INTRODUCTION — Hypocalcemia is a common metabolic problem in newborns.

The diagnosis, clinical manifestations, and treatment of neonatal hypocalcemia are reviewed here. Calcium (Ca) requirements, neonatal bone health, and the etiology of hypocalcemia after the neonatal period are discussed elsewhere. (See "Management of bone health in preterm infants" and "Etiology of hypocalcemia in infants and children".)

PERINATAL METABOLISM — During pregnancy, calcium (Ca) is transferred actively from the maternal circulation to the fetus by a transplacental Ca pump, which is regulated by parathyroid hormone-related peptide (PTHrP) [1]. The majority of fetal Ca accretion occurs in the third trimester. This process results in higher plasma Ca concentrations in the fetus than in the mother, which in turn results in fetal total and ionized Ca concentrations of 10 to 11 mg/dL (2.5 to 2.75 mmol/L) and 6 mg/dL (1.5 mmol/L), respectively, in umbilical cord blood at term [2].

After the abrupt cessation of placental transfer of Ca at birth, neonatal total serum Ca falls to 8 to 9 mg/dL (2 to 2.25 mmol/L), and ionized Ca falls to levels as low as 4.4 to 5.4 mg/dL (1.1 to 1.35 mmol/L) at 24 hours after delivery [3,4]. Serum Ca concentration subsequently rises, reaching levels seen in older children and adults by two weeks of age [5,6].

MEASUREMENT — To evaluate calcium (Ca) status, we recommend measurement of ionized Ca in whole blood rather than total Ca, because it more accurately reflects the physiologically available Ca [7].This is particularly important in the first week of life when hypocalcemia is most common and accurate assessment is needed. (See "Relation between total and ionized serum calcium concentrations".)

Within the plasma, Ca circulates in different forms. Approximately 40 percent is bound to serum proteins, principally albumin; 10 percent is complexed with citrate, bicarbonate, sulfate, or phosphate; and 50 percent exists as the physiologically important ionized (or free) Ca [8]. The ionized Ca concentration is tightly regulated by parathyroid hormone (PTH) and vitamin D.

Correlation between ionized and total Ca is poor when the serum albumin concentration is low, or to a lesser degree, with disturbances in acid-base status, both of which occur frequently in preterm or ill infants.

●With hypoalbuminemia, the total Ca concentration will be low, while the ionized fraction will be normal unless some other factor is affecting Ca metabolism. In general, the plasma Ca concentration falls by 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL (10 g/L) decrease in the plasma albumin concentration.

●Disturbances in acid-base status can change the ionized Ca concentration without affecting the total Ca level. An elevation in extracellular pH, for example, increases the binding of Ca to albumin, thereby lowering the plasma ionized Ca concentration [9]. The fall in ionized Ca with acute respiratory alkalosis is approximately 0.16 mg/dL (0.04 mmol/L or 0.08 mEq/L) for each 0.1 unit increase in pH [9]. Thus, acute respiratory alkalosis can induce signs of hypocalcemia. Conversely, with metabolic acidosis, binding of Ca to albumin is reduced, and the ionized Ca concentration will be increased.

EARLY HYPOCALCEMIA — The causes of neonatal hypocalcemia are classified by the timing of onset. Hypocalcemia is considered to be early when it occurs in the first two to three days after birth. Early hypocalcemia is an exaggeration of the normal decline in calcium (Ca) concentration after birth. It occurs more commonly in infants who are preterm or fetal growth restricted (FGR), born to mothers with diabetes, after perinatal asphyxia, or who have hypoparathyroidism. In these patients, nutritional support alone is adequate treatment to increase Ca levels. (See 'Asymptomatic infants' below.)

Prematurity — Approximately one-third of preterm infants and the majority of very low birth weight (VLBW) infants have low total serum Ca concentrations during the first two days after birth [10,11]. Multiple factors contribute to the fall in total serum Ca. These include hypoalbuminemia, which does not lower the ionized Ca, and factors that lower both total and ionized Ca, such as reduced intake of Ca because of low intake of milk, possible impaired response to parathyroid hormone (PTH), increased calcitonin levels, and increased urinary losses accompanying high renal sodium excretion [12]. Most preterm infants are asymptomatic as the fall in total serum Ca typically is greater than the fall in ionized Ca. This occurs because preterm infants are at risk for hypoalbuminemia resulting in a fall in total Ca but not ionized Ca, mild metabolic acidosis, which tends to raise the ionized Ca. (See 'Measurement' above.)

Fetal growth restriction — Hypocalcemia occurs with increased frequency in infants with FGR. The risk increases with the severity of growth failure [13,14]. The mechanism is thought to involve decreased transfer of Ca across the placenta.

Infants of diabetic mothers — Hypocalcemia occurs in at least 10 to 20 percent of infants of diabetic mothers (IDMs) and in as many as 50 percent in some series [15,16] (see "Infants of women with diabetes"). The lowest serum Ca concentration typically occurs between 24 to 72 hours after birth and often is associated with hyperphosphatemia. The extent of hypocalcemia is related to the severity and duration of maternal diabetes. Hypocalcemia is thought to be caused by lower PTH concentrations after birth in IDMs compared with normal infants [17]. Why this lower concentration occurs is not well understood. Higher serum ionized Ca concentrations in utero in IDMs may suppress the fetal parathyroid glands [17]. The development of hypomagnesemia, prematurity, and birth asphyxia may be contributing factors.

Birth asphyxia — Infants with birth asphyxia frequently have hypocalcemia and may also have hyperphosphatemia. Possible mechanisms include increased phosphate load caused by tissue catabolism, decreased intake due to delayed initiation of feedings, renal insufficiency, and increased serum calcitonin concentration [18,19]. (See "Perinatal asphyxia in term and late preterm infants".)

Hypoparathyroidism — Hypoparathyroidism associated with excess phosphorus (P) intake is a common cause of early neonatal hypocalcemia [20]. Hypoparathyroidism can be due to lack of parathyroid glands, which may occur as part of a genetic syndrome, or to defects in the synthesis or release of PTH.

Syndromes — Several syndromes have been associated with neonatal hypocalcemia, with DiGeorge syndrome (DGS) being the most common cause. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms'.)

CATCH-22 and DiGeorge syndrome — The most prevalent syndrome that includes hypoparathyroidism is DGS (also called DiGeorge anomaly). It is the most severe phenotype of a group of related disorders known as CATCH-22 syndrome, an acronym for cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia caused by chromosome 22q11 deletion [21]. DGS arises from a failure of migration of neural crest cells into the third and fourth pharyngeal pouches. Affected patients typically present in the first week after birth with signs of hypocalcemia, such as tetany or seizures, secondary to hypoplastic or absent parathyroid glands. They have characteristic facial features that include a small mouth, a submucous cleft palate, abnormal and low set ears, upturned nose, and a widened distance between the inner canthi (telecanthus) with short palpebral fissures [22,23].

Cardiac defects, especially abnormalities of the outflow tract or aortic arch (eg, truncus arteriosus, tetralogy of Fallot, or interrupted aortic arch), are frequently present. Thymic hypoplasia results in an immune defect that is highly variable. The combination of the two abnormalities increases the risk of hypocalcemia as illustrated by a case series that reported the risk of hypocalcemia was greater for infants with both DiGeorge syndrome and congenital heart disease compared with those with only DiGeorge syndrome (62 versus 41 percent) [24]. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

Other syndromes — Other, rarer syndromes that include hypoparathyroidism resulting in hypocalcemia are Kearns-Sayre and Kenny-Caffey syndromes, which are mitochondrial cytopathies.

Maternal hyperparathyroidism — Infants born to mothers with hyperparathyroidism frequently have hypocalcemia. The mechanism is related to increased transplacental transport of Ca caused by high maternal Ca concentrations, which results in fetal hypercalcemia that leads to suppression of fetal and neonatal PTH secretion. Affected infants typically develop increased neuromuscular irritability in the first three weeks after birth, but they can present later [12]. Some infants also have hypomagnesemia. In a case report, a neonate born to a mother with familial hypocalciuric hypercalcemia type 1 developed hypocalcemia and seizures [25]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Familial hypocalciuric hypercalcemia'.)

Hypomagnesemia — Hypomagnesemia causes resistance to PTH and impairs PTH secretion, both of which can result in hypocalcemia. The most common etiology in newborns is transient hypomagnesemia, although rare disorders of intestinal and/or renal tubular magnesium (Mg) transport can occur. In transient cases, the serum Mg concentration typically is 0.8 to 1.4 mg/dL (0.33 to 0.58 mmol/L) (normal values are 1.6 to 2.8 mg/dL [0.66 to 1.16 mmol/L]); more severe reductions occur in the transport defects [12].

LATE HYPOCALCEMIA — Late hypocalcemia develops after the second or third day after birth and typically occurs at the end of the first week [20]. Infants with late-onset hypocalcemia usually present with signs of hypocalcemia including severe neuromuscular irritability or seizures. (See 'Clinical manifestations' below.)

High phosphate intake — Intake of excess phosphate is a historically important cause of late hypocalcemia, which was seen in term infants fed bovine milk or a bovine milk-based formula with a high phosphorus (P) concentration. The mechanism is uncertain, but the high P level may antagonize parathyroid hormone (PTH) secretion or actions, or it may produce increased calcium (Ca) and P deposition in bones, leading to hypocalcemia [26]. Symptomatic infants typically present with tetany or seizures at 5 to 10 days of age [26]. Severe hyperphosphatemia and hypocalcemia also can be caused by phosphate enemas [27].

Other causes — Critically ill or preterm infants are exposed to therapeutic interventions that may cause transient hypocalcemia:

●Reduction in ionized Ca – Bicarbonate infusion, resulting in metabolic alkalosis, or transfusion with citrated blood, leading to formation of Ca complexes, decreases ionized Ca concentration. Lipid infusions also may reduce ionized Ca levels by formation of Ca complexes with free fatty acids.

●Mild hypocalcemia has been associated with phototherapy for hyperbilirubinemia. The mechanism may be related to decreased melatonin secretion, leading to increased Ca uptake by bone [28].

Other conditions associated with hypocalcemia include:

●Acute renal failure of any cause, usually associated with hyperphosphatemia and hypocalcemia. (See "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

●Hypocalcemia has been described with rotavirus infection [29]. (See "Clinical manifestations and diagnosis of rotavirus infection", section on 'Clinical manifestations'.)

Unclear role for vitamin D insufficiency — Preterm infants, especially extremely preterm infants (gestational age <28 weeks), have low levels of vitamin D; however, it is unclear whether these levels contribute to low Ca levels.

In one case series of 78 term neonates who presented with severe neonatal hypocalcemia, levels of 25-hydroxyvitamin D were deemed by the authors to be insufficient (ie, <25 ng/mL [62.4 nmol/L]) in all of the 42 infants in whom vitamin D levels were measured [20]. However, 25 ng/mL has not been established as a biologically valuable threshold for any clinical disorders in preterm infants. Therefore, the true role of low vitamin D status has yet to be determined. Maternal levels of low 25-hydroxyvitamin D levels were not measured, but the authors speculate based on other reports that maternal vitamin D insufficiency was a contributing factor to low vitamin D levels. In addition, these infants had severe hypomagnesemia and PTH levels that were inappropriately low. The combination of multiple biochemical abnormalities may have led to severe late-onset hypocalcemia. (See "Etiology of hypocalcemia in infants and children".) In another study in Turkey, although low vitamin D levels were common with hypocalcemia, there was no significant difference in vitamin D levels between hypocalcemic full term infants (early or late hypocalcemia) and those without hypocalcemia [30].

Maternal vitamin D deficiency — Neonatal hypocalcemia due to severe maternal vitamin D deficiency has reported in a single case report from Australia and a case series from the Middle East [31,32]. In these patients, neonatal hypocalcemia mostly occurred during the second week of life, which is later than is typical for other causes of hypocalcemia [32]. Levels of 25-hydroxyvitamin D were extremely low in mothers and most infants; however, it remains uncertain whether vitamin D insufficiency played a causative role. Further confirmation is required to establish causality.

CLINICAL MANIFESTATIONS — Most infants with hypocalcemia are asymptomatic and are identified by screening. Among symptomatic infants, the characteristic sign is increased neuromuscular irritability. Such infants are jittery and often have muscle jerking that is induced by environmental noise or other stimuli. Generalized or focal clonic seizures may occur. Rare presentations include inspiratory stridor caused by laryngospasm, wheezing caused by bronchospasm, or vomiting possibly resulting from pylorospasm [12].

In the previously mentioned case series of 78 full-term neonates admitted with late severe hypocalcemia (median levels of total and ionized Ca of 1.5 and 0.81 mmol/L [6 and 3.24 mg/dL]), most infants presented with seizure-like activity that was deemed consistent with tetany in the context of low Ca levels [20]. These patients also had hyperphosphatemia (median level of 3.2 mmol/L [9.9 mg/dL]), hypomagnesemia (median level of 0.58 mmol/L [1.4 mg/dL]), and inappropriately low PTH levels.

SCREENING — Because most infants with hypocalcemia are asymptomatic, we monitor serum or preferably ionized calcium (Ca) in infants with risk factors.

For infants who are extremely low birth weight (ELBW; BW<1000 g) or who are ill, we measure the Ca concentration at 12, 24, and 48 hours of age. For preterm infants with BW 1000 to 1500 g, Ca is measured at 24 and 48 hours. We continue monitoring until Ca values are normal and Ca intake from milk or parenteral nutrition is adequate, which usually occurs by 96 hours. The use of early parenteral nutrition is an alternate route for providing Ca to this group of very low birth weight (VLBW) infants (BW <1500 g).

Ionized Ca also is measured in any infant with signs consistent with hypocalcemia and in infants with congenital heart disease (because of the association of cardiac defects and hypocalcemia [eg, DiGeorge or CATCH-22 syndrome]). (See 'Syndromes' above.)

We do not routinely monitor asymptomatic healthy preterm infants with BW >1500 g or healthy infants of diabetic mothers (IDMs) who are taking milk feedings on the first day. (See "Infants of women with diabetes".)

We do not recommend use of electrocardiography (ECG) to screen for hypocalcemia. Although the effect of hypocalcemia on cardiac repolarization may be reflected in prolongation of the QTc interval (QT interval corrected for heart rate) to greater than 0.4 seconds, the QTc interval does not correlate reliably with blood ionized Ca levels [33].

DIAGNOSIS — The diagnosis of hypocalcemia is made based on an abnormally low serum calcium (Ca) level, which is defined by birth weight (BW) as follows:

●In term infants or preterm infants with BW ≥1500 g, hypocalcemia is confirmed when the total serum Ca is less than 8 mg/dL (2 mmol/L) or an ionized fraction of less than 4.4 mg/dL (1.1 mmol/L) where, as noted above, the ionized calcium is a more accurate reflection of calcium status. (See 'Measurement' above.)

●In very low birth weight (VLBW) preterm infants (BW <1500 g), hypocalcemia is diagnosed when the total serum Ca is less than 7 mg/dL (1.75 mmol/L) or an ionized fraction of less than 4 mg/dL (1 mmol/L). However, ionized Ca values of 0.8 to 1 mmol/L are uncommonly associated with symptoms in VLBW infants and may not need specific intervention.

FURTHER EVALUATION — Infants require further evaluation if they have persistent early hypocalcemia that does not respond to dietary treatment (see 'Asymptomatic infants' below), develop late hypocalcemia, or are symptomatic (eg, jitteriness or seizures).

Serum phosphorus (P) is the first laboratory test to be performed in infants with persistent and/or symptomatic hypocalcemia:

●Elevated P – Infants with late hypocalcemia associated with high serum P and a normal examination do not need additional studies. As noted above, these patients typically have a high P intake and are managed by dietary measures with a reduction in dietary P. (See 'High phosphate intake' above and 'Hyperphosphatemia' below.)

●Normal or low P:

•Serum magnesium (Mg) should be measured, as hypomagnesemia is often a contributing factor to neonatal hypocalcemia. (See 'Hypomagnesemia' above and 'Correction of hypomagnesemia' below.)

•For infants with persistent or severe hypocalcemia, additional evaluation includes measuring:

-Serum parathyroid hormone (PTH) – Maternal hyperparathyroidism.

-Serum 25-hydroxyvitamin D levels – Vitamin D deficiency.

-Urinary calcium (Ca) excretion – Low urinary Ca excretion is suggestive of Ca deficiency. Either 24-hour urine collections or a spot urine Ca/creatinine (Ca/Cr) ratio can be used to assess urinary Ca excretion. However, normal values, especially for spot urine samples, are poorly defined in neonates.

-Assessing renal function – Renal insufficiency. (See "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis", section on 'Clinical presentation' and "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis", section on 'Presentation due to other laboratory abnormalities'.)

•For infants with a cardiac abnormality, genetic and cardiac studies are performed to detect possible DiGeorge or CATCH-22 syndrome. (See 'Syndromes' above.)

MANAGEMENT

Asymptomatic infants — Most infants with early hypocalcemia, who are asymptomatic, generally recover with nutritional support alone. Thus, management is directed at providing adequate calcium (Ca) intake by initiating early feedings. For infants who require parenteral nutrition, Ca is added to the solution as 10 percent Ca gluconate (500 mg/kg, 50 mg/kg of elemental Ca) per day and given as a continuous infusion. If parenteral Ca infusion is continued for more than 48 hours, additional phosphorus (P) also must be provided, based on serum P measurements.

Treatment should be directed against any underlying disease, if possible. Examples include hypomagnesemia and hyperphosphatemia. (See 'Correction of hypomagnesemia' below and 'Hyperphosphatemia' below.)

Symptomatic infants

Acute therapy — As noted above, infants with late-onset hypocalcemia usually present with signs consistent with abnormally low serum Ca, including severe neuromuscular irritability or seizures (see 'Clinical manifestations' above). They are treated with 10 percent Ca gluconate 100 mg/kg (2.5 mmol/kg) or 1 mL/kg intravenously (IV) [20]. The solution, which provides about 9.4 mg of elemental calcium per mL, is infused over 10 minutes while the heart rate and infusion site are monitored. The dose can be repeated in 10 minutes if no response occurs. Alternatively, Ca chloride (20 mg/kg or 0.2 mL/kg) can be given; this preparation is metabolized more rapidly and may be preferable if it is readily available.

Similar to the asymptomatic patient, treatment should be directed against any underlying disease (hypomagnesemia, hyperphosphatemia, and vitamin D deficiency), if possible. (See 'Correction of hypomagnesemia' below and 'Hyperphosphatemia' below and "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Vitamin D deficiency or insufficiency'.)

Risks of acute calcium infusion — IV infusion of Ca gluconate is associated with risks that must be weighed against the benefits of treatment [34]. Risks include bradyarrhythmias that can result from rapid elevations in serum Ca concentration, and extravasation into subcutaneous tissues, resulting in necrosis and subcutaneous calcifications. Hepatic necrosis can be caused by infusion through an umbilical venous catheter if the tip is in a branch of the portal vein.

Ca should not be infused acutely into an umbilical artery catheter because arterial spasm may result, potentially compromising intestinal blood flow.

Maintenance therapy — After acute treatment, maintenance Ca gluconate should be added to the IV solution at a dose of up to 75 mg/kg of elemental calcium daily (1.87 mmol/kg). If enteral feedings are tolerated, we use Ca glubionate administered orally as 30 to 50 mg/kg per day in four divided doses, although its high osmolality and sugar content can cause gastrointestinal irritability or diarrhea. Alternatively, 10 percent Ca gluconate (500 mg/kg per day of the gluconate) can be divided and given in four to six feedings. Ca carbonate is not generally recommended as an alternative in the newborn period, due to the possibility, not tested in clinical studies, that the higher pH of the neonatal stomach may limit solubility and absorption of the Ca carbonate.

For late hypocalcemia, we provide 400 international units/day of vitamin D3. This usually is discontinued after one to two weeks. Alternatively, calcitriol as an adjuvant therapy to gastrointestinal absorption of Ca may be used. If calcitriol is used, a dose of 0.08 to 0.1 mcg/kg is provided. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention in the perinatal period and in infants'.)

Correction of hypomagnesemia — When hypocalcemia is associated with hypomagnesemia, correction of the hypocalcemia requires correction of the hypomagnesemia. We treat with 50 percent magnesium sulfate solution (500 mg or 4 mEq/mL). Magnesium sulfate (25 to 50 mg/kg or 0.2 to 0.4 mEq/kg per dose every 12 hours, IV over at least two hours or intramuscular [IM]) is given until the serum magnesium concentration is greater than 1.5 mg/dL (0.62 mmol/L). The magnesium concentration is measured before each dose. One or two doses usually is adequate to achieve normal levels. We avoid rapid IV infusions that may cause arrhythmias.

Hyperphosphatemia — Infants with hyperphosphatemia are fed a diet high in Ca and low in P. Human milk is preferable; if it is not available, we use a formula with low P content, such as Similac PM 60/40 or Good Start although differences in P concentration amongst routine cow milk-based formulas are small and may not be clinically significant. We also provide oral Ca supplements.

Serum concentrations of Ca and P usually improve within one to three days after starting therapy. We discontinue Ca supplements gradually after one week when the serum Ca and P have normalized, and switch the infant to a cow milk-based formula based on clinical circumstance.

SUMMARY AND RECOMMENDATIONS — Hypocalcemia is a common metabolic problem in newborns.

●Causes of hypocalcemia are classified based upon their time of onset:

•Early hypocalcemia occurs in the first two to three days after birth. Causes include prematurity, maternal diabetes, birth asphyxia, fetal growth restriction (FGR), and hypoparathyroidism. (See 'Early hypocalcemia' above.)

•Late hypocalcemia usually occurs at the end of the first week of life, but may occur earlier after the second or third day after birth. Late hypocalcemia is usually caused by high phosphate intake. It is unclear whether vitamin D insufficiency (possibly caused by maternal vitamin D deficiency) has a causative role in late neonatal hypocalcemia. (See 'Late hypocalcemia' above.)

●Most infants with hypocalcemia are asymptomatic. If symptomatic, neuromuscular irritability is the most common sign, with jitteriness and muscle jerking. Less common findings include seizures and, rarely, laryngospasm, wheezing, or vomiting. (See 'Clinical manifestations' above.)

●Calcium (Ca) levels are measured for at-risk neonates including very low birth weight (VLBW) infants (BW <1500 g), those with congenital heart disease, and in patients with symptoms consistent with hypocalcemia. (See 'Screening' above.)

●The diagnosis is made by an abnormally low serum Ca value, which is defined by BW. If available, ionized Ca is the optimal test because this measurement most accurately assesses the risk of symptoms in all neonatal patient groups. (See 'Diagnosis' above.)

•In term infants or preterm infants with BW >1500 g, hypocalcemia is confirmed when the total serum Ca is less than 8 mg/dL (2 mmol/L) or an ionized fraction of less than 4.4 mg/dL (1.1 mmol/L).

•In VLBW preterm infants (BW <1500 g), hypocalcemia is diagnosed when the total serum Ca is less than 7 mg/dL (1.75 mmol/L) or an ionized fraction of less than 4 mg/dL (1 mmol/L).

●In asymptomatic infants, we suggest providing adequate Ca intake by initiating early feedings, if possible, or parenteral nutrition (Grade 2C). In addition, any underlying disorder resulting in a low Ca value should be corrected. (See 'Asymptomatic infants' above.)

●In symptomatic patients, we suggest providing initial parenteral Ca therapy as a 10 percent Ca gluconate solution at a dose of 100 mg/kg or 1 mL/kg (Grade 2C). Further Ca supplementation is provided either parenterally or orally, if enteral feeds are tolerated. (See 'Symptomatic infants' above.)

●Further evaluation is warranted if infants have persistent early hypocalcemia that does not respond to dietary treatment, develop late hypocalcemia, or have associated seizures. (See 'Further evaluation' above.)