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Studies in calcium metabolism in infants with intrauterine growth retardation
936
June 1975 The Journal o f P E D I A T R I C S
Studies in calcium metabolism in infants with intrauterine growth retardation Serial serum Ca values in 47 infants with intrauterine growth retardation wereanalyzed in relation to clinical and biochemicalfactors. Serum Ca concentrations in IUGR infants fell within the 95% confidence limits for serum Ca in infants whose birth weights were appropriate for gestational age. Serum Ca concentrations in IUGR infants were significantly correlated with birth asphyxia and bicarbonate therapy for acidosis. Serum Ca concentration at 24 hours o f age was inversely correlated with serum P values. Thus the incidence o f neonatal hypocalcemia in 1UGR infants is not increased above the incidence expectedfrom their respective gestational ages. Infants with IUGR who are well at birth do not appear to develop neonatal hypocalcemia, but 1UGR infants who are asphyxiated at birth develop significant hypocalcemia.
R e g i n a l d C. T s a n g , M . B . B . S . , * M a r d i G i g g e r , B . A . , C i n c i n n a t i , Ohio, W i l l i a m O h , M . D . , P r o v i d e n c e , R . L, and David R. B r o w n , M . D . , C i n c i n n a t L Ohio
I N F A N T S with intrauterine growth retardation ("smallf o r - g e s t a t i o n a t - a g e i n f a n t s " or " s m a l l - f o r - d a t e s infants") often exhibit abnormal neuromuscular signs such as hyperirritability in the neonatal period, s, 2 In the clinical evaluation of abnormal neuromuscular activity in I U G R infants, hypocalcemia is often suspected, a, 4 There has been little information on the serum calcium changes in infants with IUGR. One recent study of infants with conditions "commonly associated with plac e n t a l i n s u f f i c i e n c y , ! ' i n c l u d i n g I U G R i n f a n t s , appeared to indicate lower serum concentrations of Ca in
such infants. 5 Thus it appeared important to examine serum Ca values in this group of infants, particularly in relation to clinical or biochemical factors. Recent publications have emphasized the important effects o f g e s t a t i o n a l age a n d b i r t h a s p h y x i a on neonatal calcium homeostasis. A direct positive correlation has been established between neonatal serum Ca values and both gestational age and one minute Apgar
From the Fels Division o f Pediatric Research, Newborn Division, Department o f Pediatrics, University of Cincinnati College o f Medicine; the Cincinnati Children's Hospital Research Foundation; the Michael Reese Hospital and Medical Center; and Brown University. Supported in part by National Institutes o f Health Research Grant Hd-O6-458-O1Al from the National Institute of Child Health and Human Development the Fels Institute o f Developmental Research, Yellow Springs, Ohio (Reginald C. Tsang), HD 3863-01 (William Oh, M.D.), 5TO1 HD 001683-03 (Reginald C. Tsang under Jaek Metcoff, M.D.), and HD 02912-01 (Dr. Metcoff ). *Reprint address:Children'sHospitaIReseareh Foundation, Elland and BethesdaA re., Cincinnati, Ohio45229.
scores.6, 7 Since many I U G R infants are gestationally m a t u r e , t h o u g h low in b i r t h weight, a " p r o t e c t i v e " effect for serum Ca might be envisioned. Conversely, since I U G R infants m a y be born with birth asphyxia, neonatal serum Ca values m a y be adversely affected. A s t u d y o f s e r u m Ca c o n c e n t r a t i o n s in I U G R infants would require a close examination of the two variables of gestational age and Apgar scores. The present report on serum Ca changes in infants with I U G R demonstrates that the incidence of neonatal hypocalcemia in I U G R infants is not increased beyond t h e i n c i d e n c e e x p e c t e d f r o m t h e i r g e s t a t i o n a l ages. Furthermore, infants with I U G R who are well at birth
Vol. 86, No. 6, pp. 936-941
Abbreviations used IUGR: intrauterine growth retardation AGA: appropriate for gestational age
Volume 86 Number 6
Studies in calcium metabolism with IUGR
937
Table I. Clinical associations for 47 infants with intrauterine growth retardation*
Maternal hypertension ( ~ I30190)
Maternal age
Placental abnormalities
Young ~< 17 years
(3)
Toxemia
(6)
Older ~ 35 years
(5)
Chronic hypertension
(2)
Abruptio Necrosis-infarct Retained placenta
Other (2) (1) (1)
(10) (2) (23)
Twins Gestational diabetes None of above
*Twenty-fourof 47 IUGR infants had one or more clinicalfactors commonlyassociatedwith intrauterinegrowth retardation. Table II. Gestational ages and birth asphyxia in I U G R and A G A infants
Appropriate for gestational age
Intrauterine growth retardation Gestational age
Birth asphyxia
No asphyxia
Total groups 31 32 33 34 35 36 37
1 2 2 1 3 6 2
0 0 0 3 5 10 9
Totals
17
27
I [
I
No asphyxia
Incomplete record
14 3 1 4 0 0 0
15 6 10 7 6 1 0
0 2 0 1 0 0 0
22
45
Incomplete record
Birth asphyxia
0 0 0 1 0 1 1 3
3
70
47 14 matched infant pairs
31 32 33 34 35 36
1 2 1 1 0 0
0 0 0 3 5 1
Totals
5
9 14
do not appear to develop neonatal hypocalcemia, while those I U G R infants with birth asphyxia can develop significant hypocalcemia. MATERIALS
AND METHODS
Infants were chosen from a study of low-birth-weight infants of 2,000 gm or less and admitted to a Special Care Nursery. Their clinical care has been previously described. 8 Gestational ages were determined in all infants by direct questioning of the mother for the date of her last menstrual period, and corroborated by the clinical characteristics of the infants at birth. 6If there was a question regarding the accuracy of the date of the last normal menstrual period, or if a discrepancy of more than two weeks was apparent between the calculated gestational
1
0
2
0
1 1
0 3
0 0
5 1
5
9 14
age by dates and the clinical assessment, the infant was e x c l u d e d from the study. Study i n f a n t s with birth weights less t h a n the t e n t h p e r c e n t i l e on the intrauterine growth chart of Lubchenco and associates 9 were said to have IUGR. Infants with birth weights between the tenth & ninetieth percentile were considered appropriate for gestational age. Using these criteria, 47 infants with I U G R were identified (Table I). Twenty-four of the 47 I U G R infants had one or more clinical factors commonly associated with i n t r a u t e r i n e growth retardation: y o u n g or old m o t h e r s , m a t e r n a l h y p e r t e n s i o n , placental a b n o r malities, and twinning. Their clinical course was compared with 70 A G A infants (Table II). Seventeen of 44 i n f a n t s (39%) with I U G R had b i r t h asphyxia (one minute Apgar score of 6 or less, or respiratory assist-
938
Tsang et aL
The Journal of Pediatrics June 1975
Table III, Clinical factors and symptoms in hypocalcemia of I U G R infants
Neonatal hypocalcemia (n =10) Clinical factors* Birth asphyxiat a. Bicarbonate therapy b. No bicarbonate Bicarbonate therapy for acidosis Respiratory distress
6/10 (60%) 6/10 (60%)
Neurologic signs and symptoms* Jitteriness a. With hypoglycemia b. Without hypoglycemia Twitching of extremity a. With hypoglycemia b. Without hypoglycemia Convulsion Hypert0nicity Hypotonicity High-pitched cry
4/10 3 1 1/10 1 0 0/10 3/10 2/10 3/10
Hypoglycemia
3/10 (30%)
7/9 (78%)* 6 1
(40%) (10%)
(0%) (30%) (20%) (30%)
Non hypoealeemic (n =37)
Ch# square
I
P value
10/35 (29%)* 2 8
5.38
<0.025
5/37 (14%) 7/37 (19%)
9.49 6.64
<0.005 <0.01
(35%)
0.08
ns
(5%)
0.20
ns
(3%) (40%) (5%) (11%)
3.1 0.37 2.29 0.69
ns ns ns ns
4/37 (11%)
2.29
ns
13/37 1 12 2/37 0 2 1/37 15/37 2/37 4/37
*As defined in text. tOne infant with hypocalcemia and two nonhypocalcemic infants not included because of incomplete birth record. *Number of infants with factor, with or without hypocalcemia/total number of infants, with or without hypocalcemia (percentage).
/
~ ~
9
I0
\ 8
7
95%, AGA 9
k
J
/
/
/
/
/
4
GESTATIONAL AGE (WEEKS)
Fig. 1. Lowest serum Ca concentrations in infants with intrauterine growth retardation (each dot represents one infant value) compared with the 95% fiducial limits for infants whose birth weights are appropriate-for-gestationalage. ance with positive pressure was necessary at delivery). Three I U G R infants had poor documentation of birth p r o b l e m s b e c a u s e of t r a n s f e r f r o m o t h e r hospitals. Twenty of 67 A G A infants (30%) had birth asphyxia. Three A G A infants had a poorly d o c u m e n t e d birth
history. A further comparison was made between 14 I U G R infants and 14 A G A infants, matched for gestational age ((31, 32, 33, 34, 35, and 36 weeks, respectively) and presence or absence of birth asphyxia (Table II). D e t e r m i n a t i o n s of s e r u m c o n c e n t r a t i o n s of magnesium, phosphorus, glucose, and protein, and blood pH were carried out at 12, 24, 48, and 72 hours of age, respectively, as previously described. 8 For the purposes of this study, infants with serum Ca concentrations of 7 mg/dl or less were considered hypocalcemic. Infants with serum glucose concentrations of 20 mg/dl or less were c o n s i d e r e d h y p o g l y c e m i c . F i v e I U G R i n f a n t s were treated with supplemental calcium gluconate after 24 hours of age when hypocalcemia was recognized. The following neurologic signs and symptoms were arbitrarily defined: generalized jitteriness ( " j u m p y " infant, with shaking of all extremities, spontaneously or on provocation by flicking the heels with the observer's fingers), hypertonicity (increased tone and resistance of u p p e r and lower e x t r e m i t i e s w h e n e x t e n d e d f r o m flexed positions), convulsions (generalized rhythmic flexion-extension activity of all extremities without prov o c a t i o n ) , t w i t c h i n g of e x t r e m i t i e s ( s h a k i n g m o v e ments of one or two limbs), high-pitched cry (shrill cry, by nursing observation), and hypotonicity (decreased
Volume 86 Number 6
Studies in calcium metabolism with 1UGR
'~ml~ NON-HYPOCALCEMIC 1 I0 _:~lr-.~ HYPOCALCEMIC j meon ( ) NUMBER 9
(26)
S.E.M
(7)
J .~ ~e'
~0.0~
(30
(29)
OOl * p,[QO01
6
(to)
"''T~7)
L .2 \
7
939
(37)
7.4 (6)
7.3
(18) (7)
i
I 4-12 HOURS
24-48 HOURS
7.1
-1. p~ 0.01 i
I
4-12
24-48
HOURS
HOURS
Fig. 2. Biochemical variables in IUGR hypocalcemia. Serum Ca, Mg, and P and blood pH in infants with intrauterine growth retardation at 4 to 12 hours and 24-48 hours of age. Values expressed as mean _ standard error of mean. Numbers in parenthesis indicate numbers of infants. Hypocalcemia indicates serum Ca concentration of 7 mg/dl or less. tone and resistance of all limbs when extended from flexed positions). All observations were verified by one o b s e r v e r (R. T.) prior to k n o w l e d g e of b i o c h e m i c a l values. Respiratory distress was defined as any respiratory c o n d i t i o n with r e t r a c t i o n s a n d r e s p i r a t o r y rate greater than 60 per minute for more than 4 hours. Serum concentrations of Ca, Mg, P, glucose, and protein and blood pH determinations were carried out as previously described. 8Standard t tests, paired-t tests, regression analyses, and chi-square analyses were performed according to Snedecor and CochranJ ~ RESULTS Serum Ca in IUGR infants compared with A G A infants. The lowest recorded serum Ca level in 70 A G A infants was significantly correlated with gestational age (Fig. 1). The lowest serum Ca value for all but two of 47 I U G R infants fell within the 95% fiducial limits for serum Ca levels in A G A infants of comparable gestational age (Fig. 1). By covariance analysis, with gestational age as covariate, the serum Ca concentrations in I U G R infants were not significantly different (F = 0.36)
from those in A G A infants. In addition, no significant differences were detected in serum Ca values between 14 I U G R infants and 14 A G A infants matched for gestational age and birth asphyxia (Table ti). Clinical factors related to serum Ca in IUGR. There were no significant correlations by regression analyses between maternal age or duration of labor and neonatal serum Ca concentrations or by chi-square analyses between race, gravidity, or sex and neonatal hypocalcemia. Seven of nine hypocalcemic I U G R infants had birth asphyxia as compared with ten of 35 nonhypocalcemic infants ( c h i - s q u a r e , p < 0.025, T a b l e I I I ) ; six of the seven asphyxiated I U G R infants also received bicarbonate therapy for acidosis. W h e n the total group of I U G R infants was e x a m i n e d , I U G R i n f a n t s with neonatal hypocalcemia had an increased incidence of intravenous administration of sodium bicarbonate for acidosis (p < 0.005) and of r e s p i r a t o r y distress (p < 0.01), when compared with I U G R infants without hypocalcemia. H y p o c a l c e m i a was not related to n e u r o m u s c u l a r
940
Tsang et al.
symptomatology (Table III). Four of ten infants with hypocalcemia had symptoms ofjitteriness as compared with 13 of 37 infants without hypocalcemia (not significant). Of the four hypocalcemic IUGR infants who were "jittery," three were also hypoglycemic. Overall, 17 of the 47 IUGR infants were "jittery," but 12 of the 17 were neither hypocalcemic nor hypoglycemic. Bioehemieal associations in hypoealeemia (Fig. 2). Ten of 47 IUGR infants had at least one serum Ca concentration of 7 mg/dl or less. The median age at which serum Ca reached the lowest value was 27.5 hours (range 17 to 46 hours except for one infant at 75 hours). Low serum Ca concentrations at 24 hours in all IUGR infants correlated inversely with high serum P values (r =-0.332, p (0.05). Serum Mg values were not significantly different between infants with and without hypocalcemia. Blood pH values were significantly decreased in hypocalcemic infants from 4 to 12 hours of age, but were not different from infants without hypocalcemia at 24 hours (Fig. 2). Serum glucose and protein values in hypocalcemic infants were not significantly different from infants without hypocalcemia. Serum Ca in IUGR infants with birth asphyxia. The lowest serum Ca in IUGR infants was correlated with the Apgar score at one minute (r = 0.471, p (0.01). Infants with birth asphyxia had decreased serum Ca concentrations at 24 hours (7.82 ___SE 0.25 mg/dl) when compared with infants without birth asphyxia (8.99 • 0.27 mg/dl, t test p (0.005). When compared with IUGR infants without birth asphyxia, IUGR infants with birth asphyxia had significantly decreased blood pH at 12, 24, and 48 hours, respectively; decreased calcium intake per kg birth weight on Day 1 and Day 3; shorter gestational ages and lower birth weight and a greater incidence of respiratory distress. DISCUSSION The frequency of signs and symptoms of neuromuscular hyperirritability in infants with intrauterine growth retardation has been attributed to disturbances of carbohydrate or mineral metabolism. Hypoglycemia is frequently seen in IUGR infants and has been felt to be the major cause of the neuromuscular symptoms) Serum Mg levels have been found to be relatively low in infants whose birth weights were small for dates, 12 particularly in infants of toxemic mothers. 13However, the extent to which hypomagnesemia contributes to neuromuscular symptomatology in small-for-dates infants appears to be minimal. In one study, 12only three of 38 "small-for-dates infants" had concentrations of
The Journal of Pediatrics June 1975
serum Mg below 1.5 mg/dl, with concurrent decreases in serum Ca concentrations in one infant. In the present study there was poor correlation between serum Ca concentrations and neuromuscular symptoms, similar to previous findings in premature infants and infants of diabetic mothers. 6,14Serum ionized calcium determinations might have had better correlation with clinical symptoms, particularly in association with serum Mg levels. 15However, the large number of IUGR infants in the present study with symptoms of "jitteriness" who were neither hypoglycemic nor hypocalcemic emphasizes the current lack of information regarding the reasons for neonatal neuromuscular excitability in these infants. There is little known about neonatal calcium homeostasis in infants with IUGR. A recent study of 28 infants whose mothers had "conditions commonly associated with placental insufficiency" included infants of mothers with pre-eclampsia, infants born of elderly primiparous mothers, infants who were delivered after 42 weeks' gestation, and five infants whose birth weights were sma!l-for-gestational age. s The concentration of serum Ca was generally low in this group of infants, although the frequency of birth asphyxia, or low Apgar scores, and neuromuscular symptoms were not described. The authors suggested that "placental insufficiency" was associated with impaired calcium transfer from mother to fetus which adversely affected neonatal calcium homeostasis. On a theoretical basis it is conceivable that if placental transport of calcium is impaired in conditions with placental insufficiency, the resultant deficient fetal stores of calcium may not be able to sustain neonatal calcium homeostasis. Recent studies of calcium transport across the normal placenta in monkeys and sheep have determined the net transport of calcium from mother to fetus. Fetal exchangeable pool calcium homeostasis is maintained both by calcium contribution from endogenous fetal stores and by net placental transport of calcium. At birth, since the maternal contribution of calcium is abruptly discontinued, an immediate increase of about 16-20% in the calcium supply from endogenous neonatal stores (or a corresponding decrease in calcium loss from the exchangeable pool to tissues such as bone) would be required to maintain exchangeable pool-calcium homeostasis. 16,17This need, if not met by endogenous increase or exogenous addition, would result in hypocalcemia. Thus it could be theorized that deficient fetal calcium stores might result from impaired placental transport of calcium and set the stage for neonatal hypocalcemia. Furthermore, in clinical practice, some IUGR infants apparently devel-
Volume 86 Number 6
Op " s p o n t a n e o u s " b o n e fractures with poor b o n e mineralization,3 raising the suspicion again that deficient placental calcium supply may have been a contributing factor. However, the present study suggests that there is no i n h e r e n t defect in c a l c i u m homeostasis in the syndrome of intrauterine growth retardation, at least in the e a r l y n e o n a t a l p e r i o d . T h e d i s t u r b a n c e s i n early neonatal calcium homeostasis appear to be explained by the adverse effects of the associated factors of shortened gestational age or birth asphyxia on neonatal calcium metabolism. These factors have previously been discussed.6, 7, ~8The present results do not support the hypothesis that there is impaired placental transport of calcium in I U G R i n f a n t s . Parathyroid f u n c t i o n in I U G R infants has not been studied, and such studies should give us added insight into n e o n a t a l c a l c i u m homeostasis. Additional follow-up studies of bone and calcium mineral metabolism in I U G R infants may help in understanding whether there are adverse long-term effects on bones or disturbances in calcium homeostasis. These studies are now in progress. The authors acknowledge the assistance of Dr. Irwin Light in reviewing the manuscript, and Ms. Cheryl Burton, Estelle Riley, and Mr. Art Wimberly and staff in preparation of the manuscript. REFERENCES
1. Pierog SH, and Ferrara A: Approach to the medical care of the sick newborn, St. Louis, 1971, The CV Mosby Company, pp 107-109. 2. Michaelis T, Schulte FJ, and Nolte R: Motor behavior of small for gestational age newborn infants, J PEDIATR 76:208, 1970. 3. Usher RH: Clinical and therapeutic aspects of fetal malnutrition, Pediatr Clin North Am 17:169, 1970. 4. Wald MK: Problems in chemical adaption, in Klaus MH,
Studies in calcium metabolism with IUGR
5.
6.
7.
8. 9.
10.
11.
12. 13. 14.
15. 16.
17.
18.
941
and Fanaroff AA, editors: Care of the high risk neonate, Philadelphia, 1973, WB Saunders Company, pp 168-182. Khattab AK, and Forfar JO: The interrelationship between Ca, P, and glucose levels in mother and infants in conditions commonly associated with placental insufficiency, Biol Neonate 18:1, 1971. Tsang RC, Light IJ, Sutherland JM, and Kleinman LI: Possible pathogenetic factors in neonatal hypocalcemia of prematurity, J PEDIATR82:423, 1973. Tsang RC, Chen I, Hayes W, Atkinson W, Atherton H, and Edwards N: Neonatal hypocalcemia in infants with birth asphyxia, J PEDIATR82:428, 1974. Tsang RC, and Oh W: Neonatal hypocalcemia in low birth weight infants, Pediatrics 45:773, 1970. Lubchenco LO, Hansman C, Dressier M, et al: Intrauterine growth as estimated from live-born birth-weight data at 24 to 42 weeks of gestation, Pediatrics 32:793, 1963. Snedecor GW, and Cochran WG, editors: Statistical methods, ed 6, Ames, Iowa, 1967, Iowa State University Press, pp 91-195. Cornblath M, and Schwartz R: Disorders of carbohydrate metabolism in infancy, ed 1, Philadelphia, 1966, WB Saunders Company, pp 82-104. Tsang RC, a n d O h W: Serum Mg levels in low birth weight infants, Am J Dis Child 120:44, 1970. Jukarainen E: Plasma magnesium levels during the first 5 days of life, Acta Paediatr Scand Suppl. 222, 1971. Tsang RC, Kleinman LI, Sutherland, JM, and Light IJ: Hypocalcemia in infants of diabetic mothers, J PEO1ATR 80:384, 1972. Radde IC, Parkinson DK, Holtken B, et al: Calcium ion activity in the sick neonate, Pediatr Res 6:43, 1972. Ramberg CF Jr, Delivora-Papadopoulos M, Crandall ED, and Kronfeld DS: Kinetic analysis of calcium transport across the p!acenta, J Appl Physiol 35:682, 1973. MacDonald NS, Hutchinson DL, Helper M, and Flynn E: Movement of calcium in both directions across the primate placenta, Proc Soc Exp Biol Med 119:476, 1965. Tsang RC, Chen I-W, Friedman MA, and Chen I: Neonatal parathyroid function: role of gestational age and postnatal age, J PEDIATR83:728, 1973.
June 1975 The Journal o f P E D I A T R I C S
Studies in calcium metabolism in infants with intrauterine growth retardation Serial serum Ca values in 47 infants with intrauterine growth retardation wereanalyzed in relation to clinical and biochemicalfactors. Serum Ca concentrations in IUGR infants fell within the 95% confidence limits for serum Ca in infants whose birth weights were appropriate for gestational age. Serum Ca concentrations in IUGR infants were significantly correlated with birth asphyxia and bicarbonate therapy for acidosis. Serum Ca concentration at 24 hours o f age was inversely correlated with serum P values. Thus the incidence o f neonatal hypocalcemia in 1UGR infants is not increased above the incidence expectedfrom their respective gestational ages. Infants with IUGR who are well at birth do not appear to develop neonatal hypocalcemia, but 1UGR infants who are asphyxiated at birth develop significant hypocalcemia.
R e g i n a l d C. T s a n g , M . B . B . S . , * M a r d i G i g g e r , B . A . , C i n c i n n a t i , Ohio, W i l l i a m O h , M . D . , P r o v i d e n c e , R . L, and David R. B r o w n , M . D . , C i n c i n n a t L Ohio
I N F A N T S with intrauterine growth retardation ("smallf o r - g e s t a t i o n a t - a g e i n f a n t s " or " s m a l l - f o r - d a t e s infants") often exhibit abnormal neuromuscular signs such as hyperirritability in the neonatal period, s, 2 In the clinical evaluation of abnormal neuromuscular activity in I U G R infants, hypocalcemia is often suspected, a, 4 There has been little information on the serum calcium changes in infants with IUGR. One recent study of infants with conditions "commonly associated with plac e n t a l i n s u f f i c i e n c y , ! ' i n c l u d i n g I U G R i n f a n t s , appeared to indicate lower serum concentrations of Ca in
such infants. 5 Thus it appeared important to examine serum Ca values in this group of infants, particularly in relation to clinical or biochemical factors. Recent publications have emphasized the important effects o f g e s t a t i o n a l age a n d b i r t h a s p h y x i a on neonatal calcium homeostasis. A direct positive correlation has been established between neonatal serum Ca values and both gestational age and one minute Apgar
From the Fels Division o f Pediatric Research, Newborn Division, Department o f Pediatrics, University of Cincinnati College o f Medicine; the Cincinnati Children's Hospital Research Foundation; the Michael Reese Hospital and Medical Center; and Brown University. Supported in part by National Institutes o f Health Research Grant Hd-O6-458-O1Al from the National Institute of Child Health and Human Development the Fels Institute o f Developmental Research, Yellow Springs, Ohio (Reginald C. Tsang), HD 3863-01 (William Oh, M.D.), 5TO1 HD 001683-03 (Reginald C. Tsang under Jaek Metcoff, M.D.), and HD 02912-01 (Dr. Metcoff ). *Reprint address:Children'sHospitaIReseareh Foundation, Elland and BethesdaA re., Cincinnati, Ohio45229.
scores.6, 7 Since many I U G R infants are gestationally m a t u r e , t h o u g h low in b i r t h weight, a " p r o t e c t i v e " effect for serum Ca might be envisioned. Conversely, since I U G R infants m a y be born with birth asphyxia, neonatal serum Ca values m a y be adversely affected. A s t u d y o f s e r u m Ca c o n c e n t r a t i o n s in I U G R infants would require a close examination of the two variables of gestational age and Apgar scores. The present report on serum Ca changes in infants with I U G R demonstrates that the incidence of neonatal hypocalcemia in I U G R infants is not increased beyond t h e i n c i d e n c e e x p e c t e d f r o m t h e i r g e s t a t i o n a l ages. Furthermore, infants with I U G R who are well at birth
Vol. 86, No. 6, pp. 936-941
Abbreviations used IUGR: intrauterine growth retardation AGA: appropriate for gestational age
Volume 86 Number 6
Studies in calcium metabolism with IUGR
937
Table I. Clinical associations for 47 infants with intrauterine growth retardation*
Maternal hypertension ( ~ I30190)
Maternal age
Placental abnormalities
Young ~< 17 years
(3)
Toxemia
(6)
Older ~ 35 years
(5)
Chronic hypertension
(2)
Abruptio Necrosis-infarct Retained placenta
Other (2) (1) (1)
(10) (2) (23)
Twins Gestational diabetes None of above
*Twenty-fourof 47 IUGR infants had one or more clinicalfactors commonlyassociatedwith intrauterinegrowth retardation. Table II. Gestational ages and birth asphyxia in I U G R and A G A infants
Appropriate for gestational age
Intrauterine growth retardation Gestational age
Birth asphyxia
No asphyxia
Total groups 31 32 33 34 35 36 37
1 2 2 1 3 6 2
0 0 0 3 5 10 9
Totals
17
27
I [
I
No asphyxia
Incomplete record
14 3 1 4 0 0 0
15 6 10 7 6 1 0
0 2 0 1 0 0 0
22
45
Incomplete record
Birth asphyxia
0 0 0 1 0 1 1 3
3
70
47 14 matched infant pairs
31 32 33 34 35 36
1 2 1 1 0 0
0 0 0 3 5 1
Totals
5
9 14
do not appear to develop neonatal hypocalcemia, while those I U G R infants with birth asphyxia can develop significant hypocalcemia. MATERIALS
AND METHODS
Infants were chosen from a study of low-birth-weight infants of 2,000 gm or less and admitted to a Special Care Nursery. Their clinical care has been previously described. 8 Gestational ages were determined in all infants by direct questioning of the mother for the date of her last menstrual period, and corroborated by the clinical characteristics of the infants at birth. 6If there was a question regarding the accuracy of the date of the last normal menstrual period, or if a discrepancy of more than two weeks was apparent between the calculated gestational
1
0
2
0
1 1
0 3
0 0
5 1
5
9 14
age by dates and the clinical assessment, the infant was e x c l u d e d from the study. Study i n f a n t s with birth weights less t h a n the t e n t h p e r c e n t i l e on the intrauterine growth chart of Lubchenco and associates 9 were said to have IUGR. Infants with birth weights between the tenth & ninetieth percentile were considered appropriate for gestational age. Using these criteria, 47 infants with I U G R were identified (Table I). Twenty-four of the 47 I U G R infants had one or more clinical factors commonly associated with i n t r a u t e r i n e growth retardation: y o u n g or old m o t h e r s , m a t e r n a l h y p e r t e n s i o n , placental a b n o r malities, and twinning. Their clinical course was compared with 70 A G A infants (Table II). Seventeen of 44 i n f a n t s (39%) with I U G R had b i r t h asphyxia (one minute Apgar score of 6 or less, or respiratory assist-
938
Tsang et aL
The Journal of Pediatrics June 1975
Table III, Clinical factors and symptoms in hypocalcemia of I U G R infants
Neonatal hypocalcemia (n =10) Clinical factors* Birth asphyxiat a. Bicarbonate therapy b. No bicarbonate Bicarbonate therapy for acidosis Respiratory distress
6/10 (60%) 6/10 (60%)
Neurologic signs and symptoms* Jitteriness a. With hypoglycemia b. Without hypoglycemia Twitching of extremity a. With hypoglycemia b. Without hypoglycemia Convulsion Hypert0nicity Hypotonicity High-pitched cry
4/10 3 1 1/10 1 0 0/10 3/10 2/10 3/10
Hypoglycemia
3/10 (30%)
7/9 (78%)* 6 1
(40%) (10%)
(0%) (30%) (20%) (30%)
Non hypoealeemic (n =37)
Ch# square
I
P value
10/35 (29%)* 2 8
5.38
<0.025
5/37 (14%) 7/37 (19%)
9.49 6.64
<0.005 <0.01
(35%)
0.08
ns
(5%)
0.20
ns
(3%) (40%) (5%) (11%)
3.1 0.37 2.29 0.69
ns ns ns ns
4/37 (11%)
2.29
ns
13/37 1 12 2/37 0 2 1/37 15/37 2/37 4/37
*As defined in text. tOne infant with hypocalcemia and two nonhypocalcemic infants not included because of incomplete birth record. *Number of infants with factor, with or without hypocalcemia/total number of infants, with or without hypocalcemia (percentage).
/
~ ~
9
I0
\ 8
7
95%, AGA 9
k
J
/
/
/
/
/
4
GESTATIONAL AGE (WEEKS)
Fig. 1. Lowest serum Ca concentrations in infants with intrauterine growth retardation (each dot represents one infant value) compared with the 95% fiducial limits for infants whose birth weights are appropriate-for-gestationalage. ance with positive pressure was necessary at delivery). Three I U G R infants had poor documentation of birth p r o b l e m s b e c a u s e of t r a n s f e r f r o m o t h e r hospitals. Twenty of 67 A G A infants (30%) had birth asphyxia. Three A G A infants had a poorly d o c u m e n t e d birth
history. A further comparison was made between 14 I U G R infants and 14 A G A infants, matched for gestational age ((31, 32, 33, 34, 35, and 36 weeks, respectively) and presence or absence of birth asphyxia (Table II). D e t e r m i n a t i o n s of s e r u m c o n c e n t r a t i o n s of magnesium, phosphorus, glucose, and protein, and blood pH were carried out at 12, 24, 48, and 72 hours of age, respectively, as previously described. 8 For the purposes of this study, infants with serum Ca concentrations of 7 mg/dl or less were considered hypocalcemic. Infants with serum glucose concentrations of 20 mg/dl or less were c o n s i d e r e d h y p o g l y c e m i c . F i v e I U G R i n f a n t s were treated with supplemental calcium gluconate after 24 hours of age when hypocalcemia was recognized. The following neurologic signs and symptoms were arbitrarily defined: generalized jitteriness ( " j u m p y " infant, with shaking of all extremities, spontaneously or on provocation by flicking the heels with the observer's fingers), hypertonicity (increased tone and resistance of u p p e r and lower e x t r e m i t i e s w h e n e x t e n d e d f r o m flexed positions), convulsions (generalized rhythmic flexion-extension activity of all extremities without prov o c a t i o n ) , t w i t c h i n g of e x t r e m i t i e s ( s h a k i n g m o v e ments of one or two limbs), high-pitched cry (shrill cry, by nursing observation), and hypotonicity (decreased
Volume 86 Number 6
Studies in calcium metabolism with 1UGR
'~ml~ NON-HYPOCALCEMIC 1 I0 _:~lr-.~ HYPOCALCEMIC j meon ( ) NUMBER 9
(26)
S.E.M
(7)
J .~ ~e'
~0.0~
(30
(29)
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7
939
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7.4 (6)
7.3
(18) (7)
i
I 4-12 HOURS
24-48 HOURS
7.1
-1. p~ 0.01 i
I
4-12
24-48
HOURS
HOURS
Fig. 2. Biochemical variables in IUGR hypocalcemia. Serum Ca, Mg, and P and blood pH in infants with intrauterine growth retardation at 4 to 12 hours and 24-48 hours of age. Values expressed as mean _ standard error of mean. Numbers in parenthesis indicate numbers of infants. Hypocalcemia indicates serum Ca concentration of 7 mg/dl or less. tone and resistance of all limbs when extended from flexed positions). All observations were verified by one o b s e r v e r (R. T.) prior to k n o w l e d g e of b i o c h e m i c a l values. Respiratory distress was defined as any respiratory c o n d i t i o n with r e t r a c t i o n s a n d r e s p i r a t o r y rate greater than 60 per minute for more than 4 hours. Serum concentrations of Ca, Mg, P, glucose, and protein and blood pH determinations were carried out as previously described. 8Standard t tests, paired-t tests, regression analyses, and chi-square analyses were performed according to Snedecor and CochranJ ~ RESULTS Serum Ca in IUGR infants compared with A G A infants. The lowest recorded serum Ca level in 70 A G A infants was significantly correlated with gestational age (Fig. 1). The lowest serum Ca value for all but two of 47 I U G R infants fell within the 95% fiducial limits for serum Ca levels in A G A infants of comparable gestational age (Fig. 1). By covariance analysis, with gestational age as covariate, the serum Ca concentrations in I U G R infants were not significantly different (F = 0.36)
from those in A G A infants. In addition, no significant differences were detected in serum Ca values between 14 I U G R infants and 14 A G A infants matched for gestational age and birth asphyxia (Table ti). Clinical factors related to serum Ca in IUGR. There were no significant correlations by regression analyses between maternal age or duration of labor and neonatal serum Ca concentrations or by chi-square analyses between race, gravidity, or sex and neonatal hypocalcemia. Seven of nine hypocalcemic I U G R infants had birth asphyxia as compared with ten of 35 nonhypocalcemic infants ( c h i - s q u a r e , p < 0.025, T a b l e I I I ) ; six of the seven asphyxiated I U G R infants also received bicarbonate therapy for acidosis. W h e n the total group of I U G R infants was e x a m i n e d , I U G R i n f a n t s with neonatal hypocalcemia had an increased incidence of intravenous administration of sodium bicarbonate for acidosis (p < 0.005) and of r e s p i r a t o r y distress (p < 0.01), when compared with I U G R infants without hypocalcemia. H y p o c a l c e m i a was not related to n e u r o m u s c u l a r
940
Tsang et al.
symptomatology (Table III). Four of ten infants with hypocalcemia had symptoms ofjitteriness as compared with 13 of 37 infants without hypocalcemia (not significant). Of the four hypocalcemic IUGR infants who were "jittery," three were also hypoglycemic. Overall, 17 of the 47 IUGR infants were "jittery," but 12 of the 17 were neither hypocalcemic nor hypoglycemic. Bioehemieal associations in hypoealeemia (Fig. 2). Ten of 47 IUGR infants had at least one serum Ca concentration of 7 mg/dl or less. The median age at which serum Ca reached the lowest value was 27.5 hours (range 17 to 46 hours except for one infant at 75 hours). Low serum Ca concentrations at 24 hours in all IUGR infants correlated inversely with high serum P values (r =-0.332, p (0.05). Serum Mg values were not significantly different between infants with and without hypocalcemia. Blood pH values were significantly decreased in hypocalcemic infants from 4 to 12 hours of age, but were not different from infants without hypocalcemia at 24 hours (Fig. 2). Serum glucose and protein values in hypocalcemic infants were not significantly different from infants without hypocalcemia. Serum Ca in IUGR infants with birth asphyxia. The lowest serum Ca in IUGR infants was correlated with the Apgar score at one minute (r = 0.471, p (0.01). Infants with birth asphyxia had decreased serum Ca concentrations at 24 hours (7.82 ___SE 0.25 mg/dl) when compared with infants without birth asphyxia (8.99 • 0.27 mg/dl, t test p (0.005). When compared with IUGR infants without birth asphyxia, IUGR infants with birth asphyxia had significantly decreased blood pH at 12, 24, and 48 hours, respectively; decreased calcium intake per kg birth weight on Day 1 and Day 3; shorter gestational ages and lower birth weight and a greater incidence of respiratory distress. DISCUSSION The frequency of signs and symptoms of neuromuscular hyperirritability in infants with intrauterine growth retardation has been attributed to disturbances of carbohydrate or mineral metabolism. Hypoglycemia is frequently seen in IUGR infants and has been felt to be the major cause of the neuromuscular symptoms) Serum Mg levels have been found to be relatively low in infants whose birth weights were small for dates, 12 particularly in infants of toxemic mothers. 13However, the extent to which hypomagnesemia contributes to neuromuscular symptomatology in small-for-dates infants appears to be minimal. In one study, 12only three of 38 "small-for-dates infants" had concentrations of
The Journal of Pediatrics June 1975
serum Mg below 1.5 mg/dl, with concurrent decreases in serum Ca concentrations in one infant. In the present study there was poor correlation between serum Ca concentrations and neuromuscular symptoms, similar to previous findings in premature infants and infants of diabetic mothers. 6,14Serum ionized calcium determinations might have had better correlation with clinical symptoms, particularly in association with serum Mg levels. 15However, the large number of IUGR infants in the present study with symptoms of "jitteriness" who were neither hypoglycemic nor hypocalcemic emphasizes the current lack of information regarding the reasons for neonatal neuromuscular excitability in these infants. There is little known about neonatal calcium homeostasis in infants with IUGR. A recent study of 28 infants whose mothers had "conditions commonly associated with placental insufficiency" included infants of mothers with pre-eclampsia, infants born of elderly primiparous mothers, infants who were delivered after 42 weeks' gestation, and five infants whose birth weights were sma!l-for-gestational age. s The concentration of serum Ca was generally low in this group of infants, although the frequency of birth asphyxia, or low Apgar scores, and neuromuscular symptoms were not described. The authors suggested that "placental insufficiency" was associated with impaired calcium transfer from mother to fetus which adversely affected neonatal calcium homeostasis. On a theoretical basis it is conceivable that if placental transport of calcium is impaired in conditions with placental insufficiency, the resultant deficient fetal stores of calcium may not be able to sustain neonatal calcium homeostasis. Recent studies of calcium transport across the normal placenta in monkeys and sheep have determined the net transport of calcium from mother to fetus. Fetal exchangeable pool calcium homeostasis is maintained both by calcium contribution from endogenous fetal stores and by net placental transport of calcium. At birth, since the maternal contribution of calcium is abruptly discontinued, an immediate increase of about 16-20% in the calcium supply from endogenous neonatal stores (or a corresponding decrease in calcium loss from the exchangeable pool to tissues such as bone) would be required to maintain exchangeable pool-calcium homeostasis. 16,17This need, if not met by endogenous increase or exogenous addition, would result in hypocalcemia. Thus it could be theorized that deficient fetal calcium stores might result from impaired placental transport of calcium and set the stage for neonatal hypocalcemia. Furthermore, in clinical practice, some IUGR infants apparently devel-
Volume 86 Number 6
Op " s p o n t a n e o u s " b o n e fractures with poor b o n e mineralization,3 raising the suspicion again that deficient placental calcium supply may have been a contributing factor. However, the present study suggests that there is no i n h e r e n t defect in c a l c i u m homeostasis in the syndrome of intrauterine growth retardation, at least in the e a r l y n e o n a t a l p e r i o d . T h e d i s t u r b a n c e s i n early neonatal calcium homeostasis appear to be explained by the adverse effects of the associated factors of shortened gestational age or birth asphyxia on neonatal calcium metabolism. These factors have previously been discussed.6, 7, ~8The present results do not support the hypothesis that there is impaired placental transport of calcium in I U G R i n f a n t s . Parathyroid f u n c t i o n in I U G R infants has not been studied, and such studies should give us added insight into n e o n a t a l c a l c i u m homeostasis. Additional follow-up studies of bone and calcium mineral metabolism in I U G R infants may help in understanding whether there are adverse long-term effects on bones or disturbances in calcium homeostasis. These studies are now in progress. The authors acknowledge the assistance of Dr. Irwin Light in reviewing the manuscript, and Ms. Cheryl Burton, Estelle Riley, and Mr. Art Wimberly and staff in preparation of the manuscript. REFERENCES
1. Pierog SH, and Ferrara A: Approach to the medical care of the sick newborn, St. Louis, 1971, The CV Mosby Company, pp 107-109. 2. Michaelis T, Schulte FJ, and Nolte R: Motor behavior of small for gestational age newborn infants, J PEDIATR 76:208, 1970. 3. Usher RH: Clinical and therapeutic aspects of fetal malnutrition, Pediatr Clin North Am 17:169, 1970. 4. Wald MK: Problems in chemical adaption, in Klaus MH,
Studies in calcium metabolism with IUGR
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and Fanaroff AA, editors: Care of the high risk neonate, Philadelphia, 1973, WB Saunders Company, pp 168-182. Khattab AK, and Forfar JO: The interrelationship between Ca, P, and glucose levels in mother and infants in conditions commonly associated with placental insufficiency, Biol Neonate 18:1, 1971. Tsang RC, Light IJ, Sutherland JM, and Kleinman LI: Possible pathogenetic factors in neonatal hypocalcemia of prematurity, J PEDIATR82:423, 1973. Tsang RC, Chen I, Hayes W, Atkinson W, Atherton H, and Edwards N: Neonatal hypocalcemia in infants with birth asphyxia, J PEDIATR82:428, 1974. Tsang RC, and Oh W: Neonatal hypocalcemia in low birth weight infants, Pediatrics 45:773, 1970. Lubchenco LO, Hansman C, Dressier M, et al: Intrauterine growth as estimated from live-born birth-weight data at 24 to 42 weeks of gestation, Pediatrics 32:793, 1963. Snedecor GW, and Cochran WG, editors: Statistical methods, ed 6, Ames, Iowa, 1967, Iowa State University Press, pp 91-195. Cornblath M, and Schwartz R: Disorders of carbohydrate metabolism in infancy, ed 1, Philadelphia, 1966, WB Saunders Company, pp 82-104. Tsang RC, a n d O h W: Serum Mg levels in low birth weight infants, Am J Dis Child 120:44, 1970. Jukarainen E: Plasma magnesium levels during the first 5 days of life, Acta Paediatr Scand Suppl. 222, 1971. Tsang RC, Kleinman LI, Sutherland, JM, and Light IJ: Hypocalcemia in infants of diabetic mothers, J PEO1ATR 80:384, 1972. Radde IC, Parkinson DK, Holtken B, et al: Calcium ion activity in the sick neonate, Pediatr Res 6:43, 1972. Ramberg CF Jr, Delivora-Papadopoulos M, Crandall ED, and Kronfeld DS: Kinetic analysis of calcium transport across the p!acenta, J Appl Physiol 35:682, 1973. MacDonald NS, Hutchinson DL, Helper M, and Flynn E: Movement of calcium in both directions across the primate placenta, Proc Soc Exp Biol Med 119:476, 1965. Tsang RC, Chen I-W, Friedman MA, and Chen I: Neonatal parathyroid function: role of gestational age and postnatal age, J PEDIATR83:728, 1973.