Pediatric Hypocalcemia

Calcium metabolism and function

Calcium is the most abundant mineral in the body. Of the body's total calcium, 99% is stored 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).

Serum calcium is present in two forms: the free (ionized) and the bound form. Only about 50% of circulating calcium is present in the physiologically free form. The rest is either bound to proteins (40%) or complexed (10%) with bicarbonate, citrate, and phosphate. The ionized calcium level varies based on the level of serum albumin, blood pH, serum phosphate, magnesium, and bicarbonate levels, the administration of transfused blood containing citrate and free fatty acid content in total parenteral nutrition. 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

Calcium physiology during pregnancy and lactation

The fetus requires approximately 30 g of calcium to mineralize its skeleton and to maintain normal physiologic processes. The newborn requires more than this amount during the first few months of life from breast milk. The unique adaptations of the mother’s body allow her to meet the baby’s calcium demands without adverse long-term consequences to the maternal skeleton. The bulk of the calcium transmitted to the fetus during the third trimester is derived from the maternal intestinal absorption. Intestinal absorption of calcium doubles in pregnancy. Serum calcitriol level doubles or triples and stays elevated in pregnancy despite falling PTH level. It is instead increased, as 1-hydroxylase is upregulated by PTH-related protein (PTHrP), prolactin, and placental lactogen. The rise in PTHrP allows for the rise in calcium while protecting the maternal skeleton.

There is an average daily loss of 210 mg of calcium during lactation. Unlike during pregnancy, elevated PTHrP and low estradiol result in temporary demineralization of maternal skeleton to meet the calcium needs of the breastfeeding infant. These bone density losses are significantly reversed within 12 months of weaning. ^[2]

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 in children 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 symptomatic and 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 onset neonatal hypocalcemia

Early neonatal hypocalcemia, which occurs within 48-72 hours of birth, is most commonly seen in preterm and very low birth weight infants, infants asphyxiated or depressed at birth, infants of diabetic mothers, and the intrauterine growth restricted infants. The mechanisms underlying hypocalcemia caused by these conditions are as follows:

• Prematurity: Possible mechanisms include inadequate nutritional intake, decreased responsiveness of parathyroid hormone to vitamin D, increased calcitonin level, increased urinary losses, and hypoalbuminemia leading to a decreased total (but normal ionized) calcium level. ^[3]

• Birth asphyxia: Delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load due to tissue catabolism, renal failure, metabolic acidosis, and its treatment with alkali therapy all may contribute to hypocalcemia. ^{[4, 5]}

• Infants of a diabetic mother: The degree of hypocalcemia is associated with the severity of diabetes 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. In addition, infants of diabetic mothers have higher serum calcium in utero and this may also suppress the parathyroid gland. A high incidence of birth complications due to macrosomia and difficult delivery and, in some cases, higher incidence of preterm birth in infants of diabetic mothers are contributing factors for hypocalcemia.

• Intrauterine growth restriction: Infants with intrauterine growth restriction may develop hypocalcemia because of decreased transplacental passage of calcium. In addition, decreased accretion is present if they are delivered preterm or have experienced perinatal asphyxia as a result of placental insufficiency.

Late-onset neonatal hypocalcemia

This occurs 3-7 days after birth, although occasionally it is seen as late as age 6 weeks. The following are some important causes of late neonatal hypocalcemia:

• 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). This may cause symptomatic hypocalcemia in neonates. ^[6]

• Vitamin D deficiency: In a review of the medical records of 78 term neonates with hypocalcemia, moderate-to-severe late-onset neonatal hypocalcemia developed more often in male infants and Hispanic infants. It was often a sign of coexistent vitamin D insufficiency or deficiency and hypomagnesemia. The newborns respond well to one or more of the following: calcium supplements, calcitriol, low phosphorus formula (PM 60/40), and magnesium supplements for a limited period of time. ^[7]

• Primary immunodeficiency disorder: DiGeorge syndrome is the most important immunodeficiency disorder to be aware of that is associated with hypocalcemia. DiGeorge Syndrome is a primary immunodeficiency, often but not always, characterized by cellular (T-cell) deficiency, characteristic facies, congenital heart disease and hypocalcemia. Hypoparathyroidism causes hypocalcemia; 90% of infants with the features of DiGeorge syndrome have a 22q11 chromosomal deletion.

• Data suggest an association between late-onset neonatal hypocalcemia and gentamicin therapy, especially with the newer dosing schedule of every 24 hours. ^[8]

Other causes of late-onset neonatal hypocalcemia include the following:

• Magnesium deficiency (usually transient)

• Transient hypoparathyroidism of newborn

• Hypoparathyroidism due to other causes

• Maternal hyperparathyroidism

• Blood transfusion or sodium bicarbonate (alkali) infusions

• Phototherapy for hyperbilirubinemia ^[9]

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:

• Aplasia or hypoplasia of parathyroid gland -DiGeorge syndrome also known as velocardiofacial (Shprintzen) syndrome or 22q11 deletion syndrome; fetal exposure to retinoic acid; complex of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal abnormalities (VATER/VACTERL); and association of coloboma, heart defects, choanal atresia, renal abnormalities, growth retardation, male genital anomalies, and ear abnormalities (CHARGE) (Details of DiGeorge syndrome are discussed in the late-onset hypocalcemia section above.)

• 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 (eg, GNA11 mutation) ^[10]

• Idiopathic causes

Abnormal vitamin D production or action can be caused by the following:

• 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:

• Excessive phosphate intake from feeding cow milk or infant formula with improper (low) calcium to phosphate ratio

• Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas

• Excessive phosphate or inappropriate Ca:P ratio in total parenteral nutrition

• Increased endogenous phosphate load caused by anoxia, chemotherapy, or rhabdomyolysis

• Renal failure

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

• Malabsorption syndromes

• Alkalosis: Respiratory alkalosis is caused by hyperventilation; metabolic alkalosis occurs 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): Serum calcium concentration decreases by 0.8 mg/dL for every 1 g/dL fall in concentration of plasma albumin.

• “Hungry bones syndrome:" Rapid skeletal mineral deposition is 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. Data on the incidence and prevalence rates in the neonatal period are limited. Hypocalcemia occurs frequently in very low birth weight infants (< 1500 g). In a small study of 19 infants, the reported incidence of early onset hypocalcemia was 37% by 12 hours, 83% by 24 hours, and 89% by 36 hours in very preterm infants less than 32 weeks’ gestation. ^[11] Among very preterm infants, the onset of hypocalcemia is earlier than in more mature at-risk neonates.

The risk of developing early onset neonatal hypocalcemia is also greater among infants of diabetic mothers (7% [gestational DM], 32% [pregestational]) and infants experiencing perinatal asphyxia. The overall prevalence of moderate-to-severe, late-onset neonatal hypocalcemia (onset 5-10 d after birth) is low and appears to be more common among Hispanic and male infants; the severity of hypocalcemia is greater among infants who also exhibit hyperphosphatemia, hypomagnesemia, and vitamin D deficiency or insufficiency. ^[12]

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.

A cross-sectional study conducted in India found that hypocalcemia occurred in 26% of children hospitalized because of severe acute malnutrition. Hypocalcemia was detected most often in severely malnourished children with rickets, abdominal distension, and sepsis. ^[13]

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-onset neonatal hypocalcemia resolve within 48-72 hours without any clinically significant sequelae.

Late-onset neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency responds well to phosphate restriction and magnesium repletion. A renewed emphasis on exclusive breastfeeding and use of contemporary infant formulas with more appropriate Ca:P ratios for mothers choosing not to breastfeed reduce this risk. Early supplementation with vitamin D in breastfeeding infants is another important prevention strategy.

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. ^[14]