Background

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.)
The definition of hypocalcemia is based on both gestational and postnatal age in neonates and is
different for children. Calcium data are presented as both mg/dL and mmol/L (1 mg/dL = 0.25
mmol/L)
In children, hypocalcemia is defined as a total serum calcium concentration less than 2.1 mmol/L (8.5
mg/dL).
In term infants, hypocalcemia is defined as total serum calcium concentration less than 2 mmol/L (8
mg/dL) or ionized fraction of less than 1.1 mmol/L (4.4 mg/dL)
In preterm infants, hypocalcemia is defined as total serum calcium concentration less than 1.75
mmol/L (7 mg/dL) is defined as hypocalcemia in infants weighing less than 1500 g birthweight.
Symptomatology often manifests when the ionized calcium level falls below 0.8-0.9 mmol/L.
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

Pathophysiology
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
(i.e., 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.

Etiology
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. [2]
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. [3, 4]
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. [5]

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. [6]

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. [7]
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 [8]

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
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 P450 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.

Epidemiology
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.[9] 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.[10]

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, acquiredhypoparathyroidism, activating mutations of the calciumsensing receptor, or defects in vitamin D supply or metabolism.

Prognosis
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.[11]

History
In patients with hypocalcemia, the history varies depending on age. In newborns, patient history can
include the following:

Possibly no symptoms exhibited

Lethargy
Poor feeding
Vomiting
Abdominal distension
Prematurity
Difficult birth/low Apgar score
Maternal diabetes/hyperparathyroidism
Jitteriness
Seizure
Apnea
History in children can be as follows:
Seizures
Twitching
Cramping
Laryngospasm, a rare initial manifestation

Physical Examination
Childrens symptoms include the following:

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

Cardiac murmur
Features of a "syndrome"

Diagnostic Considerations
Conditions to consider in the differential diagnosis of hypocalcemia include the following:

Anoxia
Intracranial bleeding
Narcotic withdrawal
Pseudohypoparathyroidism
Rickets, osteomalacia, or rachitis (i.e., vitamin D deficiency)
Hyperphosphatemia
Hypoalbuminemia
Hypomagnesemia
Renal failure
Metabolic disease affecting vitamin D, seizures

Differential Diagnoses

Hypernatremia in Emergency Medicine

Hypomagnesemia

Hyponatremia in Emergency Medicine

Imaging in Bacterial Meningitis

Neonatal Sepsis

Pediatric Aseptic Meningitis

Pediatric Hypoglycemia

Pediatric Hypoparathyroidism

Pediatric Malabsorption Syndromes

Approach Considerations
The following should be assessed in patients with hypocalcemia:

Total and ionized serum calcium levels

Serum magnesium levels
Serum electrolyte and glucose levels
Phosphorus levels
Parathormone levels
Vitamin D metabolite (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) levels
Urine calcium, magnesium, phosphorus, and creatinine levels
Serum alkaline phosphatase levels

Total and ionized serum calcium levels

Measuring ionized calcium level is essential to differentiate true hypocalcemia from a mere decrease
in total calcium concentration. A decrease in total calcium can be associated with low serum albumin
concentration and abnormal pH.

Serum magnesium levels

Serum magnesium levels may be low in patients with hypocalcemia, which may not respond to
calcium therapy if hypomagnesemia is not corrected. Severe hypomagnesemia (0.46 mmol/L)
causes hypocalcemia by impairing the secretion and action of parathormone (PTH).

Serum electrolyte and glucose levels

Seizures and irritability in newborns and children can be associated with hypoglycemia and sodium
abnormalities. Low bicarbonate levels and acidosis may be associated with Fanconi syndrome and
renal tubular acidosis.

Phosphorus levels
Estimating the phosphate level is essential to establish the etiology of hypocalcemia. Phosphate
levels are increased in cases of exogenous and endogenous phosphate loading and renal failure and
are usually high in patients with hypoparathyroidism. Phosphate levels are low in cases of vitamin D
abnormalities and rickets.

Parathormone levels
Hormone studies are indicated if hypocalcemia persists in the presence of normal magnesium and
normal or elevated phosphate levels.
Low PTH levels suggest hypoparathyroidism; serum calcium rises in response to PTH challenge.
Oppositely, PTH levels are elevated in patients with vitamin D abnormalities and
pseudohypoparathyroidism, and calcium levels do not rise in response to PTH challenge.
The N -terminal fragment of PTH is the only biologically active fragment of PTH. It is difficult to
measure because of its short half-life of 2-5 minutes. Circulating PTH levels are determined by
assaying for intact PTH peptide.

Vitamin D metabolite (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) levels

These may be assessed, along with hormone concentrations, to eliminate uncommon causes of
hypocalcemia (e.g., malabsorption, disorders of vitamin D metabolism).

Urine calcium, magnesium, phosphorus, and creatinine levels

These values should be assessed in patients with suspected renal tubular defects and renal failure.
Urine should also be evaluated for pH, glucose, and protein.
In patients with renal defects, calcium excretion is high in presence of hypocalcemia. A urine calciumto-creatinine ratio of more than 0.3 on a spot sample in presence of hypocalcemia suggests
inappropriate excretion.

Serum alkaline phosphatase levels

Values are generally elevated in patients with rickets.

Additional tests
Additional tests in the diagnosis of hypocalcemia include the following:

Malabsorption workup
Total lymphocyte and T-cell subset analyses - Findings are decreased in patients with
DiGeorge syndrome
Chest radiography - Evaluate for thymic shadow, which may be absent in patients with
DiGeorge syndrome
Ankle and wrist radiography - Evaluate for evidence of rickets; changes appear at an early
stage in the radius and ulna (the distal ends are widened, concave, and frayed)
Electrocardiography - A prolonged QTc (>0.4 s), a prolonged ST segment, and T-wave
abnormalities may be observed; measurements of specific intervals are of little value in predicting
hypocalcemia (see the image below)

Electrocardiogram (ECG) findings

in severe hypocalcemia.

Karyotyping - To assess for 22q11 and 10p13 deletion

Maternal and family screening - This is helpful in familial forms of hypocalcemia, such as
those caused by activating mutations of the calcium-sensing receptor

Approach Considerations
Treatment of asymptomatic patients with hypocalcemia remains controversial, especially with regard
to neonates. Some authorities suggest that treating such patients is unnecessary. Most newborns
with hypocalcemia remain asymptomatic and can be treated in a regular newborn nursery. If
persistent, the newborns can be treated with special formula PM 60/40 that provides 2:1 calcium-tophosphate ratio. Oral calcium supplements can be added to increase the calcium-to-phosphorus ratio
to 4:1 to correct the hypocalcemia until PTH function normalizes.
Most clinicians agree, however, that hypocalcemia should be promptly treated in any symptomatic
neonate or older child because of the conditions serious implications for neuronal and cardiac
function. Any child with symptomatic hypocalcemia should be admitted to the hospital unless the
diagnosis is hyperventilation.
Oral calcium therapy is used in asymptomatic patients and as follow-up to intravenous (IV) calcium
therapy. IV treatment is usually indicated in patients having seizures, those who are critically ill, and
those who are planning to have surgery.
However, IV infusion with calcium-containing solutions can cause severe tissue necrosis; this can
result in contractures and may require skin grafting. Integrity of the IV site should be ascertained
before administering calcium through a peripheral vein.
Necrosis of the liver can occur after calcium infusion through an umbilical vein catheter placed in a
branch of the portal vein. The position of all umbilical vein catheters must be confirmed on a
radiograph before infusing calcium-containing solutions.
Rapid infusion of calcium-containing solutions through arterial lines can cause arterial spasm and, if
administered via an umbilical artery catheter, intestinal necrosis.

Seizures
General medical care in patients with hypocalcemia involves stabilization with management of the
patient's airway and breathing if seizures occur. Anticonvulsants are commonly administered before
hypocalcemia is confirmed in a new patient. However, seizures usually do not respond to the usual
antiepileptic medications until calcium is intravenously administered.

Additional considerations
Magnesium administration is necessary to correct any hypomagnesemia because hypocalcemia
does not respond until the low magnesium level is corrected.
Administration of phosphate-lowering agents may be necessary if hypocalcemia is associated with
hyperphosphatemia.

In certain conditions, such as pancreatitis and rhabdomyolysis, full correction of hypocalcemia should
be avoided. After the primary condition is resolved, these patients may develop hypercalcemia due to
the release of complexed calcium.
In patients with concurrent acidemia, hypocalcemia should be corrected first. Acidemia increases the
ionized calcium levels by displacing calcium from albumin. If acidemia is corrected first, ionized
calcium levels decrease.

Diet
A diet high in calcium and low in phosphate is required in most instances. Infants drinking regular
cow's milk or evaporated milk must be given humanized infant formula instead. Patients with renal
failure should be given a low-solute, low-phosphate formula, such as Similac PM 60/40.

Consultations
Consult with the follow specialists as needed:

Pediatric endocrinologist
Geneticist

Medication Summary
Calcium therapy is the mainstay of treatment for hypocalcemia. Therapy with IV calcium is the most
effective and rapid means of elevating serum calcium concentration. After hypocalcemia is controlled,
follow-up treatment with oral therapy can be given. However, in patients with asymptomatic
hypocalcemia, therapy with oral calcium alone may be sufficient.
Vitamin D, in one of its various forms, is also indicated, depending on the metabolic abnormality
present. However, the use of vitamin D formulations in newborns to prevent hypocalcemia has not
been effective. The most important aspect of management is resolution of the primary cause (e.g.,
hyperphosphatemia, hypomagnesemia).
The American Academy of Pediatrics (AAP) published revisions to guidelines for adequate vitamin D
intake in infants, children, and adolescents. [13] The revised guidelines now recommend a minimum
daily intake of 400 IU of vitamin D beginning in the first few days following birth and continuing
through adolescence. Symptomatic hypocalcemia may occur during periods of rapid growth with
increased metabolic demands, long before any physical findings or radiologic evidence of vitamin D
deficiency occurs.
Although not used routinely due to the suggested risk of osteosarcoma, the administration of
recombinant PTH in an infant with hypocalcemia refractory to calcitriol and calcium supplementation
was reported to be effective.[14]

Calcium compounds
Class Summary
Calcium is the most abundant mineral in the human body. It is essential for blood coagulation and the
development and/or function of bone, teeth, nerves, and muscles. Calcium also functions as an
enzymatic cofactor and affects endocrine secretory function. Supplements are used to increase
serum calcium concentrations in patients with hypocalcemia. Oral preparations are prescribed to
reduce phosphate absorption from the intestine in patients with hyperphosphatemia.

Calcium Gluconate and Calcium Chloride infusions

Calcium gluconate 10% (100 mg/mL) IV solution contains 9.8 mg/mL (0.45 mEq/mL) elemental
calcium; calcium chloride 10% (100 mg/mL) contains 27 mg/mL (1.4 mEq/mL) elemental calcium.

Calcium chloride is more irritating to the veins and may affect pH; therefore, it is typically avoided in
pediatric patients.
Calcium gluconate can also be given orally. However, it is hypertonic and may potentially increase
risk of necrotizing enterocolitis in preterm infants at risk for this condition.

Calcium glubionate (Calcionate)

This is an oral calcium supplement. It is available as a liquid product containing glubionate salt (1800
mg/5 mL) and elemental calcium (115 mg /5 mL).
View full drug information

Calcium carbonate (Oyster Cal, Caltrate, Tums, Oysco 500)

Calcium carbonate is an oral supplement. In many ways, it is the calcium supplement of choice,
because it provides 40% elemental calcium. (Therefore, 1 g of calcium carbonate provides 400 mg of
elemental calcium.) It is well absorbed orally and is unlikely to cause diarrhea. Calcium carbonate is
available in tablet and liquid form.

Vitamin D metabolites
Class Summary
The active forms of vitamin D regulate calcium absorption and its uses in the body. They increase
calcium levels by promoting absorption of calcium in the intestines and retention of it in the kidneys.
View full drug information

Calcitriol (Calcijex, Rocaltrol, Vectical)

This is an active metabolic form of vitamin D (i.e., 1,25-dihydroxycholecalciferol). It is especially
useful in liver or renal impairment because these cause an inability to hydroxylate vitamin D to its
active forms. Generally, the product is rapid-acting, but it may act slowly in neonates (36-48 h).
Preterm infants may be resistant to calcitriol's actions. Calcitriol is also used to treat acute
hypocalcemia.