$o independent parameters doubles the potential for
measurement error#
Management of $&A infants# -easons for the increased incidence of
h"pogl"caemia among /G0 infants $ere discussed in /ection '#)=
counterregulator" response and 3etogenesis are blunted b" comparison $ith 0G0
infants but appear to mature on feeding# 1onseFuentl"! earl" feeding is believed to
be as important in this group as in preterm infants of normal $eight# Glucose
production rates in /G0 infants are higher than in 0G0 infants (/ection '#'#)#
We therefore commence enteral feeding in health" /G0 infants at 9G ml 3g
?1
d
?1
as
*?hourl" feeds on the first da" and increase in *G ml 3g
?1
steps dail"#
(n a 1ambridge stud" (Whitb" et al0 19,' of 'D9 infants $eighing 1#,?'#2 3g
$ho $ere provided $ith DG ml 3g
?1
d
?1
of mil3 on the first da" (increasing b"
aliFuots of *G ml 3g
?1
d
?1
onl" 2 developed h"pogl"caemia
2
# 0ll $ere
as"mptomatic# 22J of the infants $ere B$$ma4ing )ome attempt to brea)t1fee+ at
+i)charge#B 0 further 1ambridge stud" of 1D) infants belo$ the 2
th
centile birth
$eight at *7 $ee3s fed according to this regimen observed onl" 9 cases of
h"pogl"caemia (footnote
)
! most of $hich $ere in infants N' standard deviations
belo$ mean birth $eight for gestation# .ight of the 9 $ere as"mptomatic and one
$as described as B%itter"B#
There are no properl" controlled studies of the incidence of h"pogl"caemia
among small (/G0 and preterm babies e&clusivel" breastfed on demand or
breastfed $ith supplements# These are urgentl" needed to uncover the incidence
and outcome of h"pogl"caemia! the incidence of adverse effects associated $ith
formula supplementation! and the size of an" negative effect on breastfeeding#
0nother area $orth" of stud" might be the role of simple anthropometr" (e#g#
head circumference= arm circumference or length ratios in identif"ing more
precisel" those small for gestational age infants at ris3#
D#'#) /nfant of the +iabetic mother# These infants displa" transient h"perinsulinism# The
ris3 is greatest among those $ho are macrosomic (/ection '#)# H"pogl"caemia is
not li3el" to occur after the first ') hours of life# 0ffected infants should be
breastfed as soon as possible after birth and thereafter on demand# (f a pre?feed
blood glucose estimation at * hours of age is normal it is unli3el" that
supplements $ill be reFuired# >ut if the plasma glucose is N'#D mmol l
?1
at this
age! supplementar" feeds (9G ml 3g
?1
d
?1
should be instituted for the first ')?),
hours of life! bearing in mind that the abilit" of these infants to $ithstand
h"pogl"caemia can be compromised b" h"po3etonaemia# (t is reassuring to note
that most studies have found neurodevelopmental outcome among infants of
diabetic mothers similar to that of controls! provided that h"pogl"caemia $as
appropriatel" treated#
2
!e*tro)ti* value of N'2 mg dl
?1
#
%3
D#'#2 Large for ge)tational age (L,2& infant)$ 6G0 is usuall" defined as birth $eight
R9G
th
centile for gestational age# (nfants $ith persistent h"perinsulinism (e#g#
attributable to >?cell d"sregulation s"ndrome are t"picall" 6G0! as are those
born to mothers $ith unrecognised gestational diabetes# :etabolic adaptation has
not been studied so intensivel" in 6G0 infants as a group as it has been! for
e&ample! in /G0 or preterm infants# The incidence of h"pogl"caemia
D
in an
0merican stud" (Holtrop! 199* of 6G0 infants $as ,#1J but no details of
feeding regimens $ere given# (n the same stud" 1)#7J of /G0 infants $ere
h"pogl"caemic using the same criteria# H"pogl"caemia in 6G0 infants $as earl"
(mean age '#9 hours and no cases occurred in infants over , hours old# 5ersistent
organic h"perinsulinism in other$ise health" infants is ver" rare and it is doubtful
that screening and supplementar" feeding of breastfed 6G0 infants is %ustified#
/*, Additives for milk feeds
The effectiveness of supplementing feeds $ith carboh"drate $as investigated in a
randomised controlled trial involving 1*G full?term! 6G0 infants
7
(/inghal et al!
1991# (nfants $ere admitted to a nurser" for the first ') hours of life and fed
standard formula! either alone or supplemented $ith 2 g po$dered BsugarB per
1GG ml# >oth groups $ere fed ,G ml 3g
?1
')h
?1
b" bottle or gastric tube! ma3ing
the average glucose suppl" of the t$o groups 2 or 7#, mg 3g?
1
min
?1
respectivel"#
>lood glucose concentrations (determined on an 0utoanal"ser of the t$o groups
at 1' hours of age $ere 2*#* 7#1 and 71#D D#2 mg dl
?1
respectivel"# :oreover!
significantl" fe$er infants in the supplemented group ()#DJ than in the control
group (1D#9J had a blood glucose N*G mg dl
?1
recorded (-elative ris3 )#'!
92J 1( '#,,! 2#))! p NG#G2#
;nfortunatel" this stud" does not address the Fuestion as to $hether the higher
blood glucose concentration in the supplemented group $as beneficial to
outcome# :oreover! the incidence of h"pogl"caemia in both groups is li3el" to be
spuriousl" high as !e*tro)ti* $ere used to detect cases (/ection 2#1#DK /ection
2#'# There is an additional Fuestion about the safet" of increasing feed osmolalit"
b" adding sugar# (n this stud" the supplemented feed contained *D* mosm l
?1
as
opposed to '9G mosm l
?1
in the standard feed# 0bdominal distension $as not
noted but###
>$$$%<$=? of babie) on fortifie+ fee+) +i+ not reli)h the ta)te0 a)
compare+ to 7$=? on )tan+ar+ mil4$>
4urther studies of outcome and safet" are reFuired before this practice can be
endorsed#
4at supplementation of enteral feeds ma" have a role in prevention of
h"pogl"caemia (/ann et al! 19,,# There is evidence that oral administration of
lipid (as medium chain trigl"ceride increases blood glucose concentration in
unfed preterm and /G0 babies (/ann et al! 19,1! 19,'# .&cessive use of fat
supplements ma" nevertheless precipitate diarrhoea and there is the additional
6
+efined here as serum glucose concentration N*2 mg dl
?1
at N* hours of age!
N)G mg dl
?1
at *?') hours of age! N)2 mg dl
?1
at R') hours of age#
7
+efined as birth $eight R9G
th
centile on local (ndian charts#
%1
"re#ention
possibilit" of precipitating severe illness in those rare infants $ho have defective
?o&idation path$a"s#
/*- 2nfants who cannot be fed
(mmediate enteral feeding is contraindicated in some situations! for e&ample in the
presence of cardio?respirator" distress! congenital malformations of the
gastrointestinal tract! ileus! and e&treme prematurit" (gestation N', $ee3s#
Glucose infusion should be commenced at a rate appro&imating the endogenous
rate of hepatic glucose production (/ection '#'#)! that is=
4ull?term infant! appropriate $eight for gestational age#######################################################################################
5reterm infant! appropriate $eight for gestational age
/mall for gestational age infant#############################################################################################################################
*?2 mg 3g
?1
min
?1
)?D mg 3g
?1
min
?1
D?, mg 3g
?1
min
?1
Note: DG ml 3g
?1
')h
?1
1GJ de&trose supplies )#' mg glucose 3g
?1
min
?1
(footnote
,
The use of bolus or BminibolusB glucose in%ections in the treatment of

documented h"pogl"caemia is controversial (see /ection 7#' but there is
agreement that the" are unnecessar" $hen initiating glucose infusion to prevent
h"pogl"caemia in babies $ho cannot be enterall" fed# (t is undesirable to curtail
abruptl" intravenous infusions of glucose# The concentration of glucose infused
into a peripheral vein should not e&ceed 1GJ# (f glucose reFuirements e&ceed the
above! insertion of a central intravenous line ma" be necessar"! though
intravenous glucagon in%ection ('GG g 3g
?1
ma" be an alternative (/ection 7#*#1K
:ehta! 199)#
1* 3R!A3M!N3
The occurrence of h"pogl"caemia should prompt consideration of the cause# (t is
particularl" important to note that term breastfed babies do not develop
s"mptomatic h"pogl"caemia as a result of simple underfeeding# 5resence of
h"pogl"caemia in this group is li3el" to be a manifestation of underl"ing illness!
for e&ample sepsis# +etection and treatment of the cause is as important as
correction of the blood glucose concentration#
1*. !nteral feeding
:oderate! as"mptomatic h"pogl"caemia should first be treated b" ad%usting the
enteral feeding regimen# (f this approach fails! intravenous therap" should be
instituted $hen facilities are available (see /ection 7#'#
7#1#1 Oral +e*tro)e water or mil4@ /ome authorities recommend oral feeding of 1GJ
de&trose $ater 1G ml 3g
?1
(1ornblath 7 /ch$artz! 199*# Others (0"nsle"?Green!
1991K Ha$don 7 Ward 5latt! 199* point out that mil3 (1G ml 3g
?1
is more
energ" dense (1GG ml breastmil3 contains 7G 3calK 1GG ml 1GJ de&trose contains
)G 3cal and that the fat component is theoreticall" beneficialK fat $ill both
,
/trictl"! 1GJ de&trose solution contains 9#* g glucose in the unh"drated form but is
assumed to contain 1G g for most clinical purposes#
%4
promote 3etogenesis and reduce upta3e of glucose into cells (/ection '#'#*K
/ection '#*# Whether glucose or mil3 is given! a blood glucose measurement
should be repeated preferabl" $ithin the hour# 4reFuent feeds and pre?prandial
blood glucose measurements (at least ever" * hours should continue#
7#1#' Lipi+# /tudies in h"pogl"caemic infants and in preterm and /G0 infants have
sho$n that feeding lipid produces an increase in blood glucose! and non?esterified
fatt" acid concentrations (/ann et al! 19,1! 19,' (/ection '#'#*K /ection '#*#
Ha$don et al (199* administered 2 ml 3g
?1
medium chain trigl"ceride (:1T
intragastricall" and measured small but significant increases in blood glucose
concentration! together $ith a highl" variable change in the glucose production
rate# Aariabilit" $as attributed to differences in absorption (though this $as not
measured# 0lthough the gl"caemic effect of administering 'GG g 3g
?1
glucagon
$as greater than the effect of giving 2 ml 3g
?1
of :1T! 3etogenesis $as
promoted more effectivel" $ith :1T and such a change might be of eFual
importance to gl"caemic effect! given the probable importance of 3etone bodies
as a cerebral fuel (/ection *#'#
7#1#* oncentrate+ !e*tro)e ,el# There have been anecdotal reports of the use of
>Hypo)top>! a )GJ de&trose gel in treatment of neonatal h"pogl"caemia# (n an
uncontrolled stud" G#2 ml 3g
?1
Hypo)top $as massaged into the buccal mucosa
after dr"ing it $ith a gauze s$ab# /i&t" seven per cent of term infants are said to
have responded $ith a rise in blood glucose concentration of G#2 mmol l
?1
(>ourchier et al! 199'# (n the absence of controlled studies $e cannot
recommend this practice as effective and have concerns that it ma" defer
implementation of more appropriate therap" aimed at correction of
h"pogl"caemia and treatment of the cause#
1*) 2ntravenous treatment
(f facilities are available intravenous treatment should be used under an" of the
follo$ing circumstances=
0# .nteral treatment has failed (see /ection 7#1
># H"pogl"caemia is severe (N1#1 mmol l
?1

1# The bab" is un$ell or has signs $hich ma" be attributable to
h"pogl"caemia (Bs"mptomaticB h"pogl"caemia#
The place of a priming glucose BbolusB ('#2?*#G ml of 1GJ de&trose 3g
?1
min
?1
administered at a rate of 1 ml min
?1
before glucose infusion! is controversial#
/ome authorities (6ilien et al0 19,GK Ha$don et al! 199)K 1ornblath 7 /ch$artz!
199* recommend it but others have argued that the rate of glucose entr" in such
circumstances e&ceeds upta3e (:ehta! 199) provo3ing Brebound
h"pogl"caemiaB through enhancement of insulin secretion and inhibition of
glucagon secretion# .&cessivel" rapid administration of glucose moreover has
potential to cause h"perosmolar cerebral oedema! as described in older children
(/hah et al! 199'# 0n" bolus given must be follo$ed b" a continuous infusion of
glucose! initiall" providing )?, mg 3g
?1
min
?1
# There is no place for treatment $ith
intermittent glucose boluses alone#
(n the ;nited /tates it is common practice to give a ' ml 3g
?1
BminibolusB of 1GJ
de&trose intravenousl" before starting a continuous infusion! repeating the bolus
%3
"re#ention
after 1 hour if blood glucose concentration is still lo$ (@. :cGo$an! personal
communication! 1992# (n a stud" using historical controls 6ilien et al (19,G
sho$ed that blood glucose concentration $as restored more rapidl" in this $a"
than b" continuous infusion of glucose (, mg 3g
?1
min
?1
alone# Onl" one infant
became transientl" h"pergl"caemic# Ha$don et al (199) recommended using a
* ml 3g
?1
1GJ de&trose priming bolus for )ymptomatic infants! rel"ing upon
slo$er correction b" continuous infusion alone (at least 2 mg 3g
?1
min
?1
in infants
$ho are h"pogl"caemic but other$ise $ell (Ward 5latt 7 Ha$don! 199*#

The rate of infusion ma" reFuire ad%ustment until plasma glucose concentration is
corrected and stabilised# -eFuirements e&ceeding 1G?1' mg 3g
?1
min
?1
! or
dependence after 2?7 da"s of age! suggest that a cause reFuiring further
investigation and treatment ma" be present (/ection '#)#2K Table *#
Glucose infusions should not be discontinued abruptl"# The rate of infusion
should be graduall" reduced pari pa))u $ith increase in the volume of enteral
feed (steps of 1 ml 3g
?1
h
?1
have been recommended# .&travasation at drip sites
needs urgent attention both to ensure continued glucose suppl" and to prevent
tissue damageK glucose solutions are irritant and concentrations e&ceeding 1GJ
should not be infused into peripheral veins# 0 central line ma" be needed if
glucose reFuirements e&ceed 1G#2 mg 3g
?1
min
?1
(12G ml 3g
?1
d
?1
of 1GJ
de&trose# Glucagon administration ('GG g ma" be an alternative if central line
insertion is not possible#
1*, rugs
7#*#1 ,lucagon# :ehta et al (19,7 described four term infants $ho presented $ith
s"mptomatic h"pogl"caemia in association $ith BnormalB insulin concentrations#
/tudies using the tracer D!D?dideuteroglucose indicated a reduced rate of hepatic
glucose production# Glucagon in%ection ('GG mcg 3g
?1
i#v# led to a rapid and
persistent increase in hepatic glucose production rate $ith restoration of plasma
glucose concentration# Ha$don et al (199* also described rapid increases in
both plasma glucose concentration! total glucogenic substrate and glucose
production rate after an intravenous bolus of 'GG g 3g
?1
glucagon among 1GE11
h"pogl"caemic term and preterm infants# (n an uncontrolled stud" 1arter et al
(19,, described a response to continuous intravenous infusion of glucagon
among 'GE'2 h"pogl"caemic /G0 infants in $hom blood glucose concentration
had remained N'#G mmol l
?1
despite infusion of D#2 mg 3g
?1
min
?1
glucose# The
initial dose emplo"ed $as G#2 mg d
?1
! increased if necessar" to 'G mg d
?1
# (n some
respects these results are surprising as /G0 infants ma" be resistant to glucagon!
probabl" as a result of dela" in maturation of gluconeogenic path$a"s
(/ection '#'K /ection '#) (:est"an et al! 197D#
The place of glucagon in treatment of neonatal h"pogl"caemia is controversial
(:ehta! 199)K Ha$don et al! 199)# Theoreticall"! a 'GG g 3g
?1
intravenous
bolus effects enhancement of gluconeogenesis and 3etogenesis (/ection '#'
$hich persists for man" hours though an effect has been claimed for doses
ranging bet$een *?*GG g 3g
?1
# /ide?effects of glucagon include vomiting!
diarrhoea and h"po3alaemia# 0t high doses it ma" stimulate insulin release#
1ontrolled studies of the relative efficac" of glucagon and the more conventional
%%
alternative of glucose infusion at RD mg 3g
?1
min
?1
are needed# :ore information
about dosage is also reFuired#
7#*#' Other +rug): !iaAo*i+e0 )omato)tatin an+ octreoti+e# These drugs pla" a specific
part in the management of persistent h"perinsulinism and have no place in the
management of transient h"pogl"caemia associated $ith abnormal metabolic
adaptation in preterm and /G0 infants (see Ward 5latt 7 Ha$don! 199*K
1ornblath 7 /ch$artz! 199*# -eference should be made to suitable te&ts#
%,
Reserc)
@* R!$!ARCH
The follo$ing Fuestions have been identified as those to $hich an ans$er is most needed! to
improve prevention and management of h"pogl"caemia of the ne$born#
,#1 !oe) neonatal hypoglycaemia compromi)e neuro+evelopmental outcome@
0 Fuestion remains as to the effect of h"pogl"caemia! particularl" as"mptomatic
h"pogl"caemia! on neurodevelopmental outcome (/ection 1K /ection *#
-andomised intervention studies in as"mptomatic h"pogl"caemia seem li3el" to
be the onl" means of obtaining a definite ans$er# This approach $ould clearl" be
unethical in s"mptomatic h"pogl"caemia#
,#' What i) the relation)hip between early brea)tmil4 inta4e an+ pla)ma concentration) of
metabolic )ub)trate)@
The health"! breastfed! term infant must represent a biochemical norm "et data on
blood glucose and other metabolic substrate concentrations are fe$# :ost studies
refer to infants $ho $ere fed formula or glucose $ater on a scheduled basis!
often after earl" starvation# :oreover! those studies $hich do refer to breastfed
infants give no information about feed freFuenc" and the e&tent of supplementar"
feeding! let alone measurements of breastmil3 inta3e# 0 detailed stud" of the
relationship bet$een feeding patterns! breastmil3 inta3e and substrate
concentrations (including glucose is urgentl" needed to characterise the normal
pattern of metabolic adaptation# /uch studies need to be performed in less
developed as $ell as industrialised countries#
,#* What i) the inci+ence of neonatal hypoglycaemia in le)) +evelope+ countrie)@
/tudies of the incidence of h"pogl"caemia and its causes in less developed
countries are urgentl" needed# The increased incidence of lo$ birth $eight ma3es
such studies vital to formulation of recommendations for prevention and
treatment
,#) What i) a >)afe> thre)hol+ bloo+ gluco)e concentration for a preterm infant@
/everal authorities have recommended treatment $hen blood glucose
concentration is N '#D mmol l
?1
# This figure has three principal %ustifications= first
that the counterregulator" response of preterm infants is blunted! secondl" that
there is evidence of neuroph"siological d"sfunction at this level and! third! that
there is evidence of subseFuent neurodevelopmental dela" in preterm infants
e&posed to h"pogl"caemia of this severit"# .ach of these %ustifications can!
ho$ever! be challenged (/ection )#
/tudies such as those of Ha$don et al (199' have suggested that /G0 and
preterm infants are less able to mount a counterregulator" response than term
infants# Ho$ever! these studies $ere observational and could simpl" reflect the
success of medical management in preventing h"pogl"caemia rather than
metabolic immaturit"# 0gainst such an e&planation $as the lo$ 3etone bod"
concentration at blood glucose concentrations associated $ith a vigorous
3etogenic response in health" term infants# .arl" $or3 nevertheless demonstrated
%-
3etonuria in fasted BprematureB infants and there remains controvers" as to
$hether mild h"pogl"caemia (plasma glucose N'#D mmol l
?1
affects latenc" of
visualEauditor" evo3ed potentials in this group#
(ntervention studies are needed to establish more precisel" $hether
mildEmoderate h"pogl"caemia needs treatment in preterm infants# ;sing an
intervention threshold of '#D mmol l
?1
as suggested ma" be unnecessar"!
particularl" in more mature preterm infants (*'?*D $ee3s gestation $ho are
other$ise $ell#
,#2 What i) the role of glucagon a+mini)tration in prevention an+ treatment of neonatal
hypoglycaemia@
Glucagon has been sho$n to be effective in provo3ing gl"cogenol"sis and
gluconeogenesis in h"pogl"caemic infants# There are no controlled studies
comparing glucagon therap" $ith the conventional treatment! intravenous
de&trose infusion# +osage! efficac" and safet" of glucagon as an alternative to
infusion of glucose (particularl" $here reFuirements e&ceed 1G mg 3g
?1
min
?1

need to be established in randomised controlled studies#
,#D /) brea)tmil4 more 4etogenic than formulaB if )o0 why@
/ome authors have suggested that breastmil3 is specificall" 3etogenic
(/ection '#*# (t seems unclear $hether this reflects active promotion of
3etogenesis b" a breastmil3 constituent or is simpl" a conseFuence of the trend
to$ards slightl" lo$er blood glucose levels among breastfed infants#
,#7 Role for mea)urement of other )ub)trate) in clinical +eci)ion ma4ing@
:uch stress has been placed on the protective influence of alternative cerebral
metabolic substrates in h"pogl"caemia "et these are rarel" ta3en into account in
clinical management# /hould decisions on treatment be based not merel" on blood
glucose levels but on the simultaneous blood concentration of 3etone bodies and
other substrates! or the presenceEabsence of 3etonuriaU
,#, (mall for ge)tational age ((,2& babie)$
These are ver" important because the" represent the largest group li3el" to be
given supplements to prevent h"pogl"caemia# -andomised trials of supplementar"
feeding in this group are needed urgentl" to establish the incidence and outcome
of h"pogl"caemia during e&clusive breastfeeding and the adverse effects
(including cessation of breastfeeding of earl" formula supplements (/ection
D#'#*#
There is also a need to identif" better anthropometric predictors of h"pogl"caemia
in /G0 infants than $eight for gestational age (/ection D#'#*#
>oth these areas are of crucial importance in the management of /G0 infants in
less developed countries#
%7
Re!erences
References
0dam 50@! -YihY 8! -ahiala .?6! <e3omY3i : (1972 O&idation of glucose and +??OH?but"rate b"
the earl" human fetal brain# 2cta pae+iatrica (can+inavica! /-= 17?')#
0ltman +G! 1oles ./ (19,G 8omograms for precise determination of birth $eight for dates# 6riti)h
Cournal of ob)tetric) an+ gynaecology ! @1= ,1?,D#
0miel /0 (199) 8utrition of the brain= macronutrient suppl"# -rocee+ing) of the nutrition )ociety! 0,=
)G1?)G2#
0nda" .<! /tanle" 10! >a3er 6 (19,1 +elivoria?5apadopoulos :# 5lasma 3etones in ne$born infants=
absence of suc3ling 3etosis# Dournal of -e+iatric) ! A@= D',?D*G#
0nderson +:! <liegman -: (1991 The relationship of neonatal alimentation practices to the
occurrence of endemic necrotising enterocolitis# 2merican Cournal of perinatology! @= D'?D7#
0nderson /! /ha3"a <8! /hrestha 68! de 6 1ostello 0: (199* H"pogl"caemia= 0 common problem
among uncomplicated ne$born infants in 8epal# Dournal of tropical pe+iatric)! ,A= '7*?'77#
0uer -8! /ies%Z > (19,, >iological differences bet$een ischaemia! h"pogl"caemia and epileps"# 2nnal)
of neurology! )-= D99?7G7#
0uer -8! /ies%Z > (199* H"pogl"caemia= brain neurochemistr" and neuropatholog"# 6ailliere) clinical
en+ocrinology an+ metaboli)m! 1 (*= D11?D'2#
0"nsle"?Green 0 (1991 Glucose= 0 fuel for thought[ Dournal of pae+iatric) an+ chil+ health! )1= '1?*G#
>eeb" 5@! @effer" H (199' -is3 factors for necrotising enterocolitis= the influence of gestational age#
2rchive) of +i)ea)e in chil+hoo+! /1= )*'?)*2#
>eard 0G! 5anos T1! :arasigan >A! .minians @! <enned" H4! 6amb @ (19DD 5erinatal stress and the
premature neonate# ((# .ffect of fluid and calorie deprivation on blood glucose# Dournal of -e+iatrics! /@=
*'9?*)*#
>ergme"er H; (197) 'etho+) of enAymatic analy)i)! Aolume *! 'nd# .nglish .dition# +eerfield >each!
4lorida! Aerlag 1hemie (nternational#
>ier +:! 6ea3e -+! Ha"mond :W! 0rnold <@! Gruen3e 6+! /perling :0! <ipnis +: (1977
:easurement of the BtrueB glucose production rate in infanc" and childhood $ith D!D?dideuteroglucose#
!iabete)! )/= 1G1D?1G'*#
>issett W:! Watt @! -ivers -50! :illa 5@ (19,9 5ostprandial motor response of the small intestine to
enteral feeds in preterm infants# 2rchive) of +i)ea)e in chil+hoo+! /-= 1*2D?1*D1#
>land @:! 0ltman +G (19,D /tatistical methods for assessing agreement bet$een t$o methods of
clinical measurement# Lancet! i= *G7?*1G#
>oo3 6/! Herbst @@! @ung 06 (197D 1omparison of fast and slo$ feeding rate schedules to the
development of necrotising enterocolitis# Dournal of -e+iatric)! @A= )D*?)DD#
>ougn\res 54! Xemmel 1! 4err] 5! >ier +: (19,D <etone bod" transport in the human neonate and
infant# Dournal of clinical inve)tigation ! 11= )'?),#
%0
>ourchier +! Weston 5! Heron 5 (199' H"postop for neonatal h"pogl"caemia# New Eealan+ me+ical
Cournal! .B0= ''#
>ro$n .G! /$eet 0S (197, 5reventing necrotising enterocolitis in enonates# Dournal of the 2merican
me+ical a))ociation (D2'2&! )-B= ')2'?')2)#
1arter 5.! 6lo"d +@! +ufft" 5 (19,, Glucagon for h"pogl"caemia in infants small for gestational age#
2rchive) of +i)ea)e in chil+hoo+! /,= 1'D)?1'DD#
1hance GW! >o$er >+ (19DD H"pogl"caemia and temporar" h"pergl"caemia in infants of lo$ birth
$eight for maturit"# 2rchive) of +i)ea)e in chil+hoo+! -.= '79?',2#
1hantler 1! >aum @+! 8orman +0 (19D7 +e&trosti& in the diagnosis of neonatal h"pogl"caemia#
Lancet! ii= 1*92?1*9D#
1ollins @.! 6eonard @A (19,) H"perinsulinism in asph"&iated and small for dates infants $ith
h"pogl"caemia# Lancet! ii= *11?*1*#
1ollins @.! 6eonard @A! Teale +! :ar3s A! Williams +:! <enned" 1-! Hall :0 (199G
H"perinsulinaemic h"pogl"caemia in small for dates babies# 2rchive) of +i)ea)e in chil+hoo+! /0= 111,?
11'G#
1onrad 5+! /par3s @W! Osberg (! 0brams 6! Ha" WW (19,9 1linical application of a ne$ glucose
anal"ser in the neonatal intensive care unit= 1omparison $ith other methods# Dournal of pe+iatric)! ..-=
',1?',7#
1ornblath :! Odell G>! 6evin .S (1929 /"mptomatic neonatal h"pogl"caemia associated $ith
to&aemia of pregnanc"# Dournal of pe+iatric)! 00= 2)2?2D'#
1ornblath :! /ch$artz 5 (197D !i)or+er) of carbohy+rate metaboli)m in infancy! 5hiladelphia! W>
/aunders#
1ornblath :! -eisner /H (19D2 >lood glucose in the neonate and its clinical significance# New :nglan+
Cournal of me+icine! )1,= *7,?*,1#
1ornblath :! /ch$artz -! 0"nsle"?Green 0! 6lo"d @< (199G H"pogl"cemia in infanc"= The need for a
rational definition# -e+iatric)! @0= ,*)?,*7#
1ornblath :! /ch$artz - (199* H"pogl"cemia in the neonate# Dournal of pe+iatric :n+ocrinology! /=
11*?1'9#
1o$ett -:! Oh W! /ch$artz - (19,* 5ersistent glucose production during glucose infusion in the
neonate# Dournal of clinical inve)tigation0 1.= )D7?)7D#
+enne /1! <alhan /1 (19,D Glucose carbon rec"cling and o&idation in human ne$borns# 2merican
Cournal of phy)iology! )0. (.ndocrinol# :etab#= .71?.77#
+eshpande /! >artlett <! 0"nsle"?Green 0! Ward 5latt :5 (199) 5ersistent immaturit" of counter?
regulator" 3etogenesis in preterm infants# 2b)tract -%;: 6riti)h -ae+iatric 2))ociation 2nnual 'eeting$
War$ic3! >ritish 5aediatric 0ssociation#
+iGiacomo @.! Ha" WW (199' 0bnormal glucose homeostasis# (n= /inclair @1 et al#! eds# :ffective
are of the Newborn /nfant# O&ford! O&ford ;niversit" 5ress= 29G?DG1#
+ombro$s3i G@! /$iate3 <-! 1hao <6 (19,9 6actate! *?h"dro&"but"rate and glucose as substrates for
the earl" postnatal rat brain# Neurochemical re)earch0 .-= DD7?D72#
%9
Re!erences
+o"le @@! Xipurs3" 0 (199' 8eonatal blood disorders# (n= /inclair @1 et al#! eds# :ffective are of the
Newborn /nfant# O&ford! O&ford ;niversit" 5ress= )**?)*2#
.llis :! :anandhar +/! :anandhar 8! 6and @:! 5atel 8! de 6 1ostello 0: (199D 1omparison of t$o
cotside methods for the detection of h"pogl"caemia among neonates in 8epal# 2rchive) of !i)ea)e in
hil+hoo+! 10=41''?41'2#
.pstein :4! 8icholls .! /tubblefield 5G (1979 8eonatal h"pogl"caemia after beta?s"mpathomimetic
tocol"tic therap"# Dournal of pe+iatric)0 A-= )99?)2*#
4arFuhar @W (192) 1ontrol of blood sugar level in the neonatal period# 2rchive) of +i)ea)e in
chil+hoo+0 )A= 219?2'9#
4arFuhar @W (192D The significance of h"pogl"caemia in the ne$born infant of the diabetic $oman#
2rchive) of +i)ea)e in chil+hoo+0 ,.= 'G*?'11#
4ernandes @! >erger -! /mit G50 (19,) 6actate as a cerebral metabolic fuel for glucose?D?phosphatase
deficient children# -e+iatric re)earch0 .@= **2?**9#
4ernandes @! >erger - (199* H"pogl"caemia= principles of diagnosis and treatment in children#
6ailliere) clinical en+ocrinology an+ metaboli)m0 1= 291?D1G#
4luge G (197) 1linical aspects of neonatal h"pogl"caemia# 2cta pae+iatrica (can+inavica0 /,= ,'D#
4o& -.! -edstone + (197D /ources of error in glucose determinations in neonatal blood b" glucose
o&idase methods! including de&trosti&# 2merican Cournal of clinical pathology0 //= D2,?DDD#
4raser - (199) +iabetes in pregnanc"# 2rchive) of +i)ea)e in chil+hoo+0 1.= 4'')?'*G#
Gardosi @! 1hang 0! <ul"a > et al# (199' 1ustomised antenatal gro$th charts# Lancet0 ,,A= ',*?',7#
Gerich @. (199* 1ontrol of gl"caemia# 6ailliere) clinical en+ocrinology an+ metaboli)m0 1= 221?2,D#
Ginsburg >.! 6indblad >/! 5ersson >! Xetterstrom - (19,2 5lasma valine and urinar" 1?peptide in
infants# The effect of substituting breastfeeding $ith formula or formula $ith human mil3# 2cta
pae+iatrica (can+inavica0 1-= D12?D1D#
Glader >.! 8aiman @6 (1991 .r"throc"te disorders in infanc"# (n= Taeusch HW et al#! eds# (chaffer 5
2veryF) !i)ea)e) of the Newborn! Dth ed# 5hiladelphia! W> /aunders= ,''?,'*#
Goldman H( (19,G 4eeding and necrotising enterocolitis# 2merican Cournal of +i)ea)e) of chil+ren! .,-=
22*?222#
Gotlin -W! /ilver H< (197G 8eonatal h"pogl"caemia! h"perinsulinism and an absence of pancreatic
alpha cells# Lancet0 i= 1*)D#
Grazaitis +:! /e&son W- (19,G .rroneousl" high +e&trosti& values caused b" isoprop"l alcohol#
-e+iatric)0 //= ''1?'''#
Greisen G! 5r"ds O (19,9 8eonatal h"pogl"caemia (6etter# Lancet0 i= **'?***#
Griffiths 0+! >r"ant G: (1971 0ssessment of effects of neonatal h"pogl"caemia= 0 stud" of )1 cases
$ith matched controls# 2rchive) of +i)ea)e in chil+hoo+0 -/= ,19?,'7#
Griffiths 0+! 6a$rence <: (197) The effect of h"po&ia and h"pogl"caemia on the brain of the
ne$born infant# !evelopmental me+icine an+ chil+ neurology0 ./= *G,?*19#
,3
Gutberlet -6! 1ornblath : (1972 8eonatal h"pogl"cemia revisited! 1972# -e+iatric)0 0@= 1G?17#
Hales 18! >ar3er +@5 (199' T"pe ' (non?insulin dependent diabetes mellitus= the thrift" fetus
h"pothesis# !iabetologia0 ,0= 292?DG1#
Hall +:>! :ichel @: (1992 /creening in infanc"# 2rchive) of +i)ea)e in chil+hoo+0 1)= 9*?9D#
Hameed :! 5ollard -! /harief 8 (1992 >edside assessment of blood glucose in the neonatal period ? an
ongoing problem# 6r D /nt are0 /= 11)?117#
Hartmann 04! @audon @1 (19*7 H"pogl"caemia# Dournal of pe+iatric)! ..= 1#
Ha$don @:! 0"nsle"?Green 0! 0lberti <G::! Ward?5latt : (199' The role of pancreatic insulin
secretion in neonatal glucoregulation# (# Health" term and preterm infants# 2rchive) of +i)ea)e in
chil+hoo+0 /@= '7)?'79#
Ha$don @:! Ward 5latt :5! 0"nsle" Green 0 (199' 5atterns of metabolic adaptation for preterm and
term infants in the first neonatal $ee3# 2rchive) of +i)ea)e in chil+hoo+0 /1= *27?*D2#
Ha$don @:! Ward 5latt :5! :c5hail /! 1ameron H! Wal3insha$ /0 (199' 5rediction of impaired
metabolic adaptation b" antenatal +oppler studies in small?for?gestational age fetuses# 2rchive) of
+i)ea)e in chil+hoo+0 /1= 7,9?79'#
Ha$don @:! Ward 5latt :5 (199* :etabolic adaptation in small for gestational age infants# 2rchive)
of +i)ea)e in chil+hoo+0 /@= 'D'?'D,#
Ha$don @:! 0"nsle"?Green 0! Ward 5latt : (199* 8eonatal blood glucose concentrations= metabolic
effects of intravenous glucagon and intragastric medium chain trigl"ceride# 2rchive) of +i)ea)e in
chil+hoo+0 /@= '22?'D1#
Ha$don @:! Weddell 0! 0"nsle"?Green 0! Ward?5latt : (199* Hormonal and metabolic response to
h"pogl"caemia in small for gestational age infants# 2rchive) of +i)ea)e in chil+hoo+0 /@= 'D9?'7*#
Ha$don @:! Ward 5latt :! 0"nsle" Green 0 (199) 5revention and management of neonatal
h"pogl"caemia# 2rchive) of +i)ea)e in chil+hoo+0 1B= 4DG?4D2#
Ha$don @:! Hubbard :! Hales 18! 1lar3 5 (1992 The use of a specific radioimmunometric assa" to
determine preterm neonatal insulin?glucose relationships# 2rchive) of +i)ea)e in chil+hoo+0 1,= 41DD?
41D9#
Ha$orth @1! :c-ae <8 (19D2 The neurological and developmental effects of neonatal h"pogl"caemia=
0 follo$?up of '' cases# ana+ian me+ical a))ociation Cournal0 A)= ,D1?,D2#
Ha$orth @1! +illing 6! Sounoszai :< (19D7 -elation of blood glucose to haematocrit! birth $eight and
other bod" measurements in normal and gro$th retarded ne$born infants# Lancet0 ii= 9G1?9G2#
Ha$orth @1! Aid"asagar + (1971 H"pogl"cemia in the ne$born# linical ob)tetric) an+ gynecology0
.-= ,'1?,*9#
Ha" WW (1991 The placenta= 8ot %ust a conduit for maternal fuels# !iabete)0 -B %$uppl* )'= ))?2G#
Ha" WW! Osberg (: (19,* The B."etoneB blood glucose reflectance colorimeter evaluated for in vitro
and in vivo accurac" and clinical efficac"# linical chemi)try0 )A= 22,?2DG#

Ha"mond :W! <arl (.! 5agliara 0/ (197) (ncreased gluconeogenic substrates in the small?for?
gestational age infant# New :nglan+ Cournal of me+icine0 )A.= *''?*',#
,1
Re!erences
Hec3 6@! .renburg 0 (19,7 /erum glucose levels in term neonates during the first ), hours of life#
Dournal of pe+iatric)0 ..B= 119?1''#
Hernandez :@! Aannucci -1! /alcedo 0! >rennan -W (19,G 1erebral blood flo$ and metabolism
during h"pogl"caemia in ne$born dogs# Dournal of neurochemi)try! ,0= D''?D',#
Herrera 0@! Hsiang S?H (19,* 1omparison of various methods of blood sugar screening in ne$born
infants# Dournal of pe+iatric)0 .B)# 7D9?77'#
Ho <6! 6o3e H6! Tan <W (1991 0ccurac" and reliabilit" of t$o methods of screening for
h"pogl"cemia in neonates# Dournal of the (ingapore pe+iatric) )ociety0 ,,= 12D?12,#
Holtrop 51! :adison <0! <iechle 46! <archer -.! >atton +G (199G 0 comparison of chromogen test
strip (1hemstrip bG and serum glucose values in ne$borns# 2merican Cournal of +i)ea)e) of chil+ren0
.--= 1,*?1,2#
Holtrop 51 (199* The freFuenc" of h"pogl"cemia in full?term large and small for gestational age
ne$borns# 2merican Cournal of perinatology0 .B= 12G?12)#
Hume -! >urchell 0 (199* 0bnormal e&pression of glucose?D?phosphatase in preterm infants# 2rchive)
of +i)ea)e in chil+hoo+0 /@= 'G'?'G)#
@arai (! :est"an @! /chultz <! 6azar 0! Halasz :! <rass" ( (1977 >od" size and neonatal
h"pogl"caemia in intrauterine gro$th retardation# :arly human +evelopment0 .= '2?*,#
@ones -0<! -oberton 8-1 (19,D /mall for dates babies= are the" reall" a problemU 2rchive) of
+i)ea)e in chil+hoo+0 /.= ,77?,,G#
@oosten <4! /chelle3ens 05! Wael3ens @@! Wulffraat 8: (1991 .rroneous diagnosis Bneonatal
h"pogl"cemiaB due to incorrect preservation of blood samples# Ne+erlan+) .iC+)chrift voor
,enee)4un+e0 .,0= 1D91?1D9)#
@ouppila -! <auppila 0! Tuimila - et al# (19,G :aternal! fetal and neonatal effects of beta?adrenergic
stimulation in connection $ith caesarian section# 2cta ob)tetricia et gynecologica (can+inavica0 0A= ),9?
)9*#
<alhan /1! /avin /:! 0dam 50@ (197D :easurement of glucose turnover in the human ne$born $ith
glucose?1?
1*
1# Dournal of clinical en+ocrinology an+ metaboli)m0 -,= 7G)?7G7#
<alhan /1! /avin /:! 0dam 50@ (1977 0ttenuated glucose production rate in ne$born infants of
insulin dependent diabetic mothers# New :nglan+ Cournal of me+icine0 )A/= *72?*7D#
<alhan /1! Oliven 0! <ing <1! 6ucero 1 (19,D -ole of glucose in the regulation of endogenous
glucose production in the human ne$born# -e+iatric re)earch0 )B= )9?2'#
<aplan :! >londheim O! 0lon (! ."lath ;! Trestian /! .idelman 0( (19,9 /creening for h"pogl"cemia
$ith plasma in neonatal blood of high hematocrit value# ritical care me+icine0 .1= '79?','#
<oh THHG! ."re @0! 0"nsle"?Green 0 (19,, 8eonatal h"pogl"caemia ? the controvers" regarding
definition# 2rchive) of +i)ea)e in chil+hoo+0 /,= 1*,D?1*9,#
<oh THHG! 0"nsle"?Green 0! Tarbit :! ."re @0 (19,, 8eural d"sfunction during h"pogl"caemia#
2rchive) of +i)ea)e in chil+hoo+0 /,= 1*2*?1*2,#
,4
<oivisto :! >lanco?/eFueiros :! <rause ; (197' 8eonatal s"mpomatic and as"mptomatic
h"pogl"caemia= a follo$?up stud"# !evelopmental me+icine an+ chil+ neurology0 .-= DG*?D1)#
<ollee 60! :onnens 60! 1e%3a A! Wilms -H (197, 5ersistent neonatal h"pogl"caemia due to glucagon
deficienc"# 2rchive) of +i)ea)e in chil+hoo+0 0,= )''?)')#
<raus H! /chlen3er /! /ch$edes3" + (197) +evelopmental changes of cerebral 3etone bod" utilisation
in human infants# Hoppe EeylerF) Eeit)chrift fGr -hy)iologi)che hemie0 ,00= 1D)?17G#
<torza 0! >ihoreau :?T! 8ur%han 8! 5icon 6! Girard @ (19,2 (nsulin and glucagon during the perinatal
period= secretion and metabolic effects on the liver# 6iology of the neonate0 -@= 'G)?''G#
6ang /! 6a$rence 1@! Orme 16C. (199) 1up feeding= an alternative method of infant feeding# 2rchive)
of +i)ea)e in chil+hoo+0 1.= *D2?*D9#
6e+une :0 (197' (ntravenous plasma glucose tolerance and plasma insulin studies in small for dates
infants# 2rchive) of +i)ea)e in chil+hoo+0 -1= 111?11)#
6evits3" 66! 4isher +.! 5aton @> et al# (1977 4asting plasma levels of glucose! acetoacetate! +??
h"dro&"but"rate! gl"cerol and lactate in the baboon infant= correlation $ith cerebral upta3e of substrates
and o&"gen# -e+iatric re)earch0 ..= '9,?*G'#
6ilien 6+! 5ildes -/! /rinivasan G! Aoora /! Seh T4 (19,G Treatment of neonatal h"pogl"cemia $ith
minibolus and intravenous glucose infusion# Dournal of pe+iatric)0 A1= '92?'9,#
6in H1! :aguire 1! Oh W! 1o$ett - (19,9 0ccurac" and reliabilit" of glucose reflectance meters in the
high?ris3 neonate# Dournal of pe+iatric)0 ..0= 99,?1GGG#
6indblad >/ (197G The venous plasma free amino acid levels during the first hours of life# (# 0fter
normal and short gestation and gestation complicated b" h"pertension $ith special reference to the Bsmall
for datesB s"ndrome# 2cta pae+iatrica (can+inavica0 0A= 1*?'G#
6indblad >/! -ahimtoola -@! <han 8 (197G The venous plasma free amino acid levels during the first
hours of life# ((# (n a lo$er socioeconomic group of a refugee area in <arachi! West 5a3istan! $ith special
reference to the Bsmall for datesB s"ndrome# 2cta pae+iatrica (can+inavica0 0A= '1?')#
6ubchenco 6O! >ard H (1971 (ncidence of h"pogl"cemia in ne$born infants classified b" birth $eight
and gestational age# -e+iatric)0 -1= ,*1?,*,#
6ucas 0! 0drian T.! 0"nsle"?Green 0! >loom /- (19,G (atrogenic h"perinsulinism at birth# Lancet0 i=
1))?1)2#
6ucas 0! >o"es /! >loom /-! 0"nsle"?Green 0 (19,1 :etabolic and endocrine responses to a mil3 feed
in si&?da"?old term infants= differences bet$een breast and co$Cs mil3 formula feeding# 2cta pae+iatrica
(can+inavica! 1B= 192?'GG#
6ucas 0 (19,7 0(+/ and human mil3 ban3 closures# Lancet0 i= 1G9'?1G9*#
6ucas 0! :orle" -! 1ole T@ (19,, 0dverse neurodevelopmental outcome of moderate neonatal
h"pogl"caemia# 6riti)h me+ical Cournal (6'D&0 )A1= 1*G)?1*G,#
6ucas 0! 1ole T@ (199G >reastmil3 and neonatal necrotising enterocolitis# Lancet0 ,,/= 1219?12'*#
:c<eo$n -.! :arsh +! 0marnath ;! Garrison 1X! 0dd" 16! Thompson /@! 0ustin T6 (199' -ole of
dela"ed feeding and of feeding increments in necrotising enterocolitis# Dournal of pe+iatric)0 .).= 7D)?
77G#
,3
Re!erences
:cLuarrie ( (192) (diopathic spontaneousl" occurring h"pogl"caemia in infants# 2merican Cournal of
+i)ea)e) of chil+ren0 -= *99?)',#
:ehta 0! Wootton -! 1heng <8! 5enfold 5! Hallida" +! /tace" T. (19,7 .ffect of diazo&ide or
glucagon on hepatic glucose production rate during e&treme neonatal h"pogl"caemia# 2rchive) of +i)ea)e
in chil+hoo+0 /)= 9')?9*G#
:ehta 0 (1991 H"perinsulinaemic h"pogl"caemia in small for dates babies# 2rchive) of +i)ea)e in
chil+hoo+0 //= 7)9#
:ehta 0 (199) 5revention and management of neonatal h"pogl"caemia# 2rchive) of +i)ea)e in
chil+hoo+0 1B= 42)?4D2#
:elichar A! +rahota A! Hahn 5 (19D7 <etone bodies in the blood of full term ne$borns! premature and
d"smature infants and infants of diabetic mothers# 6iology of the neonate0 ..= '*?',#
:est"an @! /oltesz G! /chultz <! Horvath : (1972 H"peraminoacidaemia due to the accumulation of
gluconeogenic amino acid precursors in h"pogl"caemic /G0 infants# Dournal of pe+iatric)0 @1= )G9?)1)#
:est"an @! /chultz <! /oltesz G! Horvath : (197D The metabolic effects of glucagon infusion in
normogl"caemic and h"pogl"caemic small for gestational age infants# ((# 1hanges in plasma amino acids#
2cta pae+iatrica aca+emiae )cientiarum Hungarica0 .1= ')2?'2*#
:iller H1! -oss -0 (19)G -elation of h"pogl"cemia to the s"mptoms observed in infants of diabetic
mothers# Dournal of pe+iatric)0 ./= )7*?),1#
:ilner -+G! 0sh$orth :0! >arson 0@ (197' (nsulin release from human foetal pancreas in response to
glucose! leucine and arginine# Dournal of en+ocrinology0 0)= )97?2G2#
8ehlig 0 (199* (maging and the ontogen" of brain metabolism# Dournal of clinical en+ocrinology an+
metaboli)m0 1%,'= D'7?D)'#
8ehlig 0! 5ereira de Aasconcelos 0 (199* Glucose and 3etone bod" utilisation b" the brain of neonatal
rats# -rogre)) in Neurobiology0 -B= 1D*?''1#
8orval :0 (192G >lood sugar values in premature infants# Dournal of pe+iatric)0 ,/= 177?1,)#
Office of 5opulation 1ensuses 7 /urve"s (199' /nfant fee+ing0 %""<# 6ondon! Her :a%est"Cs /tationer"
Office#
O$en O! :organ 0! <emp H et al# (19D7 >rain metabolism during fasting# Dournal of clinical
inve)tigation0 -/= 12,9?1292#
5apagapiou :5! 0uer -8 (199G -egional neuroprotective effects of the 8:+0 receptor anatagonist
:<?,G1 (dizocilpine in h"pogl"cemic brain damage# Dournal of cerebral bloo+ flow an+ metaboli)m!
.B= '7G?'7D#
5atel :/! @ohnson 10! -a%an -! O$en O. (1972 The metabolism of 3etone bodies in developing
human brain= development of 3etone bod" utilising enz"mes and 3etone bodies as precursors for lipid
s"nthesis# Dournal of neurochemi)try0 )0= 9G2?9G,#
5earce @6! >uchanan 64 (1979 >reastmil3 and breastfeeding in ver" lo$ birth $eight infants# 2rchive)
of +i)ea)e in chil+hoo+0 0-= ,97?,99#
5edersen @! >o%sen?:^ller >! 5oulsen H (192) >lood sugar in ne$born infants of diabetic mothers# 2cta
:n+ocrinol0 .0= **?2'#
,%
5erelman -H! Gutcher G-! .ngle :@! :ac+onald :@ (19,' 1omparative anal"sis of four methods for
rapid glucose determination in neonates# 2merican Cournal of +i)ea)e) of chil+ren0 .,/= 1G21?1G2*#
5ersson >! Gentz @ (19DD The pattern of blood lipids! gl"cerol and 3etone bodies during the neonatal
period! infanc" and childhood# 2cta pae+iatrica (can+inavica0 00= *2*?*D'#
5ildes -/! 1ornblath :! Warren (! 5age?.l .! di :enza +:! 5eeva 0 (197) 0 prospective controlled
stud" of neonatal h"pogl"cemia# -e+iatric)0 0-= 2?1)#
5rociano" -/! 5inheiro 1.0 (19,' 8eonatal h"perinsulinaemia after short?term maternal beta?
s"mpathomimetic therap"# Dournal of pe+iatric)0 .B.= D1'?D1)#
5r"ds O! Greisen G! 4riis?Hansen > (19,, 1ompensator" increase of 1>4 in preterm infants during
h"pogl"caemia# 2cta pae+iatrica (can+inavica! 11= D*'?D*7#
5r"ds O! 1hristensen 8@! 4riis?Hansen > (199G (ncreased cerebral blood flo$ and plasma epinephrine in
h"pogl"cemic preterm neonates# -e+iatric)0 @0= 17'?17D#
-ennie @: (199' The ne$born= 8eonatal neurolog"# (n= 1ampbell 0G: et al#! eds# Horfar 5 2rneilF)
.e*tboo4 of -ae+iatric)! :c(ntosh 8! .dinburgh! 1hurchill 6ivingstone= '29?',1#
-e"nolds G@! +avies / (199* 0 clinical audit of cotside blood glucose measurement in the detection of
neonatal h"pogl"caemia# Dournal of pae+iatric) an+ chil+ health0 )A= ',9?'91#
/ann 6! -uitton 0! :athieu :! >ourgeois @! Genoud @ (197, .ffect of intravenous L?alanine
administration on plasma glucose! insulin and glucagon! blood p"ruvate! lactate and ?h"dro&"but"rate
concentrations in ne$born infants# 2cta pae+iatrica (can+inavica0 /1= '97?*G'#
/ann 6! :athieu :! 6asne S! -uitton 0 (19,1 .ffect of oral administration of lipids $ith D7J medium
chain trigl"cerides on glucose homeostasis in preterm neonates# 'etaboli)m0 ,B= 71'?71D#
/ann 6! +ivr" 5! 6asne S! -uitton 0 (19,' .ffect of oral lipid administration on glucose homeostasis in
small?for?gestational age infants# 2cta pae+iatrica (can+inavica0 1.= 9'*?9'7#
/ann 6! :ousson >! -ousson :! :aire (! >ethenod : (19,, 5revention of neonatal h"pogl"caemia b"
oral lipid supplementation in lo$ birth $eight infants# :uropean Cournal of pe+iatric)0 .-1= 12,?1D1#
/audubra" @:! 8arc" 1! 6"onnet 6! >onnefont @5! 5oll The >T! :unnich 0 (199G 1linical approach to
inherited metabolic disorders in neonates# 6iology of the neonate0 0@ (/uppl 1= ))?2*#
/ch$artz - (1991 8eonatal h"pogl"caemia# >ac3 to basics in diagnosis and treatment# !iabete)0 -B
(/uppl '= 71?7*#
/ettergren G! 6indblad >/! 5ersson > (197D 1erebral blood flo$ and e&change of o&"gen! glucose!
3etone bodies! lactate! p"ruvate and amino acids in infants# 2cta pae+iatrica (can+inavica0 /0= *)*?*2*#
/e&son W- (19,) (ncidence of neonatal h"pogl"cemia= 0 matter of definition# Dournal of pe+iatric)0
.B0= 1)9?12G#
/hah 0! /tanhope -! :atthe$ + (199' Hazards of pharmacological tests of gro$th hormone secretion
childhood# 6riti)h me+ical Cournal (6'D&! ,B-= 17*?17)#
/ingh :! /inghal 5<! 5aul A<! +eorari 0<! /undaram <-! Ghorpade :+! 0gadi 0 (1991
8eurodevelopmental outcome of as"mptomatic and s"mptomatic babies $ith neonatal h"pogl"caemia#
/n+ian Cournal of me+ical re)earch I6J0 A-= D?1G#
,,
Re!erences
/inghal 5<! /ingh :! 5aul A<! :alhotra 0<! +eorari 0<! Ghorpade :+ (1991 0 controlled stud" of
sugar?fortified mil3 feeding for prevention of neonatal h"pogl"caemia# /n+ian Cournal of me+ical
re)earch I6J0 A-= *)'?*)2#
/3ov 6! 5r"ds O (199' 1apillar" recruitment for preservation of cerebral glucose influ& in h"pogl"cemic
preterm ne$borns= .vidence for a glucose sensorU -e+iatric)0 AB= 19*?192#
/mallpeice A! +avies 50 (19D) (mmediate feeding of premature infants $ith undiluted breastmil3#
Lancet! ii= 1*)9?1*2'#
/rinivasan G! 5ildes -/! 1attamanchi G! Aoora /! 6ilien 6+ (19,D 5lasma glucose values in normal
neonates= 0 ne$ loo3# Dournal of pe+iatric)0 .BA= 11)?117#
/tanle" 10! 0nda" .<! >a3er 6! +elivoria?5apadopoulos : (1979 :etabolic fuel and hormone
responses to fasting in ne$born infants# -e+iatric)0 /-= D1*?D19#
/toc3s @ (19,G .ffect of nasogastric tubes on nasal resistance during infanc"# 2rchive) of +i)ea)e in
chil+hoo+0 00= 17?'1#
/unehag 0! Gustafsson @! .$ald ; (199) Aer" immature infants (*G $3 respond to glucose infusion
$ith incomplete suppression of glucose production# -e+iatric re)earch0 ,/= 22G?222#
Thomas +@>! +ore 4! 0lberti <GG: (1977 :etabolic effects of salbutamol infusion during premature
labour# 6riti)h Cournal of ob)tetric) an+ gynaecology0 @-= )97?)99#
Thurston @H! Hauhart -.! /chiro @0 (19,* 6actate reverses insulin?induced h"pogl"caemic stupor in
suc3ling?$eanling mice= >iochemical correlates in blood! liver and brain# Dournal of cerebral bloo+ flow
an+ metaboli)m0 ,= )9,?2GD#
Togari H! Oda :! Wada S (19,7 :echanism of erroneous +e&trosti& readings# 2rchive) of +i)ea)e in
chil+hoo+0 /)= )G,?)G9#
Aadasdi .! @acobs . (199* Hemo1ue ?glucose photometer evaluated for use in a neonatal intensive
care unit# linical chemi)try! ,A= '*'9?'**'#
van den >osch 10! >ullough 1HW (199G The effect of suc3ling on term neonatesC core bod"
temperature# 2nnal) of tropical pae+iatric)0 .B= *)7?*2*#
Aidnes @! O"saeter / (1977 Glucagon deficienc" causing severe neonatal h"pogl"caemia in a patient $ith
normal insulin secretion# -e+iatric re)earch! ..= 9)*?9)2#
Ward 5latt :5 (1991 H"pogl"caemia in the ne$born# R(' urr 'e+ Lit (-ae+iatric)&0 -= *1?*)#
Ward 5latt :5! Ha$don @: (199* H"pogl"caemia in the neonate# Dournal of clinical en+ocrinology
an+ metaboli)m0 1= DD9?D,'#
Wharton >0! >o$er >+ (19D2 (mmediate or later feeding for premature babies= a controlled trial#
Lancet! ii= 9D9?97'#
Whitb" 1! de1ates 1-! -oberton 8-1 (19,' (nfants $eighing 1#,?'#2 3g= should the" be cared for in
neonatal units or on postnatal $ardsU Lancet0 i= *''?*'2#
Whitela$ 0! Heister3amp G! /leath <! 0colet +! -ichards : (19,, /3in to s3in contact for ver" lo$
birth $eight infants and their mothers# 2rchive) of +i)ea)e in chil+hoo+0 /,= 1*77?1*,1#
,-
Wil3ins >H! <alra + (19,' 1omparison of blood glucose test strips in the dtection of neonatal
h"pogl"caemia# 2rchive) of +i)ea)e in chil+hoo+0 01= 9),?9DG#
Williams 5-! /perling :0! -acasa X (1979 >lunting of spontaneous and alanine stimulated glucagon
secretion in ne$born infants of diabetic mothers# Dournal of ob)tetric) an+ gynaecology0 .,,= 21?2D#
Soung -/! 5etroff O0! 1hen >! 0Fuila W@ @r#! Gore @1 (1991 5referential utilisation of lactate in
neonatal dog brain= in vivo and in vitro proton 8:- stud"# 6iology of the neonate0 0A= )D?2*#
,7
Acknowledgements
Acknowledgements
:an" than3s are due to the follo$ing people for finding the time to read an earlier draft of all or
part of this $or3 and for providing helpful! constructive criticism= 5rofessor 0nna 0lis"ahbana
((ndonesia! 5rofessor 0# 0"nsle"?Green ((nstitute of 1hild Health! 6ondon! +r 0nthon"
1ostello (6ondon! +r 0rmeda 4ernandes (>omba"! +r @ane Ha$don (;niversit" 1ollege
Hospitals! 6ondon! 5rofessor WW Ha" (1olorado! +r @ane . :cGo$an (5enns"lvania! +r 0
:ehta (+undee! and +r : Ward 5latt (8e$castle#

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