Early neonatal hypocalcemia in extremely preterm infants. High incidence, early onset, and refractoriness to supraphysiologic doses of calcitriol

Nineteen preterm infants born at or before 32 weeks of gestation were studied to determine the dose of calcitriol that would be effective in the prophylaxis of early neonatal hypocalcemia (serum calcium level, less than 7.0 mg/dL [less than 1.75 mmol/L]). In these infants the course of early neonatal hypocalcemia was not modified by calcitriol administration. Serum 1,25-dihydroxyvitamin D level rose in response to intramuscular administration of calcitriol. The incidence of hypocalcemia in these infants was 37% by 12 hours, 83% by 24 hours, and 89% by 36 hours. Thus, in extremely preterm infants, the incidence of early neonatal hypocalcemia is higher and the onset earlier than in larger preterm infants; furthermore, in these infants the hypocalcemia is refractory even to high doses of calcitriol.     

Neonatal polycythemia: I. Early diagnosis and incidence relating to time of sampling

The dynamic changes occurring in hematocrit and blood viscosity within the first 18 hours of life were studied in 50 full-term infants who were vaginally delivered and had weight appropriate for gestational age. In all cases, the cord was clamped within 30 seconds and cord blood was collected from the vein and artery. Subsequently, samples were taken from a peripheral vein at ages 15 minutes, and 2, 4, 6, and between 12 to 18 hours. Both the Hct and blood viscosity reach their peak at age 2 hours. The incidence of neonatal polycythemia varied greatly with age. Thus at the age of 2 hours, ten infants (20%) were polycythemic, whereas by age 6 hours only six (12%) of these infants were still polycythemic and by age 12 to 18 hours only one infant (2%) was polycythemic. A linear correlation was found between cord Hct levels and peripheral venous Hct levels by age 2 hours. None of the infants with cord blood Hct levels less than or equal to 56% had developed polycythemia, whereas ten of the 12 infants with cord Hct levels greater than 56% developed polycythemia. In this particular group of infants, cord blood Hct levels may be used for the screening of neonatal polycythemia.     

Postnatal changes in calcium-regulating hormones in very-low-birth-weight infants. Effect of early neonatal hypocalcemia and intravenous calcium infusion on serum parathyroid hormone and calcitonin homeostasis

In very-low-birth-weight (VLBW) infants, we studied the hypotheses that in early neonatal hypocalcemia the serum parathyroid hormone (PTH) concentration would rise; the serum calcitonin (CT) concentration would decline; and, in response to intravenous (IV) calcium (Ca) infusion, the serum PTH concentration would be lowered; and the serum CT concentration would rise. Fifteen infants appropriate for gestational age (age, less than 32 weeks; birth weight, less than 1,500 g) were enrolled in the study. In eight infants in whom the serum Ca level declined to less than 6.0 mg/dL, changes in serum magnesium, phosphorus, PTH, CT, and whole blood ionized calcium (iCa) were evaluated on entry into the study, when serum Ca declined to less than 6.0 mg/dL, immediately after infusion of 18 mg/kg of elemental calcium as calcium gluconate, and at eight hours post-Ca infusion (+ 8 hr). The serum Ca concentration declined from 7.9 +/- 0.6 baseline (mean +/- SE) to 5.2 +/- 0.2 mg/dL pre-Ca infusion and rose to 9.17 +/- 0.74 mg/dL post-Ca infusion and 7.1 +/- 0.5 mg/dL at +8 hr post-Ca infusion. Whole blood iCa declined from 4.82 +/- 0.24 to 3.72 +/- 0.19 mg/dL pre-Ca infusion, rose to 6.68 +/- 0.32 mg/dL post-Ca infusion, and was 4.12 +/- 0.21 mg/dL at + 8 hr post-Ca infusion. The serum P concentration did not change significantly. The serum PTH concentration rose from 116 +/- 17 to 204 +/- 34 pmole/L pre-Ca infusion, declined to 149 +/- 22 pmole/L post-Ca infusion, and was 187 +/- 28 pmole/L at + 8 hr post-Ca infusion. The serum CT concentration was elevated and did not change significantly. Thus, in infants less than 32 weeks' gestation, the serum PTH level rises in early neonatal hypocalcemia and is suppressed by IV Ca infusion; the serum CT level is markedly elevated and is not altered in early neonatal hypocalcemia and does not rise further in response to IV Ca infusion in VLBW infants. We suggest that hypercalcitoninemia occurs in VLBW infants and that serum CT concentrations are unresponsive to changes in serum Ca.     

Pathogenesis of early neonatal hypocalcemia: studies of serum calcitonin, gastrin, and plasma glucagon

In 64 maternal-infant pairs, we tested the hypotheses that serum calcitonin, serum gastrin, and plasma glucagon concentrations are elevated in infants at risk for early neonatal hypocalcemia, and that elevated serum gastrin and plasma glucagon result in elevated serum calcitonin and low serum calcium values in neonates. Serum Ca declined significantly in neonates at 24 hours of age, and was inversely correlated with serum calcitonin. Cord serum calcitonin, gastrin, and plasma glucagon concentrations rose significantly at 24 hours of age. Cord calcitonin was significantly higher in preterm compared with term infants, and there was no significant difference between asphyxiated and nonasphyxiated preterm neonates; in term neonates cord calcitonin concentration was inversely correlated with Apgar scores at 1 and 5 minutes. Cord calcitonin was not correlated with cord gastrin or glucagon. Cord and 24-hour gastrin and glucagon values were not related to prematurity; cord glucagon, but not gastrin, was related to birth asphyxia. We conclude that (1) serum calcitonin, gastrin, and plasma glucagon values rise postnatally; cord calcitonin is elevated in preterm and in asphyxiated term infants; serum calcitonin concentration does not correlate with the elevated serum gastrin and plasma glucagon values; and at 24 hours of age, decreased serum Ca is correlated with serum calcitonin, and hence calcitonin might play a role in the pathogenesis of early neonatal hypocalcemia.     

Postnatal development of liver and exocrine pancreas in polycythemic newborn infants.

In 35 newborn infants appropriate for gestational age the influence of neonatal polycythemia (venous hematocrit greater than 60% measured between the second and fourth hour of life) on development of enterohepatic circulation of bile acids, activities of pancreatic enzymes in duodenal juice, and the effects of hemodilution were studied during the second week of life. A significant correlation was found between the initial hematocrit and both the bile acid concentration in serum and lipase and trypsin activity in duodenal juice. Of 35 infants, 10 were not treated with hemodilution due to asymptomatic polycythemia; they had the highest concentration of serum bile acids associated with the lowest lipase and trypsin activity in duodenal juice. However, the 25 infants treated with hemodilution also showed serum bile acid concentrations and lipase and trypsin activity in duodenal juice out of the normal range when compared to normocythemic infants. These data indicate that, during the first days of life, polycythemia results in a delayed postnatal development of enterohepatic circulation of bile acids and exocrine pancreas functions independently from the occurrence of clinical symptoms. Thus, it can be concluded that, on the first day of life, all polycythemic infants should be treated with hemodilution. Moreover, the nutritional management of these infants must also account for the limited functional capacity of the gastrointestinal tract.     

Serum ionized calcium concentrations in normal neonates

Adult serum ionized calcium (iCa) concentrations are higher when using the newer, highly sensitive, ion-selective electrodes compared with older electrodes. Currently used neonatal normative ranges were established using older electrodes and not under standardized conditions or age. Thirty term infants, carefully screened to exclude confounding factors that could affect serum iCa concentration, were studied at birth and 2 and 24 hours of age for serum iCa concentrations. Mean concentrations declined from 1.45 mmol/L (5.82 mg/dL) at birth to 1.33 mmol/L (5.34 mg/dL) at 2 hours to 1.23 mmol/L (4.92 mg/dL) at 24 hours. The 95% confidence limits at 24 hours ranged from 1.10 to 1.36 mmol/L (4.40 to 5.44 mg/dL). Using newer ion-selective electrodes, normal neonatal ranges for iCa concentrations during the first 24 hours of age are higher than published references.     

Severe renal osteodystrophy without elevated serum immunoreactive parathyroid hormone concentrations in hypomagnesemia due to renal magnesium wasting

An 8 1/2-year-old girl presented with a long history of seizures, growth retardation, muscle weakness, gait disturbance, and hearing loss. Her evaluation revealed chronic moderate renal failure (serum creatinine 2.2 mg/dL), severe hypocalcemia (5 mg/dL), hyperphosphatemia (8.1 mg/dL), hypomagnesemia (1.5 mg/dL), increased urinary magnesium excretion (2 mg/kg/d), high fractional excretion of magnesium (21.7%), hypokalemia (3.2 mEq/L), and hyperkaliuria (26 mEq/L). Low circulating immunoreactive parathyroid hormone levels for the degree of the hypocalcemia (serum N-parathyroid hormone 212 pg/mL) and severe rickets without evidence of osteitis fibrosa cystica were found. The patient probably has primary renal leak hypomagnesemia (magnesuric hypomagnesemia) which caused impaired secretion of immunoreactive parathyroid hormone leading to severe hypocalcemia and calcium deficiency rickets. Treatment with magnesium and calcium supplements, calcitriol, and aluminum hydroxide resulted in marked clinical, biochemical, and radiologic improvement. Calcium deficiency rickets due to primary or secondary renal magnesium wasting in conjunction with moderate renal failure represents a largely unrecognized metabolic bone disease.     

Primary idiopathic hypomagnesemia in two female siblings

Two female siblings with primary idiopathic hypomagnesemia, born to consanguineous parents, are described. Both presented at 6 weeks of age, with convulsions and persistent hypocalcemia (calcium 1.5 and 1.6 mmol/1; normal range (NR) 2.2-2.6 mmol/1), which could not be controlled with anticonvulsants and/or calcium gluconate. On further investigation they were also found to have hypomagnesemia (magnesium 0.17 mmol/1 and 0.22 mmol/l; NR 0.65-1.05 mmol/l). Convulsions and the low serum calcium and magnesium levels were first managed by im and then by oral administration of magnesium supplements. A burst in circulating parathyroid hormone levels to well above the physiological range was observed at the start of therapy. Serum magnesium values of the mother and father were just below the normal range, with normal serum calcium. This type of infantile primary hypomagnesemia appears to be a hereditary disease with autosomal recessive characteristics, although a partially penetrant X-linked or autosomal dominant trait cannot be excluded.
Convulsions,primary hypomagnesemia     

Differential diagnosis and management of polycythemia

One percent to 5% of all newborns in the United States are polycythemic.As the venous hematocrit rises above 65%, the thickness or viscosity of whole blood also increases, potentially compromising blood flow to a variety of organs. Fortunately, relatively few infants who have neonatal polycythemia or hyperviscosity develop complications attributable to their thick blood; however, controversy and the need for continued research envelop the issue of which infants are at risk and need to be treated. This article reviews the differential diagnosis, clinical presentation, and treatment of neonatal polycythemia.     

Postnatal alteration in hematocrit and viscosity in normal and polycythemic infants

This study was done to document postnatal alterations in hematocrit and viscosity in the first 18 hours of life in 99 full-term infants, to better understand the age-dependent variations in these measurements that may have a bearing on the diagnosis of neonatal polycythemia. The peripheral venous Hct was highest at 2 hours of age, and dropped to cord blood levels by 18 hours. The whole blood viscosity of peripheral venous samples did not change significantly with age. In infants with peripheral venous Hct greater than or equal to 64%, and therefore considered to have polycythemia, a similar postnatal variation in Hct level was seen. Only 38% of infants with Hct greater than or equal to 64% at 2 hours of age continued to have a high level beyond 12 hours of age. The viscosity level in these infants tended to follow that of the Hct. The mean +/- 2 SD viscosity values obtained from peripheral venous samples was much higher than the upper limits of viscosity used in previous studies in which cord blood viscosity was used as the norm. Cord blood Hct correlated better with peripheral venous Hct than with capillary hematocrit, and provided a noninvasive method for screening. These findings suggest that the postnatal variations in Hct should be taken into consideration in the diagnosis of neonatal polycythemia.     

Circulating immunoreactive parathyroid hormone levels in premature infants and the response to calcium therapy

Serum immunoreactive parathyroid hormone (iPTH), calcium, magnesium, and phosphorus levels were measured in 13 premature infants during the first 96 hours of life. Hypocalcemia at 12-24 hours of age was associated with a markedly elevated mean serum iPTH level. Six of the hypocalcemic infants received a continuous infusion of calcium while seven were not treated. In the untreated infants, the mean serum calcium remained in the hypocalcemic range while the serum iPTH progressively increased. By contrast, the mean serum calcium in the treated infants increased to 2.35 mmol/l at 96 hours of age and was accompanied by a decline in serum iPTH. At 72 and 96 hours, the mean serum iPTH was twofold greater in the untreated than in the treated infants. The results indicate that the parathyroid glands of premature infants respond to calcium signals and that a factor(s), other than parathyroid insufficiency, plays an etiologic role in the hypocalcemia of prematurity.     

Circulating Immunoreactive Parathyroid Hormone Levels in Premature Infants and the Response to Calcium Therapy

ABSTRACT. Serum immunoreactive parathyroid hormone (iPTH), calcium, magnesium, and phosphorus levels were measured in 13 premature infants during the first 96 hours of life. Hypocalcemia at 12–24 hours of age was associated with a markedly elevated mean serum iPTH level. Six of the hypocaicemic infants received a continuous infusion of calcium while seven were not treated. In the untreated infants, the mean serum calcium remained in the hypocaicemic range while the serum iPTH progressively increased. By contrast, the mean serum calcium in the treated infants increased to 2.35 mmol/l at 96 hours of age and was accompanied by a decline in serum iPTH. At 72 and 96 hours, the mean serum iPTH was twofold greater in the untreated than in the treated infants. The results indicate that the parathyroid glands of premature infants respond to calcium signals and that a factor(s), other than parathyroid insufficiency, plays an etiologic role in the hypocalcemia of prematurity.     

Influence of the Maternal Plasma Glucose Concentration at Delivery on the Risk of Hypoglycaemia in Infants of Insulin-Dependent Diabetic Mothers

Plasma glucose concentrations at birth and at two hours of age were measured in 53 infants of insulin-dependent mothers (IDMs). The plasma glucose concentrations at delivery were measured in the mothers of 17 IDMs and in the remaining 36 mothers, glucose was estimated by interpolation from concentrations achieved just before and after delivery. Clinical and laboratory data from the two groups were otherwise similar, so the groups were combined for further analyses. The maternal plasma glucose at delivery correlated positively with the glucose concentration of the IDMs at birth (Q=0.82, p <0.001) and negatively with the glucose concentration at two hours of age (Q= -0.46, p <0.001). Maternal plasma glucose concentration was higher in mothers delivered by caesarean section than in vaginally delivered mothers ( p <0.05). Eleven IDMs became hypoglycaemic at two hours of life (plasma glucose ≥1.7 mmol/1). These infants had higher cord plasma glucose concentrations at birth than those who remained normoglycaemic; the maternal glucose concentration was also higher. None of the IDMs became hypoglycaemic if the maternal glucose concentration at delivery was less than 7.1 mmol/l. In 28 IDMs the simultaneous plasma concentrations of non-antibodybound immunoreactive insulin (IRI) were recorded. Cord plasma IRI correlated with glucose and IRI at two hours of age (Q=-0.73, p <0.001 and Q=0.77, p <0.001, respectively). Cord plasma IRI was higher in IDMs who became hypoglycaemic than in the remaining infants. The results suggest that among the factors which may be responsible for neonatal hypoglycaemia in IDMs a major factor may be the maternal plasma glucose concentration at the time of delivery.     

HYPOCALCEMIA IN INFANTS OF DIABETIC MOTHERS

ABSTRACT. Twenty-two infants of diabetic mothers (IDM) were studied and were divided into two groups: a first group of 14 IDM did not receive vitamin D3 and was studied at birth and at 2, 24, 48 and 120 hours; a second group was given daily dosage of 60 μg of vitamin D3 from 3 hours to 120 hours and was studied at 2 hours and 120 hours.
In the first group, serum calcium levels decreased markedly during the first 24 hours of life (mean ± SD: 1.77±0.3 mmol/1, p <0.01) and remained low at 5 days. Serum phosphorus levels remained normal but serum magnesium levels decreased significantly at 24 hours (mean ± SD: 0.64±0.108 mmol/1, p <0.01) and returned to normal at 5 days. Serum immunoreactive parathormone levels increased consistently to high levels at 24 hours and remained elevated at 120 hours ( p <0.001). Serum immunoreactive calcitonin levels increased at 24 hours ( p <0.001) and decreased at 120 hours to low or undetectable values in all infants.
In group II, serum 25O-HD levels and 1.25 OH₂ D levels increased significantly ( p <0.001) respectively to 27.2±2.7 ng/ml and 114±20 pg/ml at 5 days. The results of this study show hypocalcemia to be a common event in IDM during the first days of life and furthermore hypophosphatemia, hypoparathyroidism, hypomagnesemia or defect of vitamine D metabolism would not seem to be the main etiological factors.     

Effects of neonatal polycythemia and partial exchange transfusion on cardiac function: an echocardiographic study

Although infants with neonatal polycythemia and hyperviscosity often present with cardiorespiratory distress, little information is available regarding the cardiac function of such babies before or after partial exchange transfusion. To assess cardiac function, we performed M-mode echocardiograms in 19 asymptomatic newborn infants (4 to 12 hours of age) who had venous hematocrits greater than 65%. The echocardiograms were performed immediately prior to and following partial exchange transfusion and were repeated at 48 hours of age. Eighteen matched newborn controls also underwent echocardiography within the first 12 hours of life and again at 48 hours. Polycythemic newborns had elevated right ventricular preejection period to right ventricular ejection time ratios compared with controls (0.46 +/- 0.11 v 0.37 +/- 0.04, P = .002), suggestive of increased pulmonary vascular resistance. These indexes normalized following partial exchange transfusion. In addition, the polycythemic newborns were relatively bradycardic prior to exchange (116 +/- 13 beats per minute v 125 +/- 16 beats per minute, P less than .05), but heart rates normalized following the procedure. At 48 hours, the polycythemic and control groups were different only in that the mean shortening fraction of the polycythemic group was lower than that of the controls (32% +/- 4% v 36% +/- 6%, P = .02). The findings are consistent with elevated pulmonary vascular resistance associated with polycythemia and hyperviscosity. Cardiac output may be lower in polycythemic infants. The finding of reduced fractional shortening in polycythemic infants at 48 hours following partial exchange transfusion is unexplained.     

Elevated calcitonin gene-related peptide in polycythemic newborn infants

In this study, calcitonin gene-related peptide levels were measured in cord and at 16-36 h of extrauterine life in 43 polycythemic newborns; 20 healthy term infants were also studied as controls. Calcitonin gene-related peptide values were significantly higher in polycythemic neonates in comparison with controls both at delivery and at 16-36 h after birth. Five polycythemic (11.6%) infants who develop hypocalcemia had greater elevated calcitonin gene-related peptide concentrations. Our data suggest that calcitonin gene-related peptide may be implicated in the circulatory adaptation to extrauterine life. In polycythemic neonates, calcitonin gene-related peptide is probably increased to compensate for blood hyperviscosity; in some cases, high calcitonin gene-related peptide concentrations may induce hypocalcemia.     

Neonatal polycythemia and chest roentgenograms

Chest roentgenograms of 34 newborns with a hematocrit of 75 or more at the age of 12 hours were studied. An analysis was made of the findings during the first four days of life and the results were compared with those of 18 newborns with a hematocrit of 65 or less.The cardiothoracic ratio (CTR) was found to be greater in the polycythemic infants than in the non-polycythemic infants, and greatest of all in infants with symptomatic polycythemia. Prominent pulmonary vascularity and pulmonary hyperaeration were seen more often in polycythemic newborns than in nonpolycythemic infants. Eleven infants in the polycythemic group and three in the non-polycythemic group had some symptoms or signs.     

Influence of the maternal plasma glucose concentration at delivery on the risk of hypoglycaemia in infants of insulin-dependent diabetic mothers

Plasma glucose concentrations at birth and at two hours of age were measured in 53 infants of insulin-dependent mothers (IDMs). The plasma glucose concentrations at delivery were measured in the mothers of 17 IDMs and in the remaining 36 mothers, glucose was estimated by interpolation from concentrations achieved just before and after delivery. Clinical and laboratory data from the two groups were otherwise similar, so the groups were combined for further analyses. The maternal plasma glucose at delivery correlated positively with the glucose concentration of the IDMs at birth (rho = 0.82, p less than 0.001) and negatively with the glucose concentration at two hours of age (rho = -0.46, p less than 0.001). Maternal plasma glucose concentration was higher in mothers delivered by caesarean section than in vaginally delivered mothers (p less than 0.05). Eleven IDMs became hypoglycaemic at two hours of life (plasma glucose less than or equal to 1.7 mmol/l). These infants had higher cord plasma glucose concentrations at birth than those who remained normoglycaemic; the maternal glucose concentration was also higher. None of the IDMs became hypoglycaemic if the maternal glucose concentration at delivery was less than 7.1 mmol/l. In 28 IDMs the simultaneous plasma concentrations of non-antibody bound immunoreactive insulin (IRI) were recorded. Cord plasma IRI correlated with glucose and IRI at two hours of age (rho = -0.73, p less than 0.001 and rho = 0.77, p less than 0.001, respectively). Cord plasma IRI was higher in IDMs who became hypoglycaemic than in the remaining infants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of hypocalcemia on cardiac function in very-low-birth-weight preterm neonates: studies of blood ionized calcium, echocardiography, and cardiac effect of intravenous calcium therapy

Traditionally, in infants, a serum calcium value less than 7.0 mg/dL is considered to impair cardiac function. In very-low-birth-weight infants, we studied the hypotheses that decline in serum calcium to 6.0 mg/dL (1) would not impair cardiac function and (2) ionized calcium would remain greater than 3.0 mg/dL. We also evaluated the effect of calcium infusion on cardiac function. We studied 15 normokalemic and normonatremic infants whose birth weights were 822 to 1,450 g and were less than 32 weeks' gestation. When serum calcium declined to less than 6.0 mg/dL, 18 mg/kg of calcium as 5% calcium gluconate was infused for 10 minutes. Serum total calcium concentration, blood ionized calcium concentration, ECG, and M-mode echocardiogram were obtained on entry into the study, when the infants were hypocalcemic, immediately after treatment with calcium, and eight hours after treatment. Ionized calcium values were calculated based on serum total calcium and serum protein, and corrected calcium values were calculated based on serum total calcium, serum albumin, and blood pH. In all infants, serum calcium value declined to less than 7.0 and in eight infants to less than 6.0 mg/dL. Assessment of heart rate, systolic blood pressure, ejection fraction, left ventricular systolic time interval, right ventricular systolic time interval, fiber shortening index, and left ventricular mean velocity of circumferential fiber shortening showed no significant alteration from baseline during hypocalcemia or in association with intravenous slow bolus infusion of 18 mg/kg of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypocalcemia in the Newborn

Healthy term babies undergo a physiological nadir in serum calcium levels by 24–48 hours of age. This nadir may be related to the delayed response of parathyroid and calcitonin hormones in a newborn. This nadir may drop to hypocalcemic levels in high-risk neonates including infants of diabetic mothers, preterm infants and infants with perinatal asphyxia. This early onset hypocalcemia which presents within 72 hours, requires treatment with calcium supplementation for at least 72 hours. In contrast late onset hypocalcemia usually presents after 7 days and requires long term therapy. Ionized calcium is crucial for many biochemical processes and total serum calcium is a poor substitute for the diagnosis of hypocalcemia.