eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypocalcemia

Author: Abhay Singhal, MD, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Indiana University School of Medicine
Coauthor(s): Deborah E Campbell, MD, Professor of Clinical Pediatrics, Albert Einstein College of Medicine; Director, Department of Pediatrics, Division of Neonatology, Weiler Hospital Division of Montefiore Medical Center
Contributor Information and Disclosures

Updated: Oct 23, 2009

Introduction

Background

Hypocalcemia is a relatively frequently observed laboratory and clinical abnormality seen especially in neonates. Laboratory hypocalcemia is often asymptomatic, and its treatment in neonates is controversial. However, children with hypocalcemia in pediatric ICUs (PICUs) have mortality rates higher than those of children with normal calcium levels. 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.

Pathophysiology

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.

Although total serum calcium levels are often measured and reported, ionized calcium is the active and physiologically important component. Total calcium level includes both 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 (TPN). 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% is 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 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 both 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.

Frequency

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

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.

Mortality/Morbidity

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

Sex

No sex-based variation in incidence is known.

Age

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.

Clinical

History

In patients with hypocalcemia, the history varies depending on age.

• Newborns
  • Possibly no symptoms
  • Lethargy
  • Poor feeding
  • Vomiting
  • Abdominal distension
• Children
  • Seizures
  • Twitching
  • Cramping
  • Laryngospasm, a rare initial manifestation

Physical

• Lethargy
• Cyanosis
• Tremulousness
• Seizures
• Apnea
• Tetany and signs of nerve irritability, such as the Chvostek sign, carpopedal spasm, the Trousseau sign, and stridor
• Abdominal distension
• Prematurity, birth asphyxia, or congenital heart disease (features associated with infants of mothers with diabetes mellitus)

Causes

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 (within 48-72 h of birth)
  • Prematurity: Possible mechanisms include poor intake, decreased responsiveness to vitamin D, increased calcitonin, and hypoalbuminemia leading to decreased total but normal ionized calcium.
  • 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 hypomagnesemic state in the fetus. This hypomagnesemia induces functional hypoparathyroidism and hypocalcemia in the infant. A high incidence of birth asphyxia and prematurity in infants of diabetic mothers are also contributing factors.
  • Intrauterine growth retardation (IUGR): Infants with IUGR may have hypocalcemia if they are also preterm or have had perinatal asphyxia.
• Late neonatal hypocalcemia (3-7 d after birth, though occasionally as late as age 6 wk)
  • Exogenous phosphate load: This is most commonly seen in developing countries. Hypocalcemia is caused by feeding 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).
  • Magnesium deficiency
  • Transient hypoparathyroidism of newborn
  • Hypoparathyroidism due to other causes
  • Gentamicin use: Data have suggested association with gentamicin use, especially with the newer every-24-hour dosing schedule.²
• Hypocalcemia in infants and children
  • Hypoparathyroidism
    • 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
    • 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
    • Excessive phosphate intake because of improper formula
    • Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas
    • Loading in total parenteral nutrition (TPN)
    • Increased endogenous loading caused by anoxia, chemotherapy, or rhabdomyolysis
    • Renal failure
  • Others
    • 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

• Search for CME/CE on This Topic »

• Hypocalcemia (Nephrology)
• Hypocalcemia (Emergency Medicine)
• Hypoparathyroidism (Emergency Medicine)
• Pseudohypoparathyroidism (Endocrinology)

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