Pediatric Hypocalcemia 

Hypocalcemia is a laboratory and clinical abnormality that is observed with relative frequency, especially in neonatal pediatric patients. Laboratory hypocalcemia is often asymptomatic, and its treatment in neonates is controversial. However, children with hypocalcemia in pediatric intensive care units (PICUs) have mortality rates higher than those of children with normal calcium levels. (See Prognosis, Clinical, Workup, and Treatment.)

Hypocalcemia is defined as a total serum calcium concentration of less than 2.1 mmol/L (8.5 mg/dL) in children, less than 2 mmol/L (8 mg/dL) in term neonates, and less than 1.75 mmol/L (7 mg/dL) in preterm neonates.

Calcium metabolism and function

Calcium is the most abundant mineral in the body. Of the body's total calcium, 99% is in bone, and serum levels constitute less than 1%.^[1] Various factors regulate the homeostasis of calcium and maintain serum calcium within a narrow range. These include parathormone (PTH), vitamin D, hepatic and renal function (for conversion of vitamin D to active metabolites), and serum phosphate and magnesium levels. (See Etiology and Workup.)

Although total serum calcium levels are often measured and reported, ionized calcium is the active and physiologically important component. Total calcium level includes the ionized fraction and the bound fraction. The ionized calcium level is affected by the albumin level, blood pH, serum phosphate, serum magnesium, and serum bicarbonate and may be reduced by exogenous factors that may bind calcium, such as citrate from transfused blood or free fatty acids from total parenteral nutrition. At a physiologic pH of 7.4, 40% of total calcium is bound to albumin; 10% is complexed with bicarbonate, phosphate, or citrate; and the remaining 50% exists as free ionized calcium. The normal range for ionized calcium is 1-1.25 mmol/L (4-5 mg/dL).

The concentration of calcium in the serum is critical to many important biologic functions, including the following:

• Calcium messenger system by which extracellular messengers regulate cell function
• Activation of several cellular enzyme cascades
• Smooth muscle and myocardial contraction
• Nerve impulse conduction
• Secretory activity of exocrine glands

Hypocalcemia manifests as central nervous system (CNS) irritability and poor muscular contractility. Low calcium levels decrease the threshold of excitation of neurons, causing them to have repetitive responses to a single stimulus. Because neuronal excitability occurs in sensory and motor nerves, hypocalcemia produces a wide range of peripheral and CNS effects, including paresthesias, tetany (ie, contraction of hands, arms, feet, larynx, bronchioles), seizures, and even psychiatric changes in children.

Tetany is not caused by increased excitability of the muscles. Muscle excitability is depressed because hypocalcemia impedes acetylcholine release at neuromuscular junctions and, therefore, inhibits muscle contraction. However, the increase in neuronal excitability overrides the inhibition of muscle contraction. Cardiac function may also be impaired because of poor muscle contractility.

Overall, one of the most common causes of hypocalcemia is renal failure, which results in hypocalcemia because of inadequate 1-hydroxylation of 25-hydroxyvitamin D and hyperphosphatemia due to diminished glomerular filtration.

Although hypocalcemia is most commonly observed among neonates, it is frequently reported in older children and adolescents, especially in PICU settings. The causes of hypocalcemia can be classified by the child's age at presentation.

Early neonatal hypocalcemia

• Early neonatal hypocalcemia, which occurs within 48-72 hours of birth, can result from the following factors:
• Prematurity - Possible mechanisms include poor intake, decreased responsiveness to vitamin D, increased calcitonin, and hypoalbuminemia leading to a decreased total (but normal ionized) calcium level
• Birth asphyxia - Delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load, and alkali therapy all may contribute to hypocalcemia
• Diabetes mellitus in the mother - Magnesium depletion in mothers with diabetes mellitus causes a hypomagnesemic state in the fetus, which induces functional hypoparathyroidism and hypocalcemia in the infant; a high incidence of birth asphyxia and prematurity in infants of diabetic mothers is also a contributing factor
• Intrauterine growth retardation (IUGR) - Infants with IUGR may have hypocalcemia if they are also preterm or have had perinatal asphyxia.

Late neonatal hypocalcemia

This can occur 3-7 days after birth, although occasionally it is seen as late as age 6 weeks. One cause of late neonatal hypocalcemia is an exogenous phosphate load; this is most commonly seen in developing countries. The problem results when the neonate is fed with phosphate-rich formula or cow's milk. Whole cow's milk has 7 times the phosphate load of breast milk (956 vs 140 mg/L in breast milk).

Data have suggested that an association also exists between late neonatal hypocalcemia and gentamicin use, especially with the newer dosing schedule of every 24 hours.^[2]

Other causes include of late neonatal hypocalcemia include the following:

• Magnesium deficiency
• Transient hypoparathyroidism of newborn
• Hypoparathyroidism due to other causes

Hypocalcemia in infants and children

Hypoparathyroidism, abnormal vitamin D production or action, and hyperphosphatemia are among the causes of hypocalcemia in infants and children.

Hypoparathyroidism can result from the following causes:

• Aplasia or hypoplasia - DiGeorge syndrome; velocardiofacial syndrome; gestational diabetes mellitus, fetal exposure to retinoic acid; complex of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal abnormalities (VATER); and association of coloboma, heart defects, choanal atresia, renal abnormalities, growth retardation, male genital anomalies, and ear abnormalities (CHARGE)
• Parathormone (PTH) receptor defects - Pseudohypoparathyroidism
• Autoimmune parathyroiditis
• Infiltrative lesions - Hemosiderosis, Wilson disease, thalassemia
• Activating mutations of the calcium-sensing receptor leading to inappropriately suppressed PTH secretion
• Idiopathic causes
• Abnormal vitamin D production or action can result from the following causes:
• Vitamin D deficiency - Dietary insufficiency and maternal use of anticonvulsants have been reported.
• Acquired or inherited disorders of vitamin D metabolism
• Resistance to actions of vitamin D

Liver disease - Liver disease can affect 25-hydroxylation of vitamin D; certain drugs (eg, phenytoin, carbamazepine, phenobarbital, isoniazid, and rifampin) can increase the activity of P-450 enzymes, which can increase the 25-hydroxylation and also the catabolism of vitamin D

Hyperphosphatemia can result from the following causes:

• Excessive phosphate intake because of improper formula
• Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas
• Loading in total parenteral nutrition
• Increased endogenous loading caused by anoxia, chemotherapy, or rhabdomyolysis
• Renal failure

Other causes of hypocalcemia in infants and children include the following:

• Malabsorption syndromes
• Alkalosis - Respiratory alkalosis caused by hyperventilation; metabolic alkalosis with the administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in during massive blood transfusions
• Pancreatitis
• Pseudohypocalcemia (ie, hypoalbuminemia)
• Hungry bones syndrome - Rapid skeletal mineral deposition seen in infants with rickets or hypoparathyroidism after starting vitamin D therapy

Occurrence in the United States

The incidence of neonatal hypocalcemia varies in different studies. Hypocalcemia occurs in as many as 30% of infants with very low birth weight (< 1500 g) and in as many as 89% of infants whose gestational age at birth was less than 32 weeks. A high incidence is also reported in infants of mothers with diabetes mellitus and in infants with birth asphyxia.

International occurrence

No variation is reported across national boundaries. However, late-onset hypocalcemia is more common in infants in developing countries where babies are fed cow's milk or formulas containing high amounts of phosphate than in countries where infants are fed human milk or formulas containing low amounts of phosphate.

Age-related demographics

Most pediatric patients with hypocalcemia are newborns. In older children, hypocalcemia is usually associated with critical illness, acquired hypoparathyroidism, activating mutations of the calcium-sensing receptor, or defects in vitamin D supply or metabolism.

Most cases of early neonatal hypocalcemia resolve within 48-72 hours without any clinically significant sequelae.

Late neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency responds well to phosphate restriction and magnesium repletion.

When caused by hypoparathyroidism, hypocalcemia requires continued therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature of the hypoparathyroidism, which can be transient, last several weeks to months, or be permanent.

Higher mortality rates have been reported in children with hypocalcemia than in normocalcemic children in PICU settings.