(Received July 15, 1969; revision accepted for publication January 9, 1970.)
Supported in part by Grant #HD 3863-01-4610-01 and #5 TOl HD00168-03 U.S. Public Health
Service, Bethesda, Maryland, and Mead Johnson Company, Evansville, Indiana.
PRESENT ADDRESS: (R.C.T.) Children’s Hospital Research Foundation, Cincinnati, Ohio 45229.
ADDRESS FOR REPRINTS: (W.O.) Department of Pediatrics, UCLA School of Medicine at Harbor
Gen-eral Hospital, 1000 W. Carson, Torrance, California 90509.
PEDIATRICS, Vol. 45, No. 5, May 1970 773
NEONATAL
HYPOCALCEMIA
IN
LOW
BIRTH
WEIGHT
INFANTS
Reginald C. Tsang, M.B.B.S., and William Oh, M.D.
Fro,,i the Department of Pediatrics, Michael Reese Hospital and Medical Center, Chicago
ABSTRACT. During an 8-month period, 37 of 124 infants (29.8%) admitted to a low birth weight
(LB\V) nursery developed hypocalcemia at a
mean age of 29 hours. Ten factors were associated
with hypocalcemia, three of which appear
particu-larly relevant: (1) low gestational age (32 weeks or less) with appropriate birth weight, (2) low oral calcium intake, (3) correction of acidosis with NaHCO:. Biochemical determinations showed that, in hypocalceniic infants, there were: (1) lower serum total calcium values at 8 hours of life, prior
to the actual development of hypocalcernia at 29 hours; (2) elevated serum phosphorus values; (3)
acidotic values in the first hours of life, corrected
to normal values at the time of hypocalcemia, and (4) lower serum protein values at 8 hours of life. Three signs were significantly related to hypocalce-mia, namely, twitching of one or more extremities,
high-pitched cry, and hypotonia. Pediatrics,
45:773, 1970, HYPOCALCEMIA, LOW BIRTH WEIGHT
INFANTS, PREMATURE INFANTS, CALCIUM METABO-LISM, SERUM CALCIUM.
N
EONATAL hypocalcemia (NHC) occursin full-term infants and, more
fre-quently, in low birth weight (LBW)
in-fants. This entity has been variously termed
“early NHC.” “first day NHC,”l or “NHC in
the first 36 hours of life,”2 as distinguished
from cow’s milk-induced infantile
hypo-calcemia which usually occurs at the end of
the first week of life.3’ The incidence of
NHC is not well defined, although in
“pre-mature” infants it appears to range from 26
to 50%.1,5 Functional hypoparathyroidism
and/or renal immaturity have been
in-voked as possible etiologic factors in
NHC of term infants,6 but no precise
mech-anism has been described for NHC in LBW
inf ants 1, 2,1
This report is a completed survey of the
incidence of NHC in a LBW nursery. The
clinical and biochemical factors associated
with NHC were also appraised with
partic-ular emphasis on their etiologic
implica-tions.
MATERIALS AND METHODS
From July 1, 1968, to February 28, 1969,
there were 165 LBW infants weighing
be-tween 615 and 2,000 gm admitted to the
Michael Reese Hospital LBW Nursery.
Forty-one infants were excluded from the
study because of: (1) death within 48
hours of age (29 infants), (2) admission#{176}
after 48 hours of age (10 infants), and (3)
severe Rh erythroblastosis requiring
ex-change transfusion (2 infants). Of the
re-maining 124 infants, clinical data in the
ma-ternal history, labor, delivery, and neonatal
course were recorded. On admission all
in-fants were placed in incubators with
ap-propriate temperature, humidity, and
oxy-gen environment. The amount of sodium
bicarbonate infused for buffer base
correc-tion of the acidosis in the respiratory
dis-tress syndrome was calculated according to
the blood pH and buffer base values. If
tol-erated, all infants were fed orally with an
increasing amount of commercial formulasf
by gavage or bottle feeding, beginning at 6
to 24 hours of age. Otherwise, intravenous
fluids (10% dextrose or invert sugar with
electrolyte addition) were given. The exact
#{176}Infants referred from other Chicago hospitals.
I Calcium content: Similac, 33 mg/100 ml;
Clinical Faders
Maternal age (yr)
(;ra’idit
-“IC
.5±1.1 (37)
14
S
‘29
4
65
75 14
‘25 61
*All differences not statistically significant by X2 analyses or “Student’s” t test.
amount of oral intake was recorded and the
calcium content was calculated.
Serial determinations of serum calcium,
magnesium, phosphorus, protein, glucose,
and blood pH were done at approximately
12, 24, 48, 72, and 96 hours of age. Blood
samples were obtained by heel puncture.
Serum calcium and magnesium
determina-tions were done by atomic absorption
spec-troscopy,7 serum phosphorus by the method
of Fiske and Subbarow,8 serum protein by
the Biuret reaction,9 serum glucose by the
glucose oxidase method,’#{176} and blood pH by
the Astrup microequipment.
Infants with two sequential serum
cal-cium values of 7.0 mg/ 100 ml or less were
considered hypocalcemic. These infants
were treated with intravenous and oral
cal-cium gluconate.
A specific list of neurological
symptom-atology was made (see results). One of the
authors observed each infant for these signs
at designated times without knowing the
biochemical results.
When the data were collated at the end
of the survey period, the study infants were
divided into two groups: hypocalcemic and
nonhypocalcemic. Statistical analyses were
performed by either Chi-square analysis or
“Student’s” t test.12
RESULTS
During the survey period, 37 of 124
in-fants (29.8%) developed neonatal
hypo-calcemia (NHC) at 29 ± 2 hours of age.
Table I shows that no differences were
observed between the control and NHC
in-fants in regard to a specific set of clinical
factors. These factors include maternal age,
race, gravidity, toxemia of pregnancy,
dia-betes mellitus (six gestational and one
insu-lin treated), renal disease, multiple
preg-nancy, mode of delivery, anesthesia or
analgesia, duration of labor, duration of
membranes being ruptured, presentation,
placental pathology (previa, abruptio, and
gross infarction), infant’s sex, and
occur-rence of neonatal hypoglycemia.
Table II shows the clinical events that
were significantly associated with NHC.
For instance, 11 of 22 infants whose
moth-ers had a previous abortion were
hypocal-cemic. In contrast, of the 102 mothers who
did not have a previous abortion, only 26 of
their infants developed hypocalcemia. The
condition of infants at birth also influenced
the incidence of hypocalcemia. Those
in-fants who were in poor condition at birth,
characterized by a low Apgar score (<5),
and required resuscitation had a higher
in-cidence of hypocalcemia. Infants with
re-TABLE I
C’LINICAL F.%rrotts I. NIIEL ATED TO NEONATAl. IIYI’OCALCEMIA (NIIC)*
Race
Caucasian
Negro
Priniiparous Mutt iparous
(;raiide mutt ip (>gravida 7) Nongrande multiparous
Non-NII(’
TABLE I (coni.)
Clinical Factors NIIC Non-NJIC
Yes ‘2 7
Toxemia --
---
- -- ---
- - ---No 35 80
Yes 3 4
Maternal diabetes mellitus
---
--- ------
---H---
----
-
-
---
--No 34
Yes 0 3
Maternal renal diseases
---
---
---
----
--- -- --No 37 84
Multiple 7 13
Multiple pregnancy ---
---
---- ---.--- --- ----Singleton 30 74
C-section 5 6
Mode of delivery - --- --
-\agmal 3’2 81
Yes 5 10
Anesthesia or analgesia
-
- -- --- --- - - --- --- --- - ---- ---No 3’2 77
Total duration of labor (hr) 8.’2 ± 1.’2 (31) 6.’2 ± .6 (74)
Duration of ruptured membranes (hr) 18.’2±4 (35) 18.7 ±3.4 (75)
Non vertex 7 14
Presentation --- ---
---
-- ---Vertex 30 73
Yes 6 8
Gross placentalpathologyf
---
----No 18 55
Male ‘23 47
Sex
-
-----
- ----Female 14 40
Yes 3 5
Hypoglycemia
---
---No 34
f See text.
= Number of infants.
spiratory distress during the neonatal pe- while, in those who were small for
gesta-nod were also more prone to hypocalcemia. tional age,13 the incidence of hypocalcemia
Infants whose birth weights were appropri- was lower (9 of 51 infants). Bacteriological
ate for gestation were more liable to be- sepsis was also associated with
TABLE II
CLINICAL FAcrons ASSOCIATED WITH N EONATAL IIYPOCALCEMI .& (NIIC)
Total Von- .\‘umber
.viic of Infants
11 76 10 11 41 47 14 31 7-2 91 ‘a) 60 7(1 41 70 4 .51 86 119
‘AGA =appropriate for gestational age; SGA =small for gesta-tional age according to time intra-uterine growth chart of Lub-chenco, ci aiD
Apgar scores were notrecorded in 41 infants transferred from other hospitals; hence, there is a discrepancy between time total num-ber of infants listed here and those studied.
who did not have sepsis). All differences
calculated by Chi-square analyses were
sig-nfficant.
Additional clinical factors related to
TABLE III
CLINICAL FACTORS ASSOCIATED WITH
NEONATAL IIYPOCALCEMIA (NHC)
Clinical Factors iiypo-calcernmc
Gestation 31.8 (wk) ±0.6(37)
Birth weight I 480 (gm) ±54(37) Non-hypocalec,nmc 33.9 ±0.3(87) 1 668 ±33(87) p J’alum <0.010 <0.010
Oral (‘a intake 15.3
(nmg/kg/first48hours) ±2.3(37)
NaIICO,administeredt 1.8 (mEq/kg) ± 0.3 (37)
27.3
±2.1(87)
0.8 ± 0.2 (87)
<0.001
<0. 025
#{149}By “Student’s’ t test. =Number of infants. First 48 hours of age. (1,,, lent Factors .VIIC
Previous Yes II
abortion
No
Apgarscoret <5
at I minute
>6 6
Resuscitation Yes 17
at birth
No 19
Respiratory Yes 4
distress --- ---
-No 10
Weight-gestation AGA 8
rdationsliip
SGA’ 9
Sepsis Yes 4
bacteriologic
-No 33
NHC are listed in Table III. NHC infants
had significantly lower gestation ( 31.8
sus 33.9 weeks
),
smaller birth weight(
1,480versus 1,668 gm
)
,
and lower oral calciumin-pVaLue take during the first 2 days of life
(
15.3yen-by x sus 27.3 mg
)
. Also, they required greater-;i-;;--
amounts of sodium bicarbonate for thecon--- nection of metabolic acidosis
(
1.8 versus 0.8---- --- mEq/kg) during the first 48 hours of life.
<0.005 The biochemical data are shown in Table
---
Iv.
At 8 hours of age, non-NHC infants had---
a mean serum calcium value of 9.6 ± 0.1mg/
100 ml. This fell to a mean value of9.0 ± 0.1 mg/100 ml at 29 hours. NHC
in---;-;:
fants at 8 hours of life had a significantly---- lower serum calcium level of 8.9 ± 0.2
--- mg/ 100 ml. At 29 hours of age, the value
<0.010 fell to 6.3 ± 0.1 mg/100 ml. Therapy was
-- --- instituted when a repeat serum calcium
de---
-
---- termination confirmed the hypocalcemic<0.t5
state.
Serum phosphorus values were
signifi-cantly higher in NHC infants. The values
were 7.6 ± 0.4 mg/100 ml and 8.1 ± 0.3
mg/ 100 ml versus 6.3 ± 0.2 mg/ 100 ml and
6.7 ± 0.2 mg/ 100 ml at 8 and 29 hours of
age, respectively. The apparent rise in
phos-phonus levels with increasing age in each
group of infants was not significant.
The blood pH for NHC infants at 8 hours
of age
( prior
to becoming
hypocalcemic)was in the acidotic range of 7.27 ± 0.03
versus a normal value of 7.35 ± 0.01 for
non-NHC infants. At 29 hours of age, the
occurrence of hypocalcemia in the NHC
groups was associated with a correction of
blood pH to the normal range.
Serum protein values were lower in NHC
infants at 8 hours of age, with a mean value
of 4.9 ± 0.1 gm/100 ml versus 5.2 ±0.1
gm/ 100 ml for non-NHC infants. There
was no significant difference in serum
pro-tein values at 29 hours of age between the
NHC and non-NHC group. Serum
mag-nesium and glucose values showed no
cor-relation with NHC.
The results of biochemical
determina-tions performed beyond 36 hours on
non-NHC infants were within normal limits.
These infants did not develop
TABLE IV
Age
Serum calcium (mg/100 ml)
p value
NHC
8hr
Non-X!IC
8.9 ± 0 ‘2 (22)
29 hr
7)Value*
9.6±0.1 (55)
6.3±0.1 (37) 9.0±0.1 (79)
<0.001
Serum phosphorus (mg/100 ml)
p value
<0.01
<0.001
<0.01 8 hr
29 hr
7.6 ± 0.4 (22)
8.1±0.3 (34)
11.5.
Blood pH
p value
8 hr 29 hr
6.3±0.2 (62)
6.7±0.2 (75)
fl.S.
7.35±0.01 (61)
7.39±0.01 (73)
<0.01
<0.001
<0.02
‘I-s.
7.27±0.03 (22) 7.37 ±0.01 (33)
Serum protein (gm/100 ml)
p value
<0.005
8 hr
<0.01
4.9±0.1 (1’?) 5.2±0.1 (5’2)
‘29hr 5.1±0.1(29) 5.2±0.1(76)
n.s.
Serum magnesium (mg/100 ml)
p value
n.s.
8 hr 29 hr
‘2.1±0.1(16)
2.2±0.1 (27)
n.s.
<0.05
11.5.
‘IS.
I1.5.
11.5. 2.1±0.1 (27)
2.2±0.1(68)
n.s.
Serum glucose (mng/100 ml)
p value
8 hr 54±6 (19)
29 hr
50±3 (65)
Mean values given with SEM. = number of infants.
* by “Student’s” t test.
n.s.= not significant.
61±6 (31) 58±3 (74)
I1.S. u.S.
Il-S.
The relationship between clinical
symp-tomatology and NHC is depicted in Figure
1. Hyperactivity, “jitteriness” (generalized
involuntary jerking movements),
hypertoni-city, and convulsion were not related to
hy-pocalcemia. Carpopedal spasm, repetitive
blinking, Chvostek’s signs, and Trousseau’s
signs were looked for but were not
de-tected. Three signs were signfficantly
re-lated to NHC: (1) twitching of the
extrem-ities was seen in 7
of
37 (19%) infants versus2 of 87 (2%) in non-NHC infants; (2) high
pitched cry occurred in 6 of 37 (16%) NHC
infants versus 3% of 87 (3%) non-NHC
in-fants; (3) hypotonicity was noted in 10 of
37 (27%) hypocalcemic infants versus 8 of
87 (9%) non-NHC infants.
DISCUSSION
Various lower limits of serum calcium
levels have been used to define neonatal
hypocalcemia. Saville and Kretchmert4 used
I-Iypocolrsmic
El
Non.hypocolcemmc90
80
70
60
50
HYPE PACT) V TV HYPE RTON CI TV
GENERALIZED
‘JITTER) NESS CONVULSION
TWITCHING
OF HYPOTONICITY
EXT REM IT I ES
H IG H.PITCHED CRY
20
10
p value [x2]
n-’-1830 924 2 I
3787 3787
FIG. 1. Symptoms of neonatal hypocalcemia.
72 63 108
3787 3787 3787
778
(I)
0
I-0.
>-U)
I
I-U)
I-z
z
40 0
Lii 30
I-z
Lii
U
Lii
a-a.,.
n.e. flu.9 mgI 100 ml in full-term and LBW infants;
Gittleman, et al. and Craig and Buchanan2
tlsed S nig/ 100 ml for term infants and
LBW infants, while Bruck and Weintraub
suggested 7 mg/ 100 ml for LBW infants.
We choose 7 mg/ 100 ml as the level below
which we considered infants as
hypocal-cemic. The incidence of 29.8% in the
pres-ent survey is very similar to the results
ob-tained by Bruck and Weintraub, but lower
than those obtained by Gittleman, et al.1 It
is apparent that the discrepancy in the
inci-dence is due to the selection of lower limits
of normal for serum calcium. It should also
be emphasized that our results represent
the incidence of neonatal hypocalcemia in
LBW infants weighing less than 2,000 gm
who survived the first 48 hours of age. It is
conceivable that the incidence of NHC will
l)e lower if infants weighing between 2,000
and 2,500 gm were included in this study.
Maternal factors of age. graviditv, and
race, possibly indicative of maternal
nutni-<0.005 <0.025 <0.025
tional status, appear to play an insignificant
role in NHC. This is in keeping with
stud-ies by Booher and Hansman&5 and Coons
and Blunt,16 which suggest that the fetus
appears to be entirely parasitic in regard to
calcium demands on the mother, and it
de-rives from her whatever is required for its
own calcium metabolism, regardless of
ma-ternal nutritional status.
NHC was not associated with infants
who were small for dates non with neonatal
hypoglycemia. In addition, the lack of
correlation between NHC and factors
com-monly associated with intra-uterine growth
retardation (IUGR )17-2o (viz., toxemia,
renal disease, multiple pregnancy, and
pla-cental pathology) suggests that there is no
defect in the intra-utenine transfer,
metabo-lism, and assimilation of calcium from
mother to fetus in IUGR.2’
Maternal diabetes or prediabetes has
often been mentioned as a predisposing
mater-nal diabetes was found in the present
study. It should be pointed out that this
Se-ries includes only one insulin-dependent
mother and six gestational diabetic
moth-ers.
Cesarean section, placenta previa,
abrup-tio, and prolonged labor have been
men-tioned as associated with NHC in term
in-fants.l,2,14 No statistical relationship was
established between these factors and NHC
in the present study.
Low gestation and its associated factors,
such as history of previous abortion, low
birth weight, and birth weight appropriate
for gestational age, could predispose a
neo-nate
to
NHC. Fetal ash studies have shownthat the deposition of minerals, including
calcium, assumes a steep rise toward the
last 2 to 3 months of intra-uterine life.23
Approximately 140 to 280 mg of calcium is
deposited daily during the last 2 months of
pregnancy. Birth at an earlier gestation
de-prives the
infants
of
this optimum storageof calcium which may strain the
homeosta-tic mechanisms for calcium during the
early neonatal life.
The lack of oral calcium intake in the
first 24 to 48 hours may further compound
this problem. LBW infants of low
gesta-tional age require several days before an
adequate oral intake is established and,
since commercial formulas consist of 30 to
60 mg calcium/100 ml, an oral intake less
than 100 mI/kg/day will result in a calcium
intake of much less than that which the
fetus was receiving in utero. Furthermore,
the oral intake
of
LBW infants who areser-iously ill in the first 48 hours tends to be
curtailed with
a greater
risk of
NHC.The possible relationship between
aci-dosis and its correction and NHC is
intrigu-ing. Acidosis may mobilize calcium from
bone.24 With correction of acidosis by
NaHCO3 infusion in infantile diarrhea,
Ra-poport, et al.25 demonstrated a drop in
serum total calcium by 1 to 4.5 mg/ 100 ml.
It has been postulated that, during the
pe-riod
of diarrhea
and acidosis, calcium ismobilized from bone and lost from the
body, causing a depletion of body calcium.
With correction of the acidosis, the
extra-cellular calcium is redeposited into bone
and soft tissue, resulting in hypocalcemia.
In LBW infants with a low total body
cal-cium and lack of oral calcium intake, the
administration of bicarbonate for correction
of acidosis could conceivably have a similar
effect.
When one is alerted to the possibility of
LBW infants developing NHC by the
presence of high-risk factors in the history
and neonatal course, serial serum calcium
values should be followed. Cord serum
cal-cium values are generally higher than
ma-ternal values, and they bear no relationship
to subsequent calcium values. However, at
12 hours of age, a level of less than 9
mg/ 100 ml appears to have predictive
value in assessing the possibility of
subse-quent development of NHC. Elevated
serum phosphorus values have repeatedly
been reported in the literature in
associa-lion with NHC. The exact relationship is
unclear. In the present study, the elevated
serum phosphorus was perhaps related to
respiratory distress, since the latter is
fre-quently accompanied by a high endogenous
phosphorus load resulting from increased
cellular breakdown.#{176},
Hyperphospha-temia, whatever its etiology, could depress
serum calcium values.28 On the other hand,
both hyperphosphatemia and hypocalcemia
may be manifestations of
hypoparathy-roidism, although a separate study from our
laboratory suggested that the renal
phos-phorus excretion of infants with NHC does
not differ significantly from non-NHC
infants. The lower serum protein values
initially in NHC infants may have been
re-lated to respiratory distress in which lower
serum protein values have been reported.3#{176}
The lack of correlation of calcium levels
with magnesium values is interesting since
several reports suggest a possible
relation-ship between hypomagnesemia and
hypo-calcemia in older infants3l33 as well as a
positive correlation between the serum
cal-cium and magnesium levels of term
neonates.34
symptom-780
atology does not correlate well with the
de-gree of hypocalcemia.2’35 If LBW infants
are observed closely, the incidence of
neu-romuscular symptomatology is generally
high, hence individual neuromuscular signs
are often nonspecific and not helpful in the
diagnosis of NHC, as shown in this study.
The three signs which were significantly
re-lated to hypocalcemia may be of value in
recognition of this condition. Severe
symp-toms, like convulsions, may not have
ap-peared in infants in this study because of
early therapy, since serum calcium values
of 7 mg/ 100 ml or less, when discovered on
two sequential determinations, prompted
intravenous and oral calcium therapy.
SPECULATION
With elucidation of the associated
clini-cal and biochemical factors in NHC, work
can be directed toward determining the
exact pathophysiology of this entity.
High-risk infants could be selected prior to
de-velopment of NHC, and the process of
de-velopment of NHC could be followed and
analyzed from the first hours after birth.
It is also conceivable that NHC can be
obviated if high-risk infants are
prophylac-tically given calcium supplementation
dur-ing the high risk period (first 3 days of
life), particularly those infants who are
re-ceiving intravenous fluids with low oral
cal-cium intake and requiring NaHCO3
correc-tion of acidosis.
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Acknowledgment
The authors are indebted to Mrs. Joyce Guy for
