SYMPTOMATIC
NEONATAL
HYPOGLYCEMIA
Studies
of
Carbohydrate
Metabolism
in the
Newborn
Infant
VIII
Marvin Cornblath, M.D., Susan H. Wybregt, M.D., Gloria S. Baens, M.D.,
and Reuben I. Klein, M.D.
Departments of Pediatrics, Research and Educational HospitaLs,
University of Illinois College of Medicine and Michael Reese
Hospital and Medical Center, Chicago, Illinois
(Submitted August 15; accepted for publication November 15, 1963.)
Supported in part by P.H.S. Research Grant HD 00235-03 (HED) from the National Institute of
Child Health and Human Development, Public Health Service, a grant from the United Cerebral Palsy
Research and Educational Foundation, and a grant from the Psychiatric Training and Research Fund
of the Illinois Department of Mental Health.
ADDRESS: (MC.) University of Illinois College of Medicine, 840 South Wood Street, Chicago,
Illinois 60612.
PEDIATRICS, March 1964
388
P
REviousLY, low levels of blood sugarassociated with symptoms of
hypogly-cemia were reported in eight newborn
in-fants.1 Subsequently, Harris and Tizard
described electroencephalographic changes
in neonates with convulsions and 6 of
the 14 premature infants in their series
had hypoglycemia. Zetterstr#{246}m et al. found
that 12 of 31 newborn infants with
con-vulsions were hypoglycemic and responded
promptly to glucose administration. More
recently, Haworth et al. described 6
in-fants and Brown and Walhis,5 10, with
symptomatic hypoglycemia occurring
be-tween 6 and 76 hours of age. Farquhar6
and others79 have seen infants with similar
findings. In the past two and one-half
years, 24 infants have been observed with
symptomatic hypoglycemia occurring in
the first week of life. The purpose of this
paper is to define the clinical
character-istics of this syndrome, and discuss its
pathogenesis and therapy.
PATIENT MATERIAL AND METHODS
Twenty-four infants were observed with
blood glucose levels less than 20 mg/100
ml associated with symptoms during the
first week of life at the Research and
Edu-cational Hospitals, University of Illinois
College of Medicine and the Michael Reese
Hospital and Medical Center between
Oc-tober, 1960, and January, 1963. Five of
the infants were delivered at Michael Reese
Hospital, 3 at Research and Educational
Hospitals, 13 at other hospitals in the
Chicago area, and 3 at home.
Glucose was analyzed by a specific
glu-cose oxidase method’0 on filtrates of
capil-lary blood, which had been precipitated
with Ba(OH)2 and Zn5O411 at the cribside
as described previously.12 Rapid
intrave-nous glucose tolerance tests (1 gm/kg as a
25% solution) were performed on 6 infants.
Twenty-three glucagon or combined
glu-cagon and epinephrine tolerance tests were
done in 14 infants. Ten oral leucine (150
mg/kg) and 6 intravenous tolbutamide (10
mg/kg) tolerance tests were performed as
well. The techniques for administering the
test material, blood sampling, and analysis
of the sugars have been reported.13
Other laboratory analyses, e.g., CBC,
urines, blood, and spinal fluid chemistries
were performed in the routine clinical
lab-oratory. Levels of bilirubin in serum were
analyzed in the research laboratory by the
method of Hsia, Hsia and Gellis.14
#{176}Recently, Relander and R#{228}ih#{228}mdemonstrated an inhibition of glucose oxidase by reduced
glu-tathione (GSH) which resulted in low levels of
blood glucose with their technique. Adding 30,
45, or 75 mg/100 ml reduced glutathione to the
lysed blood samples from 3 newborn infants and
precipitating with Ba(OH)2 and ZnSO4 resulted
in levels of glucose indistinguishable from the
ARTICLES 389
RESU LTS
Clinical Characteristics (Tables I-Ill)
The 24 infants, as well as their mothers,
presented a number of clinical features in
common. Therefore, the pertinent data
about the mothers, their pregnancy, labor,
and delivery, and the infants, their
condi-tion at birth, weight, clinical course,
ther-apy, and diagnostic studies have been
grouped together in order to characterize
symptomatic hypoglycemia in the neonate.
Two representative case histories are
pre-senteci in the appendix.
Mothers
The mothers were 15 to 41 years of
age. Ten were nonwhite, 14 white; 14
primiparae and 10 multiparae, having had
2 to 7 previous babies. Six mothers were
Rh negative, unsensitized. None of the
mothers had any chronic medical illness or
known metabolic disturbance. Only 1 of
the 10 multiparae had had a previous
pre-mature infant and 4 had previous
abor-tions. During the current gestation, 14 had
an uneventful pregnancy, 8 had toxemia
as manifested by edema, albuminuria, and/
or hypertension (Table II). Six of the 8
mothers with toxemia of pregnancy were
primiparae. One mother (DUB) had a
posi-tive serological test for syphilis which was diagnosed and adequately treated during the current pregnancy and 1 (DIA) had vaginal bleeding from a ruptured marginal
sinus.
Labor and Delivery
The duration of labor varied from 20
minutes to 10 hours, 40 minutes. Four
in-fants were born after a labor of less than
2 hours. The time of rupture of the fetal
membranes was unknown in 3, within 2
hours of birth in 11, and up to 5 days in
10. Nineteen mothers received no analgesia;
1, morphine; and 4, meperidine HCL
(DemeroP1). Sixteen women were delivered
without anesthesia, 2 received general anes-thesia, 4, local, 1, spinal, and 1, a
combi-nation of local and spinal. All infants were
: LJ1 I I I . ITR5jTRir( WOGHT CVE
. :f’s. :b6ctp41 i%3 ,..,
:
-: .: :
I.
:J-
:
I:
I
-eSatoss1
ate.
n eontdAlSyrnpforaiI.tc Uypo1!yceiiia..FIG. 1. The birth weight of each infant is plotted
versus the weeks of gestation as calculated from
the mother’s last menstrual period.
delivered vaginally. Twenty infants were
delivered spontaneously from a cephalic
presentation; 1, with low forceps; 2,
spon-taneously from a breech presentation; and
1, from a breech presentation after
induc-tion of labor.
Infants
Of the 24 infants, 15 were male. Birth
weights varied from 910 to 2,740 gm. Three were less than 1,000 gm, 6 between 1,001
and 1,500 gm, 12 between 1,500 and 2,250
gm, and 3 between 2,500 and 2,740 gm.
Twenty-one infants were below the 10th
percentile in weight for their period of
ges-tation and 3 were between the 10th and
25th percentile (Fig. 1).15 In the 7 sets of
twins, 3 of the hypoglycemic infants were
first born (Table I). In six instances, where
the weights of both twins were known, the
affected twin weighted from 200 to 1,715 gm less than his sibling. Seventeen infants
were in good condition at birth and
breathed and cried spontaneously. Four
in-fants (HOW, DUB No. 2, KRE, HOD No.
2’) were in fair condition, requiring oxygen
Mother
history
.4ge
Ihirt-Prenatal
Gesta-tion
(u-ks) Sex
Birth Length
u-(kg)
Infant
WI.
Admis-of Condition
twin (It ag
(kg) Birth (hrs)
Negative 34 M I.8 44 1.64 Good
First
Symptoms
age (hr.’)
Jitteriness
Blrod glucose mg 100 ml
age (hra)
Age-Glucose
(hr) (mj/100 ml)
82-5
89-Il
2.69
still born
I)
Plethoric Good
Good Oh’
(‘AM No. I 19 ‘sV 0-1-1
1101) No. 2 31 SV 0--I-I Toxemia 35 M 1.75 45
l)OR No. 1 19 C 0-1-2 Negative 28 M 0.92 3.5
ETRI No. 2 2.5 S\’ 0-1-3 Negative 40 M 1.85 44 2.60 Good
MeN No.2 18 \V 0-1-2 Negative 38 M 1.36 41 1.72 Fair
Meningo-myelocele
1)LTBNo.2 36 ( 1-1-5 Kahn 1:8, 40 F 0.93 38.5 2.66 Fair V1)RL 1:2
KAS No. I 21 0-2-2 FO(emia 36 M 1.53 40 1.73 Good
Convulsions
Eye rolling
7days
Tremors
50
Cyanosis 30
6-0
1-7 days N
7days-9
8 days--fl
50-17
52-15
30-13 48-8 14
30
30
SAbortion-premature -No. o(living chil(Iren. t Cerebral spinal fluid.
Jitteriness .59-15
30 56-16
Hesp.
distress 26-18
50-15
390 NEONATAL HYPOGLYCEMIA
TABLE I
SYMPTOMATIC HYPOGLYCEMIA IN THE NEONATE-TIlE SMALLER OF TwINs
poor condition at birth; JEN required 45
minutes of assisted ventilation, whereas
WILL and WILS were intubated and given
positive pressure oxygen.
Onset and Symptoms
The age on admission to the premature
nursery varied from % to 56 hours after
birth. In 4 infants, the symptoms preceded
admission by 7 to 30 hours. The onset of
signs and symptoms varied from 2% hours
to 7 days of age. In 6 infants, symptoms
occurred before 6 hours of age; in 3,
be-tween 6 and 24 hours; in 9, between 24
and 48 hours; in 5, between 48 and 96
hours; and in 1 at 7 days. The presenting
signs were tremors in 13, episodes of
cyano-sis in 6, convulsions in 3, apnea or
respira-tory distress in 2, and eye rolling in 2
(Table IV). At the time of symptoms either
single or replicate values of blood glucose
varied between 0 and 19 mg/100 ml (Tables
I-Ill). Other symptoms included limpness,
apathy, a weak or high pitched cry, and
difficulty in feeding (Table IV).
Routine La boratory Determinations
Complete blood counts were done on
every infant. Six infants (HOD No. 2, DOR No. 1, KAS No. 1, DAR, DAN, JEN) had polycythemia as evidenced by a
hemo-globin concentration exceeding 25 gm/100
ml the first week of life or 20 gm/100 ml
the second week. In 3 infants, platelets
were decreased, 1 (DUB) on smear, 1 (JEN)
had a platelet count of 50,000/mm and 1
(DAR), 89,000/mm.3 Twenty-three infants
had one or more urinalyses. No acetonuria
nor glycosuria was present. Levels of
cal-cium in blood were measured in 8 infants
and found to be less than 7 mg/100 ml in
3 (DAR, YOU, DAN) and 7.6 mg/100 ml
in 1 infant (DUB). Lumbar punctures were
performed successfully in 8 babies and the
cerebrospinal fluid was normal in all,
Symptoms - Treatment Laboratory
Remarks &Follow-up
a ll C.) a a. . -. y I. -:, : z I I d. -. . .-‘ ra . I-. “: CBC
Ibb=gm/100 snl Urin Ca/P mg/JOG ml CSFt BU.V mg/ILk) (at
+ + + + + + + Normal N
9-4
-4.9
N 14 24 normal
+ + + + + + + + + + + + + + + N N -‘Is 22 21 N + ++ ++ +
15 mo normal
-JOmo slow, arrested
hydro-cephalus
24 mo normal
+ ++
+ +
Normal N
+ Platelets N 7.6
(lecreasetI
l1b26
lict 81% N 2yr normal
ARTICLES
TABLE I
SYMPTOMATIC HYPOGLYCEMIA IN THE NEONATE-TIlE SMALLER OF TSVINS
391
111) 27 llct 85%
lIb 25
lict 73%
+ Normal N
+
bilirubin were obtained in 13 infants and
never exceeded 18 mg/100 ml.
Therapy, Course, and Follow-up
In all infants, improvement followed the
initiation of therapy. Since the symptoms
were variable in their manifestation and
due to inexperience and difficulty in
main-taming parenteral fluids, a number of
dif-ferent therapies were administered.
Twenty-one infants received oral 10%
glu-cose as a supplement either to their
regu-lar feedings or to intravenous therapy.
Eighteen infants were given glucose or
invert sugar in 10% concentrations into a
peripheral vein for periods of 2 to 6 days.
When symptoms were severe or recurred,
2-4 ml of 50% glucose were given
intra-venously as a single injection. Despite
par-enteral fluids, the level of glucose in blood
remained very low and/or some of the
manifestations of hypoglycemia persisted in
1)ied at 2 mo meningornyelo-cele hy(Irocephalus.
congeni-tal heart disease
4 mo normal
many of the infants. Therefore, in addition,
15 of the babies were given ACTH (10) or
cortisone (3) or both (2) with a subsequent
rise in the level of glucose. ACTH was given intramuscularly in a dose of 4 units every 12
hours, and cortisone, orally, 5 mg twice
daily. Two infants were treated with ACTH
alone and 2 with cortisone alone. Steroids
or ACTH were given for 5 to 24 days and
gradually discontinued over a 3-S day
pe-nod. Frequent measurements of glucose in
blood were made during and after therapy.
In the 3 infants with hypocalcemia (< 7
mg/100 ml), intravenous and/or oral
cal-cium supplements were given with further
improvement in 1 infant (see DAN, Case
2) and no change in 2. Of the 6 infants
with polycythemia, 3 (DOR No. 1, HOD
No. 2, DAN) had phlebotomies on one or
more occasions with a temporary fall in
the hematocrit. All of the infants were
kept in heated incubators maintaining
(35.5#{176}-U 0 1 1
KltI-Mother Infant
!list)ry
.\nme if/C I?arP
-
Gent.(wAs)
01’ PrCnot(Ilf
HAK 41 40 F
33 M
391 F
lye
(he)
1dm
is-,kym ptoms
Age (tm) I.ength
(rm
44
41
441
Itirt!,
Ut
(kg)
1.73
1.28
1.86
2.51
(and.
Birth
Good
tair
Good U
Blood Glucose
,ug /00 ml
-lye (tm)
-1g-Glueos
20-19
24-12
36-16
60-13
12-16
4--iS
20--I 4
36-0
38-41
I 6-jittery
14 resp. (list. 20-apnea
26-cyanosis
36-tremors
I 4-cyanosis
apnea
56 56-tremors
F
F Good
F 37
M
I 5-jittery 36-10
40-17
392 NEONATAL HYPOGLYCEMIA
TABLE II
“YMI’TOM.TI( lIY1’OGI(I-ai1A IN THE N:os.tT,.:s OF I’OXEMIC MOTHERS
VI \ I) 1 0 sporadic
bleeding
lIAR -13 55 0 1 0
5-Il.l, 10 C I) 0 1 38
1)A It I S \V 0 1 1 37
VOL 30 (‘ 2- 1 8
1101) No. ‘I See fable I
KAS No. I ee ‘fable I M
. .I)ortu)m1 - premature
-
No. of living children. t All mothers mid toxemia of pregnan(-y.:(erebral spinal fluid.
36.7#{176}C). Oxygen was administered as
in-dicated.
Prior to the onset of hypoglycemia, blood
glucose determinations had been done in
4 infants (CAM No. 1, DOR No. 1, BAN,
BEE) and were normal from 24 hours to
7 days before low values of glucose were
found. Eighteen infants have had no
recur-rences of their hypoglycemia. In three
in-fants (HOD No. 2, KRE, ROD), low levels
of glucose and symptoms recurred between
30 hours and 4 days of age when the
par-enteral fluids infiltrated. To date 3 infants
have had one other episode of
hypogly-cemia: ROD at 18 days of age, CAM No.
1 at 50 days, and ROP at 8 months.
Of the 24 infants, 2 (McN No. 2, BAR)
died with congenital anomalies involving
the central nervous system and 4 (DEE,
WILS, KRE, DUB) have been lost to
fol-low-up. Eight infants have been seen
be-tween 1 and 2% years of age and appeared
47 Poor
47 1.70
1.55 43 Good
normal in development. Three infants
(DOR No. 1, YOU, DIA) were definitely
retarded in motor and intellectual
achieve-ment at 2 years of age. Five of 7 infants,
followed for less than 1 year, were
per-forming at their proper level and the other
two were probably normal. Complete
neu-rological, psychometric, and social
evalua-tions of the infants are in progress.
Laboratory Investigations of
Carbohydrate Metabolism
A number of tolerance tests were
per-formed in selected infants in an attempt
to elucidate the mechanism of the
hypo-glucosemia. Since individual levels of blood
glucose tend to vary over a wide range with
fasting,1 the tolerance tests were grouped
for analysis, where possible. Otherwise, the
tests were analyzed for each infant in
Laboratory
mg,iOO ml (‘SF
+
+
BUN
my; 100 ml
11
&mamA-s . Follow up
11 mo normal
5 mu? normal
8 mu normal
11 mu normal
H
10 days NormalJIB =20 platelets
89,000
Normal
+ Normal
3 mo normal
breath holding
spells
2yr. slow motor
development
6 N
7(d2) N 18
9(d5)
done in hypoglycemic infants between 6
and 75 days of age. One infant (DOR) had
an initial level of glucose of 20 mg/100 ml,
and another infant (YOU) was receiving
ACTH. As a group (Fig. 2) the fall in
glucose after leucine was greater than that
in a comparable control group (at 45
mm-utes p = < .025) and was between 15- and
r-nAn --‘n
-__
Fic. 2. Tests of carbohydrate tolerance in infants with Symptomatic hypoglycemia as compared with those in normal premature infants of comparable
age. ARTICLES
TABLE II
YM P’I’OMATIC HYpoIYcE1IA IN THE NEONATES OF ToxEMic MOTh F;RS
Symptoms Treatment
.,
.
CRC- . hIb=gm,-lOO ml Lrmne
a
-:,
-+ + + I Normal Normal
+ + + + + Normal Normal
+ + + + Normal Normal
+ + + + Normal Normal
+ ++ + +++
I
-Glucagon, Tolbutamide, and Leucine
Tolerance Tests
Glucagon (30 g/kg IV) was given to
estimate glycogen stores in the liver.
Tol-butamide (10 mg/kg IV) tolerance tests
were done as a measure of the capacity of
the pancreas to release insulin. The
re-covery from the hypoglucosemia induced
by tolbutamide has been used as an
in-direct index of the capacity of the liver to
respond to low levels of blood glucose. The
glucagon, tolbutamide, and leucine
toler-ance tests were grouped together and
com-pared to results obtained in
nonhypogly-cemic premature infants (Fig. 2). In 13
glucagon tolerance tests, all of the infants,
between 1 and 16 days of age, showed a
significant hyperglycemia comparable to
well premature infants (Fig. 2). Since 9
infants were either on intravenous
glu-cose therapy or receiving steroids or ACTH
at the time of the glucagon test, the
con-ditions were quite different from that of
the controls. Leucine tolerance tests were
NEONATAL HYPOGLYCEMIA
TABLE III
PTOMATIC HYPOGLYCEMIA IN THE NEON ATE 394
l)AN
Mothet
.-1t 110CC
Jlo2ory
Oh’ Pvewtol
0--I-i meg.
Gest.
(u-ks)
40 is \v
llirth
- wt_
Sex (leg)
M 2.74
Inf(Int
Adm. Leu;th (ond.
cm. at bitt!, (hrs)
43 Good 54
First
Symptoms
age
(hrs)
24-twitching
cyanosis
I.86 45 Poor hi .94-cyanosis
(15 mm twitching
Resus)
L1
---
-
----
--
-JEN 10 w o-i-i
A. Polycythemia
--
_________
1101) No. 2 ee table I
LI)0RNlSeeTaUeI
_____----K.%No.1 ‘t-ei’ahlel
1)-SR See ‘I’ambie II
1 BAR 25 ( 1 -1 -4 37 M 1 .3J 41.5 Good 2k-jittery.
B. Central Ner
-
1)OR No. I See ‘fable Ious .System
---
--
-.-
---.-----
---
-
---
---
--
----
--
--
__________
Pathology McN No. 2 ‘eeral)le I
I)AN eeabove (A) _______
lEN ee above (A)
I 15 ( 0- 1 I cc . 33 I’ 1
.
20 :19 (,(snl I 36-jitteryI)l.- 9.i V 2- 2-4 hlee-ling 38 !tl 1 .74 4. God 14 21-tremor rmmarginal
sm)s
HOP) :1.; W 0-0-7 ,-,. 41) I 2.55 47 Good 44 32-convulsion
C. I.cw Ilirth J---
----
-- --- ---.- --- -- ------- ---
-- --- ----J#’eighl Only BEE 23 W 0-0-2 ne. 36 M i.7i 45 God 4 24-tremors
IIAN 21 \V 0-1-1 ne:. 36 M 1.62 44 Good 50 40-twitching
110W 32 U 0-1-5 ne.. 30 M 0.1)2 3 Fair 16 89-eye-rolling
WILS is C 0-i-i ne,. 36 M 2. i7 46 l’o )C 4 72-tremors
(ROS)
JOII 22 C 0-1-2 neg. 40 F I .44 43 Good 1 3-jittery
aAbortion--premature--no. of living children
ARTICLES 395
TABLE III
SYMPTOMATIC H’POGLYCEM1A IN THE NEONATE
BkOd Symptoms Treatment Laboratory
glucose --- I_____
mg/100 ‘I
ml age . -‘
-
a
CRC--
BUN Remarks & Follow-up(hrs) 4 - - . Hb=gm/ Urine CSFt mgi
Age- -
,m
:_ ) 1(X) ml mg100 100Glucose C..) ‘ -“: t- .a ;_ -.. Z’r ml ml
54-0 + + + + + + + + + + 111, 27.6 N 4.0 N 21 i ? normal
59-i6 liet77’ 7.4 26
8.4 2i
34-17 + + + + + + + + fib 21 N - 8 mo ? normal
36-18 llct 70%
(day II) platelets 50,000
21-8 + + + + + normal N - died S mo. CNS and
laryngeal anomaly
45 -0 + + + + + + normal N 12 8 mo-recurrence of
y-2t poglycemia. ?normal
24-0 + + + + + norrral N 1 1.4 1 years slow motor and
7-0 intellectual
4-9 development
46-0 + + + + + + + + normal N 9. 3 N 26 1 year-normal
58- 16
2-23 + + + normal N No follow-up
48-18, 16
50-4 + + + + + normal N 8.6 N 19 moa normal
.52 -0
77-Ri
--
‘i---
_i__ii -i;i
iii-
nominal X 2RmoRlebrile89-0 convulsion ? normal
75-l5.1&+ - ---- normal
H
snorma1-H---
- -----H
-
-i---
normal NL
TABLE IV
SYM PTOMATOI.OGY IN NEONATAL SYMPTOMATIC
HYPOGLYCEMIA
Symptoms & Signs Age in
hours (range)
0-So
13
6
0
3
(ILk-tress
Cry, high pitched or weak
Limpness Poor feeding
1’ve rolling
19
9
H
H
6
a
3
(I
6-40
11 6-0
0
0
0)
It 89-168
48% in 3 infants (HAN, YOU, Tolbutamide tolerance tests
formed in 6 infants between
and URI).
were
per-11 and 60
396 NEONATAL HYPOGLYCEMIA
Tremors
Cyanosis Apathy Convulsions Apnea, respiratory
Presenling Symptoms
infants
(ito.) infants
(iw.)
days of age. All responded with a marked
hypoglucosemia and the mean fall was
sig-nificantly greater and more prolonged than
that observed in 7 control infants (Fig. 2).
Therefore, on the basis of the leucine and
tolbutamide tolerance tests, it is postulated
that a sensitive insulin release mechanism
appears to be present in these infants.
Iv Glucose Tolerance Tests
Intravenous glucose tolerance tests were
done to determine the rate of
disappear-ance of glucose as an indirect measure of
insulin secretion or activity. Six
intrave-nous glucose tolerance tests were done. A
disappearance constant (K) was calculated
after plotting the values
semi-logarithmi-cally.16 In 5 infants, ages 1% to 7 days of age,
the values of K varied from 1.1% per minute
to 1.57% per minute. These values are
simi-lar to those observed in control premature
infants.1 Two infants were receiving ACTH
or IV fluids. In 1 infant (ROP) at 5 days
of age, while being given IV fluids and
ACTH, the K was 2.27% per minute (in 6
controls 3-7 days of age, mean K ± S.D. =
1.55% ± 0.5% per minute).13 This infant was
not sensitive to leucine at 20 days of age
nor at 8 months, at which time she was
readmitted to the hospital for a recurrence
of her hypoglycemia. In only 1 infant was
the rate of disappearance of an exogenous
load of glucose faster than that observed
in nonhypoglycemic premature infants,
suggesting hyperglucosemia was not a
po-tent stimulus of insulin secretion.
Combined Epinephrine and Glucagon
Tolerance Tests
Combined epinephrine and glucagon
tolerance tests were performed in an
at-tempt to quantify glycogen reserves in the
liver. The epinephrine (5 gIkg) was given
subcutaneously to inhibit peripheral
utili-zation of glucose and the glucagon (300
p.g/kg) was given intravenously
immedi-ately thereafter. Nine tolerance tests were
done on 4 infants (DOR No. 1, CAM No.
1, HAN, DIA). In 2 infants at the time of
symptomatic hypoglycemia, glucagon and
epinephrine produced a minimal rise in
blood sugar, 20 mg/100 ml in CAM No. 1,
and 6 mg/100 ml in HAN. After steroids
the glycemic response in CAM No. 1 was
110 mg/100 ml and in HAN 25 mg/100 ml.
On the other hand, in another infant (DIA),
the glycemic response was marked (a rise
of 57 mg/100 ml) at 9 hours of age at
which time the infant was symptomatic
and had a level of blood glucose of 18
mg/100 ml. Two subsequent tolerance tests
at 6 and 10 days of age resulted in
incre-ments of 22 and 48 mg/100 ml even though
the infant was being given ACTH. In 1
infant (DOR No. 1), only 1 tolerance test
was done after therapy and revealed a
rise in the level of blood glucose of 43
mg/100 ml over the fasting level of 21 mg/
100 ml. Therefore, in 2 of 3 infants, it
would appear that glycogen stores were
diminished at the time of hypoglycemia
and rapidly replenished on steroid therapy.
It was of interest that this sequence of
events occurred at the initial episode of
symptomatic hypoglycemia in HAN and at
the time of a recurrence in CAM No. 1 (see
ARTICLES 397
SUMMARY OF CLINICAL AND
LABORATORY DATA
Although presented as a homogeneous
group, several clinical and laboratory
char-acteristics tend to subdivide this syndrome
into distinctive, but overlapping, entities.
Seven sets of twins were observed with
hypoglycemia occurring only in the smaller
infant (Table 1). Toxemia of pregnancy
was present in 8 mothers (Table II). Six
infants had polycythemia (Table lilA) and
5 central nervous system injury or anoma-lies, which were considered the primary
disease (Table IIIB). In 8 infants, no
as-sociated conditions were found except for
the low birth weight for the period of
ges-tation noted in all of these babies (Fig. 1).
The studies of carbohydrate metabolism,
although incomplete, suggest inadequate
stores of glycogen in the liver initially with
rapid restoration after therapy (Fig. 2), no
increase in the utilization of an exogenous
load of glucose, and a sensitive insulin
re-lease mechanism as triggered by leucine
or tolbutamide (Fig. 2). These speculations
require verification by additional data and
assay of the hormones involved.
COMMENT
As reported previously in 8 infants,
symp-tomatic neonatal hypoglycemia is
character-ized by a self-limited course, and a prompt
improvement after glucose administration.
All of the mothers were reported to have
pre-eclampsia, and the infants were
pre-dominantly males of low birth weight for
gestation. Not enough data were available,
however, to determine the etiology of the
low levels of sugar or to explain the
syn-drome on the basis of known causes of
hypoglycemia. Subsequently, a number of
additional infants with symptomatic
hy-poglycemia have been seen.3#{176}These, with
the 24 patients reported here, permit a
re-evaluation of this syndrome, its
pathogene-sis, and therapy.
Although pre-eclampsia in the mother
was considered a sine qua non in this
syn-drome previously,1 it is apparent now that
toxemia of pregnancy occurs only in
ap-proximately 50% of reported cases 36 of
73 (Table II).’-’ Iii many instances,
the pregnancy, labor, and delivery have
been completely uneventful. There is no
correlation between hypoglycemia in the
infant and the mode of delivery, parity, or
previous medical or obstetrical history. The
condition of the infant at birth is often
good. Although symptoms, signs, and low
levels of glucose did appear any time
be-tween 2% hours and 7 days of age, the
ma-jority occurred between 2 and 4 days of
life (15 of 24, Tables I-Ill).
The infants are often male: 47 male, 15
female (Tables I_Ill),’ :-a and usually of
low birth weight for gestation (Fig. 1).’-
-The predominance of male infants has
also been noted in neonatal hypocalcemic
tetany’ but the significance of these
ob-servations is obscure. Low birth weight for
gestation has been associated with a
num-ber of problems in the neonate, as recently
reviewed by Warkany, Monroe, and
Suth-erland in their description of intrauterine
growth retardation. Of 22 patients
ported by these authors, 13 had an
tin-eventful or “good” neonatal course and 7
had cyanosis or clonic seizures.’ Scott,
Usher, and MacLean reported a high
mci-dence of hypoglycemia and neonatal
mor-bidity in the underweight, wasted infant.’
Correlating birth weight and gestation can
be criticized, since the latter is based on
the history of the mother’s last menstrual
period. However, in 8 sets of twins, whose
birth weights were known, the smaller
in-fant was always the one with symptomatic
hypoglycemia (Table 7 This
observa-tion strongly supports the concept that the
infant of low birth weight is the one most
susceptible to hypoglycemia. Therefore, it
would appear that this disturbance in
car-bohydrate metabolism has its origin in
utero as evidenced by its early appearance
in underweight infants and its transient
course.
The presenting symptoms and signs vary
from rolling of the eyes, apnea, cyanotic
398 NEONATAL HYPOGLYCEMIA
convulsions. All of the symptoms improved
after therapy. However, due to difficulties
In niaintaining adequate intravenous fluids
and the limitation in quantity of fluid
im-posed by’ the size and age of the infants,
steroids or ACTH had to be given to most
infants in order to maintain normal levels
of blood glucose and to correct all
symp-toms and signs. The self-limited course of
this syndrome is apparent in that of the 22
surviving infants, only 1 (ROP) has had
another episode of hypoglycemia at 8
months of age. Five other babies had
other episodes of hypoglycemia, but these
occurred either within 4 days of onset,
when iareiiteral fluid in5iltrated, or at 18
and 50 days of life associated with other
illnesses. However, follovv-up has not been
of sufficient time in all infants to rule out
late recurrences.
The pathogenesis of the hypoglucosemia
and of the symptoms may vary depending
UOfl the associated conditions in the
in-fants. The low birth weight and transient
course suggests malnutrition related to the
intrauterine environment. Yet, 4 infants had
normal levels of glucose for 24 hours to
7 days prior to onset of the hypoglycemia.
Two of these infants, however, had
in-volvement of the central nervous system,
which could be responsible for the
symp-toms and hypoglycemia.’ In at least 5 of
the infants reported (Table III), a primary
defect of the brain was postulated and was
verified either at autopsy or by the
subse-quent course in 4. Characteristically in this
group, some of the symptoms disappeared
after glucose was given, but others per-sisted despite normal levels of glucose (DAN,
Case 2). Furthermore, the high incidence
of motor and intellectual retardation in
infants with intrauterine growth
retarda-tion’8 and hypoglycemia (Tables I-Ill)
would support the concept’4’20’21 that
dam-age to or a congenital anomaly of the brain
may be responsible for a number of infants
with neonatal symptomatic hypoglycemia.
In addition, some of the hypoglycemic
infants had polycythemia (Table III) and
low levels of calcium. Convulsions have
been reported with polycythemia in the
newborn infant, but levels of glucose were
not measured.22 The hypoglycemia here
may be secondary to reduced blood flow,
the high rate of glycolysis present in the
erythrocytes of the neonate,12 or to other
factors. All of the polycythemic infants
re-sponded to glucose administration. The significance of the low levels of calcium
observed in the infants with hypoglycemia
is difficult to interpret. The signs and
symptoms are similar in both hypoglycemia
and neonatal tetany.l 2 One infant DAN
(Case 2) with probable brain damage,
im-proved after the administration of both
glucose and calcium, but some symptoms
persisted. Two infants with low levels of
calcium were born to mothers with
tox-emia. More levels of calcium will have to
be measured at the time of symptoms
be-fore any speculations are justified.
Unfor-tunately, in infants reported to have tetany
due to hypocalcemia, levels of blood
glu-cose were either not obtained or not
re-ported.1T 23 However, in the infants with
hypocalcemic tetany, there was a high
in-cidence of traumatic deliveries, cesarean
sections, and diabetes mellitus in the
moth-ers. These complications were not present
in the mothers of infants with symptomatic
hypoglycemia.
A number of tolerance tests were
per-formed to estimate glycogen stores in the
liver as well as the insulin-secreting
capac-ity of the pancreas in infants with
symp-tomatic hypoglycemia. Although
prelimi-nary, the data suggest a pattern which
requires verification. Initially, just before
or at the onset of symptomatic
hypogly-cemia, the liver appears to be depleted of
its stores of glycogen, as evidenced by the
reduced hyperglycemic response to the
ad-ministration of both glucagon and
epineph-line. With parenteral glucose and
ster-oids or ACTH, glycogen stores were quickly
replenished as demonstrated by the
nor-mal hyperglycemic response to glucagon
(Fig. 2). However, these infants seem to
have an abnormal or inordinately sensitive
ARTICLES 399
the hypoglycemia after leucine and
tolbuta-mide (Fig. 2). The significantly greater and
more prolonged hypoglycemia, as compared
to normal premature infants after the
lat-ter substance, occurred in every infant
be-tween 11 and 60 days of age. The
pro-longed hypoglycemia after tolbutamide
may reflect faulty regulating mechanisms
for glycogenolysis and glucose release from
the liver as well. Although alternative
ex-planations may be offered, the current
evi-dence indicates that both tolbutamide and
leucine produce hypoglycemia by
increas-ing the release of insulin.25’ ‘#{176}Whether the
increased sensitivity to leucine and
tolbuta-mide results from the intravenous glucose
and ACTH administered to the infants
de-mands further investigation.
Regardless of etiology, the diagnosis of
symptomatic hypoglycemia is based on
blood glucose values less than 20 mg/100
ml associated with “jitteriness,” lethargy,
cyanosis, apnea, convulsions, apathy,
high-pitched cry, difficulty in feeding, or eyes
rolling upward. The prompt alleviation of
symptoms by intravenous administration of
2-3 ml of 50% glucose in water, followed
by a constant infusion of 10% glucose helps
to confirm the diagnosis. If symptoms or
low levels of glucose perisist, ACTH, 4
units every 12 hours, or hydrocortisone, 5
mg twice daily, should be added to the
therapy. Treatment should be continued
until the levels of glucose have stabilized
and then gradually discontinued to prevent
the iatrogenic recurrence of symptomatic
hypoglycemia.
SUMMARY
1. Symptomatic hypoglycemia occurs
predominantly in male infants of low birth
weight for the period of gestation.
2. Approximately 50% of the mothers had
toxemia of pregnancy.
3. Low levels of glucose were found in
the smaller of twins, with central nervous
system pathology, and in the presence of
polycythemia. On occasion, low levels of
calcium were also present.
4. Therapy consists of intravenous
glu-cose, plus ACTH or steroids as needed to
relieve symptoms and maintain normal
levels of blood glucose.
5. The pathogenesis may reflect
intra-uterine malnutrition with low stores of
gly-cogen present at birth associated with an
abnormally sensitive insulin release
mech-anism resulting in hypoglycemia and
symp-toms.
CASE REPORTS
Two case histories are presented in
de-tail to illustrate salient features, i.e. ,
recur-rence of hypoglycemia and symptoms,
nor-mal levels of glucose in blood prior to
on-set of symptomatic hypoglycemia, low
birth weight for gestation, central nervous
system involvement, polycythemia, and
hypocalcemia.
Case 1
CAM No. 1. (M.R.H. No. H901), a 1.28
kg white male infant, first of twins, was
born at home on December 13, 1960. The
mother was a 19-year-old primipara. The
pregnancy had been uneventful until the
precipitous delivery of twins. There was a
time lapse of half an hour between the
birth of the two infants. The weight of the
second twin was 1.64 kg. Blood sugars
ob-tamed from the unaffected infant at 53, 11,
and 36 hours of age were 68, 25, and 41
mg/100 ml. This infant developed
respira-tory distress and expired at 40 hours of
age.
The first twin breathed and cried
spoil-taneously after birth and was in fair
con-dition when transferred to vIichael Reese
Premature Station at 4 hours of age. The
physical examination was within normal
limits. Blood sugars obtained at 53 and 12%
hours of age were 43 and 84 mg/100 ml.
After 24 hours he started moaning,
grunt-ing, and had subcostal retractions as well
as periods of pallor and apnea. These
symp-toms were more pronounced at 50 hours
of age, and cyanosis, jitteriness, and
jaun-dice were also observed. At that time, the
level of glucose in blood was 6 mg/100
400 NEONATAL HYPOGLYCEMIA
mg/100 ml. Therapy was initiated and
in-cluded intravenous glucose and ACTH. The
symptoms subsided shortly thereafter, but
at 62 hours of age the infant was still
tremulous following stimulation. This
sub-sided in the next 10 hours at which time
the blood sugar was 52 mg/100 ml.
Be-peated determinations of blood glucose
were within the normal range. At 80 hours
of age intravenous glucose was
discontin-ned. An intravenous glucagon tolerance
test (30 g/kg) was done on the 5th day
with tile following results: Fasting blood
glucose 58 mg/100 ml; at 30 minutes, 90;
at 60 minutes, 67; at 90 minutes, 61; and at
120 minutes, 58 mg/100 ml. A fasting blood
sugar on the 6th day was 45 mg/100 ml.
On the 7th day an oral leucine tolerance
test was done with an initial blood sugar
of 42 mg/100 ml and no change in
subse-quent values. Throughout his
hospitaliza-tion fasting blood sugars were obtained at
regular intervals and were normal. His
fa-vorable clinical course was interrupted by
pneumonitis Oil the 43rd day, which
re-sponded well to antibiotics and supportive
measures. On tile 43rd day a fasting blood
sugar of 13 mg/100 ml was noted and
similarly low levels persisted during the
next 3 days without symptoms. Therefore,
treatment was withheld. A combined
glu-cagon and epinephrine tolerance test was
done at 50 days of age. Two fasting levels
of glucose were 6 and 11 mgJlOO ml, and
30 minutes after glucagon and epinephrine,
the level of glucose was 27 mg/l00 ml; at
120 minutes 9 mg/100 ml; and at 180
mm-tites 15 mg/100 ml. The test was
discon-tinned, because the infant became very
“jittery.” An injection of 5 ml of 50%
dcx-trose in water was given intravenously and
hydrocortisone started with immediate
re-lief of symptoms. Twelve hours later, the
blood glucose was 59 mg/100 ml. On the
51st day he received 20 ml of whole blood
because of a Hb of 7 gm/100 ml. The
blood glucose levels remained within the
normal range and hydrocortisone was
dis-continued by 59 days of age. On the 72nd
day a right hemiorraphy was done and
tol-erated well. Four days later the baby was
discharged in good condition.
At 13 months, CAM No. 1 weighed 8.75
kg and was 74 cm tall. He could crawl,
climb out of his playpen, babble, play “pat
a cake,” and walk with support. He seemed
to understand his mother’s commands. A
3-hour fasting blood sugar was 94 mg/100
ml. When last seen at 2 years he weighed
11.4 kg and was 85 cm tall. He was a very
active, normal boy. He could run, climb,
say single and paired words, and was
suffi-ciently well co-ordinated to push his
tn-cycle around the house. He had had no
episodes of fainting, convulsions, or any
other abnormal behavior. The blood sugar
at this time was 88 mg/100 ml.
COMMENT: This patient was male, of
low birth weight for his gestational age
and in comparison with his twin. Normal
levels of blood glucose were found prior
to symptomatology and hypoglycemia here
as in 3 other infants (DOR, BAN, BEE). A
recurrence of hypoglycemia with
symp-toms occurred on the 50th day of life after
recovery from pneumonia and responded
to therapy. At this time, a glucagon plus
epinephnine tolerance test indicated
lim-ited stores of glycogen. The twin brother
had normal levels of glucose in blood and
died after 40 hours of respiratory distress.
Case 2
DAN (M.R.H. No. H-29055), a 2.70 kg
white male infant, was born on February
16, 1962, after a gestation of 40 weeks, at
a hospital in Chicago. Tile mother was an
18-year-old pnimigravida, blood group B,
Rh positive, with a negative serological test
for syphilis. The fetal membranes ruptured
25 hours before delivery. Duration of labor
was 8% hours (2nd stage % hour). Three
hours before delivery the mother received
100 mg of meperidine hydrochloride
(DemeroP) and 1/150 grain of scopolamine
The delivery was spontaneous;
presenta-tion was vertex. The infant was covered
with meconium, but breathed and cried
immediately. His condition was good until
twitch-ARTICLES 401
ing and cyanosis of the face and
extrem-ities. He was given 8 mg of sodium pheno-barbital every 6 hours for 3 doses. A blood sugar obtained at 35 hours was reported
as 60 mg/100 ml. The bilirubin was 8.5 mg/100 ml., Hb 23.6 gm/100 ml, and the
Coomb’s test negative. He was transferred
to Michael Reese Hospital at 54 hours of age. Physical examination revealed a
jaun-diced, cyanotic, limp infant with a very
weak cry, an incomplete Moro reflex, and a
poor sucking reflex. Intermittent coarse tremors of the extremities were present.
The anterior fontanelle was soft and flat.
The respiratory rate was 20 per minute and irregular. Breath sounds were diminished bilaterally. The pulse rate was 140 per minute and the temperature was 98.4#{176}F (36.9#{176}C). A lumbar puncture was
per-formed. The cerebrospinal fluid was
in-itially bloody, but eventually cleared. Bi-lateral subdural taps were negative. After blood was obtained to determine the levels
of calcium, glucose and electrolytes, 2 ml
of 50% dextrose was given intravenously as
a single injection. No improvement
oc-curred. Then 1.5 ml of 10% calcium
glu-conate were administered intravenously without any change. After the Hb was re-ported to be 27.6 gm/100 ml, 26 ml of
blood was removed, followed by some
im-provement in the infant’s color. Subse-quently, the cerebrospinal fluid and blood glucose levels were reported to be 0. The electrolytes were within normal limits.
BUN was 24 mg/100 ml, bilirubin, 18 mgI
100 ml, and calcium 4 mg/100 ml. The in-fant was given calcium
gluconogalacto-gluconate (neocalglucon#{174}-). The level of
calcium on the 4th day was 7.4 mg/100 ml.
At 59 hours of age an intravenous infusion
of 10% invert sugar was started as well as
ACTH. The blood sugar at this time was
16 mg/100 ml. Ten hours after admission
the infant had a generalized seizure, which
subsided after 3 ml of 50% glucose were
given IV. However a series of seizures
fol-lowed 3, 8, and 11 hours later, at which
time the blood sugar was 96 mg/100 ml.
Between the 4th and 5th day of life, he had
3 more convulsions associated with
cyano-sis and vomiting. On the 6th day because
of a Hb of 26 gm/100 ml, HCT of 82% and
RBC 6.5 million/mm, 25 ml of blood were
removed and replaced by plasma. During
the next 3 days his course was stormy with
improvement on the 9th day. A leucine
tol-erance test was done on the 10th day with
the following results: Fasting level of
glu-cose 40 mg/100 ml, at 15 minutes, 60
mg/100 ml; at 45 minutes, 58 and at 60
minutes, 50 mg/100 ml. During the
fol-lowing week the calcium and ACTH were
discontinued. On the 18th day a glucagon
tolerance test was done with the following
results: Fasting blood glucose 41 mg/100
ml; at 30 minutes, 67; at 60 minutes, 48; at
90 minutes, 44; and at 120 minutes, 40
mg/100 ml. Thereafter the infant improved
and was discharged on the 21st day in
satisfactory condition.
COMMENT: The patient represents one of
5 babies (DOR No. 1, MeN No. 2,
BAR, and JEN, Table IIIB), who seemed
to have primary central nervous system
damage. In addition, this baby had
pro-found hypoglycemia, hypocalcemia, and
polycythemia. Raising the levels of glucose
and calcium produced a marked reduction
in symptomatology, but convulsions, eye
rolling, and cyanotic episodes persisted. For
these reasons, an underlying defect in the
central nervous system was postulated.
REFERENCES
1. Cornblath, M., Odell, G. B., and Levin, E. Y.:
Symptomatic neonatal liyx)glyemia
asso-ciated with toxemia of pregnancy. J. Pediat.,
55:545, 1959.
2. Harris, R., and Tizard, J. P. M. : The
elec-troencephalogram in neonatal convulsions.
J. Pediat., 57:501, 1960.
3. Zetterstr#{246}rn, R., Eeg-Olofson, 0., and Nilsson,
L. : Conference on Fetal and Infant Liver Function. N.Y. Academy of Sciences,
No-vember, 1962, to be published.
4. Haworth, J. C., Coodin, F. J., Finkel, K. C.,
et a!.: Hypoglycemia associate(l with svmp-toms in the nevhorn )eriol. Caiiad. Med.
Ass. J., 88:23, 1963.
5. Brown, R. J. K., and \Vallis, P. G.: I-Ivpoglv-cemia in the newborn infant. Lancet, 1:
402 NEONATAL HYPOGLYCEMIA
6. Farquhar, J. W. : Maternal hyperglycemia and foetal hyperinsulinism in diabetic
preg-nancy. Postgrad. Med. J., 38:612, 1962.
7. Rosen, L., Nitowsky, H. M., and Seidel, H.
M. : Personal communications.
8. Neligan, C. A., Robson, E., and Watson, J.:
Hypoglvcaemia in the newborn. Lancet, 1: 1282, 1963.
9. Tvnan, NI. J., and Flaas, L. : Hypoglvcaeniia
in thy newborn. Lancet, 2:90, 1963.
10. Marks, V. : An improved glucose oxidase method for deternining blood, C.S.F., and
urine glucose levels. Clin. Chim. Acta, 4: 395, 1959.
11. Somogvi, M.: A new reagent for the
determi-nation of sugars. J. Biol. Cheni., 160:61,
1945.
12. Baens, C. S., Lundeen, E., and Cornblath, M.: Studies of carbohydrate metabolism in the
newborn infant. VI. Levels of glucose in
blood in premature infants. PEDIATRICS,
31:580, 196-3.
13. Cornblath, M., \Vvbregt, S. H., and Baerts, G. S. : Studies of carbohydrate metabolism in the newborn infant. VII. Tests of carbo-hydrate tolerance in premature infants.
PEDIATRICS, 32:1007, 1963.
14. Hsia, D. Y., Hsia, H., and Gellis, S. S. : A
micro-method for serum bilirubin. J. Lab. Clin. Med., 40:610, 1952.
15. Luhchenco, L., Hausman, C., Dressler, M.,
et al.: Intrauterine growth: a standard
de-rived from liveborn infants 24 to 42 weeks
of gestation. PEDIATRICS, 32:793, 1963.
16. West, K. M., and Wood, D. A.: The
intra-venous glucose tolerance test. Amer. J.
Med. Sci., 238:25, 1959.
17. Saville, P. D., and Kretchmer, N.: Neonatal tetanv: a report of 125 cases and review of the literature. Biol. Neonat., 2:1, 1960. 18. Warkanv, j., Monroe, B. B., and Sutherland,
B. S. : Intrauterine growth retardation.
Amer. J. Dis. Child., 102:249, 1961.
19. Scott, K., Usher, R., and MacLean F. :
Post-natal study of fetal malnutrition syndrome.
Abstract 31; Proceedings of Society for Pediatric Research 33rd Annual Meeting Atlantic City, N.J., May 1-2, 1963. 20. Darrow, D. C. : Mental deterioration
associ-ated with convulsions and hypoglycemia.
Amer. J. Dis. Child., 51:575, 1936.
21. Haworth, J. C., and Coodin, F. J.: Idiopathic
spontaneous hypoglycemia in children :
re-port of 7 cases and review of the
litera-hire. PEDIATRICS, 25:748, 1960.
22. Wood, J. L. : Plethora in the newborn infant associated with cyanosis and convulsions.
J. Pediat., 54: 143, 1959.
23. Craig, W. S., and Buchanan, M. F. C. : Hypo-calcemic tetany developing within 36 hours
of birth. Arch. Dis. Child., 33:505, 1958.
24. DiGeorge, A. M., Auerbach, V. H., and Mabry,
C. C.: Elevated serum insulin associated with leucine-induced hypoglycemia.
Na-hire, 188:1036, 1960.
25. Yalow, R. S., Black, H., Villazon, M., et al.:
Comparison of plasma insulin levels follow-ing administration of tolbutamide and
glu-cose. Diabetes, 9:356, 1960.
26. Relander, A., and R#{228}ih#{228},C. E. : Differences
between the enzymatic and 0-toluidine
methods of blood glucose determinations. Scand. J. Clin. Lab. Invest., 15:221, 1963.
Acknowledgment
The authors wish to thank the resident and
nursing staffs at both Research and Educational
Hospitals and Michael Reese Hospital for their
co-operation, help, and devoted care of these patients. We wish to thank Drs. S. Hagler, R.
