1. Definition. Neonatal hypocalcemia is defined as a total serum calcium concentration of <7 mg/dL or an ionized calcium concentration of <4 mg/dL (1 mmol/L). In very low birth weight (VLBW) infants, ionized calcium values of 0.8 to 1 mmol/L are common and not usually associated with clinical symptoms. In larger infants, and in infants of >32 weeks’ gestation, symptoms may more readily occur with an ionized calcium concentration of <1 mmol/L.

a. Calcium ions (Ca²⁺) in cellular and extracellular fluid (ECF) are essential for many biochemical processes. Significant aberrations of serum calcium concentrations are frequently observed in the neonatal period.

i. Hormonal regulation of calcium homeostasis. Regulation of serum and ECF-ionized calcium concentration within a narrow range is critical for blood coagulation, neuromuscular excitability, cell membrane integrity and function, and cellular enzymatic and secretory activity. The principal calciotropic or calcium-regulating hormones are parathyroid hormone (PTH)
and 1,25-dihydroxyvitamin D, (1,25(OH)₂D, also referred to as calcitriol).

ii. When the ECF-ionized calcium level declines, parathyroid cells secrete PTH. PTH mobilizes calcium from bone, increases calcium resorption in the renal tubule, and stimulates renal production of 1,25(OH)₂D. PTH secretion causes the serum calcium level to rise and the serum phosphorus level to either be maintained or fall.

iii. Vitamin D is synthesized from provitamin D in the skin after exposure to sunlight and is also ingested in the diet. Vitamin D is transported to the liver, where it is converted to 25(OH)D (the major storage form of the hormone). This is transported to the kidney, where it is converted to the biologically active hormone 1,25(OH)₂D (calcitriol). Calcitriol increases intestinal calcium and phosphate absorption and mobilizes calcium and phosphate from bone.

a. Prematurity. Preterm infants are capable of mounting a PTH response to hypocalcemia, but target organ responsiveness to PTH may be diminished.

b. Infants of diabetic mothers (IDMs) have a 25% to 50% incidence of hypocalcemia if maternal control is poor. Hypercalcitoninemia, hypoparathyroidism, abnormal vitamin D metabolism, and hyperphosphatemia have all been implicated, but the etiology remains uncertain.

c. Severe neonatal birth depression is frequently associated with hypocalcemia, hypomagnesemia, and hyperphosphatemia. Decreased calcium intake and increased endogenous phosphate load are likely causes.

d. Congenital. Parathyroids may be absent in DiGeorge sequence (hypoplasia or absence of the third and fourth branchial pouch structures) as an isolated defect in the development of the parathyroid glands or as part of the Kenny-Caffey syndrome.

e. Pseudohypoparathyroidism. Maternal hyperparathyroidism

f. Magnesium deficiency (including inborn error of intestinal magnesium transport) impairs PTH secretion.

g. Vitamin D deficiency (frequency in newborn period is uncertain)

h. Alkalosis and bicarbonate therapy

i. Rapid infusion of citrate-buffered blood (exchange transfusion) chelates ionized calcium.

j. Shock or sepsis

k. Phototherapy may be associated with hypocalcemia by decreasing melatonin secretion and increasing uptake of calcium into the bone.

l. For late-onset hypocalcemia, high phosphate intakes lead to excess phosphorus and decreased serum calcium.

a. Hypocalcemia increases both cellular permeability to sodium ions and cell membrane excitability. The signs are usually nonspecific: apnea, seizures, jitteriness, increased extensor tone, clonus, hyperreflexia, and stridor (laryngospasm).

b. Early-onset hypocalcemia in preterm newborns is often asymptomatic but may show apnea, seizures, or abnormalities of cardiac function although identifying these as primarily due to the calcium level is often difficult.

c. Late-onset syndromes, in contrast, frequently presents as hypocalcemic seizures. Often, they must be differentiated from other causes of newborn seizures, including “fifth-day” fits.

a. For late-onset presentation, mothers may report partial breastfeeding but rarely, if ever, exclusive breastfeeding. Abnormal movements and lethargy may precede obvious seizure activity. Rarely, use of goat’s milk or whole milk of cow may be reported. Symptoms are usually described beginning from the third to fifth days of life.

b. Hispanic background as a risk factor has been described but is unproven.

c. Overfeeding may also be identified in the history although this can be difficult to ascertain.

a. General physical findings associated with seizure disorder in the newborn may be present in some cases. Usually, there are no apparent physical findings.

a. There are three definable fractions of calcium in serum: (i) ionized calcium (˜50% of serum total calcium); (ii) calcium bound to serum proteins, principally albumin (˜40%); and (iii) calcium complexed to serum anions, mostly phosphates, citrate, and sulfates (˜10%). Ionized calcium is the only biologically available form of calcium.

b. Assessment of calcium status using ionized calcium is preferred, especially in the first week of life. Correction nomograms, used to convert total calcium into ionized calcium, are not reliable in the newborn period.

c. Calcium concentration reported as milligrams per deciliter can be converted to molar units by dividing by 4 (e.g., 10 mg/dL converts to 2.5 mmol/L).

d. Postnatal changes in serum calcium concentrations. At birth, the umbilical serum calcium level is elevated (10 to 11 mg/dL). In healthy term babies, calcium concentrations decline for the first 24 to 48 hours; the nadir is usually 7.5 to 8.5 mg/dL. Thereafter, calcium concentrations progressively rise to the mean values observed in older children and adults.

e. Although an association with vitamin D deficiency is uncommon, an assessment of both maternal and neonatal serum 25-hydroxyvitamin D level may be warranted. Values <10 to 12 ng/dL are suggestive of severe deficiency that may be associated with clinical symptoms in some, but probably not most, infants.

f. Hypomagnesemia is often seen in association with late-onset hypocalcemia.

a. Suggested schedule for monitoring calcium levels in infants such as VLBW, IDM, and birth depression who are at risk for developing hypocalcemia:

i. Ionized calcium: at 12, 24, and 48 hours of life