Neonatal hypocalcemia

INTRODUCTION — 

Hypocalcemia is a common metabolic problem in newborns. The etiology of neonatal hypocalcemia is classified based on the timing of onset (ie, within the first three days after birth or thereafter). For neonates with signs of hypocalcemia, immediate treatment with calcium is necessary. However, many newborns with hypocalcemia are asymptomatic. Calcium levels are monitored in those with signs of and/or certain risk factors (eg, very low birth weight <1500 grams) for hypocalcemia. Additional testing may be warranted to determine the underlying cause and direct treatment.

The definition, etiology, evaluation, and management of neonatal hypocalcemia are reviewed here. Calcium 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".)

DEFINITION OF HYPOCALCEMIA — 

Abnormally low serum calcium (Ca) levels in neonates are defined by birth weight (BW) as follows:

●Term and preterm neonates with BW ≥1500 g – Hypocalcemia is defined as ionized Ca <4.4 mg/dL (<1.1 mmol/L) or total serum Ca <8 mg/dL (<2 mmol/L).

●Preterm very low BW (VLBW; BW 1000 to <1500 g) and extremely low BW (ELBW; BW <1000 g) neonates – Hypocalcemia is defined as ionized Ca <4 mg/dL (<1 mmol/L) or total serum Ca <7 mg/dL (<1.75 mmol/L). Ionized Ca values of 0.8 to 1 mmol/L are rarely associated with symptoms in VLBW and ELBW neonates and may not need specific intervention.

As noted below, the ionized Ca is a more accurate reflection of calcium status. (See 'Preferred test' below.)

PERINATAL METABOLISM — 

During pregnancy, calcium (Ca) is transferred actively from the circulation of the pregnant parent to the fetus by a transplacental Ca pump, which is regulated by parathyroid hormone-related peptide [1]. Approximately two-thirds of fetal Ca accretion occurs in the third trimester. This process results in higher plasma Ca concentrations in the fetus than in the pregnant parent, 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 infants and children by two weeks of age [5,6].

ETIOLOGY — 

The causes of neonatal hypocalcemia are classified by the timing of onset.

Early hypocalcemia — Early hypocalcemia refers to hypocalcemia occurring within the first three days after birth. It is an exaggeration of the normal decline in calcium (Ca) concentration after birth. It occurs more commonly in neonates who are preterm or fetal growth restricted (FGR), born to pregnant persons with diabetes, after perinatal asphyxia, or who have hypoparathyroidism. In these patients, nutritional support alone is adequate treatment to increase Ca levels. (See 'Asymptomatic neonates' below.)

Prematurity — Approximately one-third of preterm neonates and most very low birth weight (VLBW) neonates have low total serum Ca concentrations during the first two days after birth [7,8]. This rarely causes symptoms. Multiple factors contribute to the fall in total serum Ca, including:

●Factors that lower total Ca but not ionized Ca (eg, hypoalbuminemia). (See 'Preferred test' below.)

●Factors that lower both total and ionized Ca. These include [9]:

•Reduced intake of Ca because of low milk intake

•Possible impaired response to parathyroid hormone (PTH)

•Increased calcitonin levels

•Increased urinary losses accompanying high renal sodium excretion

Fetal growth restriction — Hypocalcemia occurs with increased frequency in neonates with FGR. The risk increases with the severity of growth failure [10,11]. The mechanism is thought to involve decreased transfer of Ca across the placenta. (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns".)

Diabetes in the pregnant parent — Hypocalcemia occurs in at least 10 to 20 percent of neonates born to pregnant persons with diabetes and in as many as 50 percent in some series [12,13]. (See "Infants of mothers with diabetes (IMD)".)

The lowest serum Ca concentration typically occurs between 24 to 72 hours after birth and often is associated with hyperphosphatemia. Strict glucose control during pregnancy appears to be associated with a lower incidence of and less severe neonatal hypocalcemia [14]. Hypocalcemia is thought to be caused by lower PTH concentrations after birth in neonates born to pregnant persons with diabetes compared with unaffected neonates [15]. Why this lower concentration occurs is not well understood. Higher serum ionized Ca concentrations in utero in these newborns may suppress the fetal parathyroid glands [15]. The development of hypomagnesemia, prematurity, and birth asphyxia may be contributing factors.

Perinatal asphyxia — Neonates with perinatal asphyxia frequently have hypocalcemia and may also have hyperphosphatemia. Possible mechanisms include increased phosphorus load caused by tissue catabolism, decreased intake due to delayed initiation of feedings, renal insufficiency, and increased serum calcitonin concentration [16,17]. (See "Perinatal asphyxia in term and late preterm infants".)

Critical illness — Hypocalcemia is a common finding in neonates with critical illness, including sepsis. Hypocalcemia in this setting is likely multifactorial and is often related to prematurity and/or fluid and electrolyte disturbances. In one study involving VLBW neonates with neonatal sepsis, low ionized Ca levels correlated with the severity of sepsis and independently predicted mortality [18]. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at less than 35 weeks gestation".)

Hypoparathyroidism — Hypoparathyroidism associated with excess phosphorus intake is a common cause of early neonatal hypocalcemia [19]. Hypoparathyroidism can be due to a lack of normal parathyroid gland function, 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 being the most common cause. (See "Etiology of hypocalcemia in infants and children", section on 'Genetic mechanisms'.)

DiGeorge (22q11 deletion) syndrome — The most prevalent syndrome that includes hypoparathyroidism is DiGeorge (chromosome 22q11) syndrome. The classic triad of features of DiGeorge syndrome is congenital heart disease (CHD), hypoplastic thymus, and hypocalcemia, although the phenotype is variable (table 1 and table 2). (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

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 in infants with DiGeorge syndrome was higher among those with CHD compared with those without CHD (62 versus 41 percent) [20].

Other syndromes — Other, rarer syndromes that include hypoparathyroidism resulting in hypocalcemia are Kearns-Sayre and Kenny-Caffey syndromes, which are mitochondrial cytopathies. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'CPEO and Kearns-Sayre syndrome'.)

Hyperparathyroidism in the pregnant parent — Neonates born to pregnant persons with hyperparathyroidism frequently have hypocalcemia. The mechanism is related to increased transplacental transport of Ca caused by high Ca concentrations in the pregnant parent, which results in fetal hypercalcemia that leads to suppression of fetal and neonatal PTH secretion. Affected neonates typically develop increased neuromuscular irritability in the first three weeks after birth, but they can present later [9]. Some neonates also have hypomagnesemia. In a case report, a neonate born to a mother with familial hypocalciuric hypercalcemia type 1 developed hypocalcemia and seizures [21]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Familial hypocalciuric hypercalcemia'.)

Hypomagnesemia in the neonate — Hypomagnesemia causes resistance to PTH action 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 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 [9].

Late hypocalcemia — Late hypocalcemia refers to hypocalcemia developing after the third day after birth and typically occurs at the end of the first week [19]. Neonates with late-onset hypocalcemia usually present with signs of hypocalcemia, including severe neuromuscular irritability or seizures. (See 'Signs and symptoms' below.)

High phosphorus intake — Excess phosphorus intake can occur in the following settings:

●Neonates fed bovine milk or formula with high phosphorus levels – The mechanism is uncertain. Symptomatic neonates typically present with tetany or seizures at 5 to 10 days of age [22].

●Use of phosphate enemas – Severe hyperphosphatemia and hypocalcemia also can be caused by phosphate enemas [23].

Other causes — Critically ill or preterm neonates 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 the formation of Ca complexes, decreases ionized Ca concentration. Lipid infusions also may reduce ionized Ca levels by the 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, or to effects on parathyroid function [24,25]. This may be mitigated by covering the head of the neonate during phototherapy [26].

Other conditions associated with hypocalcemia include:

●Acute kidney injury 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 [27]. (See "Clinical manifestations and diagnosis of rotavirus infection", section on 'Clinical manifestations'.)

Unclear role for vitamin D insufficiency — Vitamin D insufficiency in the newborn and pregnant parent has been suggested as a potential cause of late hypocalcemia. In particular, preterm newborns, especially extremely preterm newborns (gestational age <28 weeks), have low levels of vitamin D. However, it is unclear whether this contributes to low Ca levels, and if so, what vitamin D level is specifically associated with low Ca levels.

Studies evaluating the effect of vitamin D insufficiency in newborns are inconclusive:

●In a meta-analysis of 10 observational studies, including 2974 term and preterm newborns, low 25-hydroxyvitamin D levels in the newborn were associated with increased risk for neonatal hypocalcemia [28]. Vitamin D insufficiency was defined at variable 25-hydroxyvitamin D levels among studies (ie, five studies: <30 ng/mL [<74.9 nmol/L], two studies <20 ng/mL [<49.9 nmol/L], three studies <10 ng/mL [<25 nmol/L]). However, this does not establish causality. Indeed, in the largest retrospective study including 750 term and preterm newborns in Turkey, low 25-hydroxyvitamin D levels were observed in preterm and term newborns both with and without hypocalcemia [29].

●In a case series of 78 term newborns who presented with severe neonatal hypocalcemia, 25-hydroxyvitamin D levels were deemed by the authors to be deficient (ie, <25 ng/mL [<62.4 nmol/L]) in all of the 42 newborns in whom vitamin D levels were measured [19]. However, 25 ng/mL has not been established as a biologically relevant threshold for any clinical disorders in preterm newborns. Therefore, the true role of low vitamin D status has yet to be determined. In addition, these newborns had severe hypomagnesemia and inappropriately low PTH levels. The combination of multiple biochemical abnormalities may have led to severe late-onset hypocalcemia (See "Etiology of hypocalcemia in infants and children".)

Studies evaluating the effect of vitamin D insufficiency in the pregnant parent are also inconclusive:

●In a meta-analysis of three observational studies including 207 mostly term newborns, vitamin D deficiency in the pregnant parent (25-hydroxyvitamin D levels of <10 ng/mL [<25 nmol/L]) was associated with increased risk for neonatal hypocalcemia [28]. Case studies have also reported this finding [30,31].

●In a case series of 19 newborns in the Middle East, neonatal hypocalcemia mostly occurred during the second week of life, which is later than is typical for other causes of hypocalcemia [31]. Although levels of 25-hydroxyvitamin D were extremely low in the pregnant parent and most newborns, it is unclear whether vitamin D insufficiency played a causative role.

SIGNS AND SYMPTOMS — 

Most newborns with early hypocalcemia are asymptomatic and are identified by screening. (See 'Early hypocalcemia' above.)

Among symptomatic neonates, the characteristic presenting signs include [9,19]:

●Neuromuscular irritability – Neonates are jittery and often have limb jerking that is induced by environmental noise or other stimuli

●Generalized or focal clonic seizures

●Other rare presentations include:

•Inspiratory stridor caused by laryngospasm

•Wheezing caused by bronchospasm

•Vomiting possibly resulting from pylorospasm

In particular, neonates with late hypocalcemia usually present with severe neuromuscular irritability or seizures. (See 'Late hypocalcemia' above.)

TESTING FOR HYPOCALCEMIA

Patient selection — Because many newborns with hypocalcemia are asymptomatic, we monitor calcium (Ca) levels (preferably ionized Ca) in neonates with risk factors.

We routinely measure ionized Ca levels in the following patients:

●Very low birth weight (VLBW; BW 1000 to <1500 g) and extremely low birth weight (ELBW; BW <1000 g) neonates (see 'Prematurity' above).

●Neonates who are critically ill (see 'Critical illness' above).

●Neonates with congenital heart disease (CHD) (because of the association of cardiac defects and hypocalcemia from DiGeorge [22q11 deletion] syndrome) (see 'DiGeorge (22q11 deletion) syndrome' above).

●Neonates with signs consistent with hypocalcemia (eg, abnormal limb jerking, seizures, tetany) (see 'Signs and symptoms' above).

We do not routinely monitor asymptomatic healthy preterm neonates with BW >1500 g or healthy neonates born to pregnant persons with diabetes who are taking milk feedings on the first day. (See "Infants of mothers with diabetes (IMD)".)

Timing — The timing of testing depends on the BW and clinical status:

●For ELBW neonates and those who are critically ill, we measure the Ca concentration at 12, 24, and 48 hours of age

●For VLBW neonates, 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. Early parenteral nutrition is an alternate route for providing Ca to ELBW and VLBW neonates. (See "Parenteral nutrition in premature infants".)

Preferred test — When evaluating Ca status in neonates, we suggest measuring ionized Ca in whole blood rather than total Ca because ionized Ca more accurately reflects the physiologically available Ca [32]. 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".)

We suggest not using electrocardiography 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].

Measurement of ionized calcium is preferred because of:

●Variable distribution of Ca within plasma – Within the plasma, Ca circulates in different forms:

•Approximately 50 percent exists as the physiologically important ionized (or free) Ca [34]. The ionized Ca concentration is tightly regulated by parathyroid hormone and vitamin D.

•Approximately 40 percent is bound to serum proteins, principally albumin.

•10 percent is complexed with citrate, bicarbonate, sulfate, or phosphate.

●Effects of physiologic changes on Ca – Clinical decisions are generally based on ionized Ca to help distinguish hypocalcemia resulting from physiologic changes (eg, hypoalbuminemia) as opposed to other conditions (eg, hypoparathyroidism). 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 newborns.

•Hypoalbuminemia – 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.

•Acid-base disturbances – 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 [35]. 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 [35]. 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.

ADDITIONAL TESTING — 

Further evaluation to identify the cause of hypocalcemia (algorithm 1) is generally warranted if the neonate has any of the following:

●Persistent early (0 to 3 days after birth) hypocalcemia that does not respond to dietary treatment (see 'Asymptomatic neonates' below)

●Late hypocalcemia (≥4 days after birth) (see 'Asymptomatic neonates' below)

●Symptomatic hypocalcemia (eg, jitteriness or seizures) (see 'Signs and symptoms' above and 'Symptomatic neonates' below)

Additional laboratory testing includes:

●Serum phosphorus – To evaluate for hyperphosphatemia (see 'High phosphorus intake' above and 'Hyperphosphatemia' below).

●Serum magnesium – Hypomagnesemia is often a contributing factor to neonatal hypocalcemia (see 'Hypomagnesemia in the neonate' above and 'Hypomagnesemia' below).

●Serum parathyroid hormone (PTH) – Serum PTH may be elevated in vitamin D deficiency or suppressed due to hypoparathyroidism in the neonate or, rarely, hyperparathyroidism in the pregnant parent. Neonatal hypocalcemia due to parental hyperparathyroidism can be confirmed by measuring the parent's calcium level, followed by serum PTH if it is elevated. (See 'Hypoparathyroidism' above and 'Hyperparathyroidism in the pregnant parent' above.)

●Serum 25-hydroxyvitamin D levels – To evaluate for vitamin D deficiency (defined as a value <20 ng/100 dL) (see "Management of bone health in preterm infants", section on 'Vitamin D requirements' and "Vitamin D insufficiency and deficiency in children and adolescents").

●Urinary calcium (Ca) excretion – Low urinary Ca excretion is suggestive of Ca deficiency and is typically found in neonatal hypoparathyroidism. The level can vary depending on the severity of hypocalcemia, dietary Ca intake, and kidney function.

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.

●Basic metabolic panel – Elevated Cr or electrolyte imbalances are suggestive of acute kidney injury (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').

●Genetic testing in selected neonates – For neonates with congenital heart disease or other concerning features (eg, hypoparathyroidism), genetic testing is performed to evaluate for DiGeorge (22q11 deletion) syndrome (see 'DiGeorge (22q11 deletion) syndrome' above).

MANAGEMENT

Asymptomatic neonates — For asymptomatic neonates with early or late hypocalcemia, treatment begins with dietary management (algorithm 1). In neonates with persistent hypocalcemia, additional testing is obtained to evaluate for an underlying cause (eg, hypomagnesemia, hyperphosphatemia) and direct treatment. (See 'Additional testing' above and 'Correction of underlying disease' below.)

●Early hypocalcemia – Most asymptomatic neonates with early hypocalcemia generally recover with nutritional support alone. Thus, management is directed at providing adequate calcium (Ca) intake by initiating early feedings. For neonates who require parenteral nutrition, Ca gluconate 10 percent solution is added to parenteral nutrition at a dose of 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 also must be provided, based on serum phosphorus measurements.

If hypocalcemia persists, additional testing is warranted to evaluate for the underlying cause. (See 'Additional testing' above.)

●Late hypocalcemia – For asymptomatic neonates with late hypocalcemia, measurement of the serum phosphorus level will help guide the need for additional testing. Neonates with late hypocalcemia associated with high serum phosphorus and a normal examination usually do not need additional studies. These patients typically have a high phosphorus intake and are managed by dietary measures that reduce dietary phosphorus. (See 'High phosphorus intake' above and 'Hyperphosphatemia' below.)

For asymptomatic neonates with persistent hypocalcemia that is not responsive to dietary management, or those with normal or low serum phosphorus levels, additional laboratory tests are obtained to evaluate for the underlying cause. (See 'Additional testing' above.)

Symptomatic neonates — In symptomatic neonates, immediate treatment with parenteral calcium should be initiated and additional testing obtained to evaluate for the underlying cause (algorithm 1). (See 'Additional testing' above.)

Acute therapy — Acute treatment for symptomatic neonates is as follows:

●Ca gluconate 10 percent (100 mg/mL) solution is given intravenously (IV) at a dose of 100 mg/kg (0.233 mmol/kg) delivered as 1 mL/kg infused over 10 minutes. This solution provides approximately 9.3 mg (0.233 mmol) of elemental calcium per 1 mL. The neonate's heart rate and the infusion site should be monitored during the infusion. (See 'Risks of acute calcium infusion' below.)

●Alternatively, IV Ca chloride (20 mg/kg or 0.2 mL/kg per dose) can be given. This preparation is metabolized more rapidly and may be preferable in life-threatening situations, if it is readily available.

The dose can be repeated in 10 minutes if the neonate does not respond to the initial dose.

As for asymptomatic neonates, treatment should be directed against any underlying disease (hypomagnesemia, hyperphosphatemia, and vitamin D deficiency). (See 'Correction of underlying disease' below.)

Risks of acute calcium infusion — IV infusion of Ca gluconate is associated with risks that must be weighed against the benefits of treatment [36]. Risks include:

●Bradyarrhythmias that can result from rapid elevations in serum Ca concentration

●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 it may cause arterial spasm and potentially compromise 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 (1.87 mmol/kg) of Ca gluconate daily. If enteral feedings are tolerated, Ca is administered orally. We prefer to use Ca gluconate 10 percent IV solution administered orally as 500 mg/kg per day of Ca gluconate (approximately 46.5 mg/kg per day of elemental Ca) divided and given in four to six feedings. This is due to the possibility (not tested in clinical trials) that the higher pH of the neonatal stomach may limit the solubility and absorption of Ca carbonate and result in intolerance or other adverse effects. At some institutions, Ca carbonate oral suspension 1250 mg/5 mL (500 mg of elemental Ca per 5 mL) is administered orally as 30 to 75 mg/kg per day of elemental Ca divided and given in four to five doses over 24 hours. 

For neonates with late hypocalcemia, we also provide 400 international units (10 mcg) per 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 usually provided. Endocrine consultation is often warranted in this case. (See "Vitamin D insufficiency and deficiency in children and adolescents", section on 'Prevention in the perinatal period and in infants' and "Management of bone health in preterm infants".)

Correction of underlying disease — When identified by additional testing (algorithm 1), the underlying cause of hypocalcemia should be addressed. (See 'Asymptomatic neonates' above and 'Symptomatic neonates' above.)

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) 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 as this may cause arrhythmias.

Hyperphosphatemia — Neonates with hyperphosphatemia (due to high phosphorus intake) are fed a diet high in Ca and low in phosphorus. Human milk is preferable; if it is not available, we use a standard cow-milk-based formula. We do not use preterm formulas as they contain a high level of phosphorus. We also provide oral Ca supplementation. We prefer to use Ca gluconate 10 percent IV solution administered orally as 500 mg/kg per day of Ca gluconate (approximately 46.5 mg/kg of elemental Ca) divided and given in four to six feedings because the higher pH of the neonatal stomach may limit the solubility and absorption of Ca carbonate. At some institutions, Ca carbonate oral suspension 1250 mg/5 mL (500 mg of elemental Ca per 5 mL) is administered orally as 30 to 75 mg/kg per day of elemental Ca divided and given in four to five doses over 24 hours. 

Serum concentrations of Ca and phosphorus usually improve within one to three days after starting therapy. We discontinue Ca supplements gradually after one week when the serum Ca and phosphorus levels have normalized and switch the neonate to a cow milk-based formula.

Other causes of hyperphosphatemia (eg, acute kidney injury, perinatal asphyxia, and therapeutic interventions such as phosphate enemas) should be addressed, if present. (See 'Other causes' above and 'Perinatal asphyxia' above and 'High phosphorus intake' above.)

Other conditions — Management of vitamin D deficiency, bone health in preterm and very low birth weight neonates, and kidney injury are discussed in more detail separately. (See "Vitamin D insufficiency and deficiency in children and adolescents" and "Management of bone health in preterm infants" and "Neonatal acute kidney injury: Evaluation, management, and prognosis".)

SUMMARY AND RECOMMENDATIONS

●Definition of neonatal hypocalcemia – The definition of hypocalcemia varies depending on birth weight (BW). Clinical decisions are generally based on ionized Calcium (Ca). (See 'Definition of hypocalcemia' above.)

•BW >1500 g – For term or preterm neonates with BW >1500 g, hypocalcemia is defined as ionized Ca <4.4 mg/dL (<1.1 mmol/L) or total serum Ca <8 mg/dL (<2 mmol/L).

•BW <1500 g – In preterm neonates with BW <1500 g, hypocalcemia is defined as ionized Ca <4 mg/dL (<1 mmol/L) or total serum Ca <7 mg/dL (<1.75 mmol/L).

●Causes of hypocalcemia – Causes of hypocalcemia are classified based upon timing of onset (see 'Etiology' above):

•Early hypocalcemia – Early hypocalcemia refers to hypocalcemia occurring within the first three days after birth. Causes include prematurity, diabetes in the pregnant parent, birth asphyxia, fetal growth restriction, and hypoparathyroidism. (See 'Early hypocalcemia' above.)

•Late hypocalcemia – Late hypocalcemia usually occurs at the end of the first week of life but may occur any time after the third day after birth. Late hypocalcemia is usually caused by high phosphorus intake. It is unclear whether vitamin D insufficiency (possibly caused by vitamin D deficiency in the pregnant parent) has a causative role in late neonatal hypocalcemia. (See 'Late hypocalcemia' above.)

●Signs and symptoms – Most neonates with early hypocalcemia are asymptomatic. In symptomatic neonates, findings may include neuromuscular irritability (eg, jitteriness, limb jerking) or seizures. Less common findings include laryngospasm, wheezing, or vomiting. (See 'Signs and symptoms' above.)

●When to test for hypocalcemia – Ca levels are routinely measured in (see 'Testing for hypocalcemia' above):

•Preterm neonates with BW <1500 g

•Critically ill neonates

•Neonates with congenital heart disease

•Neonates with symptoms consistent with hypocalcemia

●Preferred testing method – We suggest measuring ionized Ca rather than total Ca, because ionized Ca more accurately reflects the physiologically available Ca. (See 'Preferred test' above.)

●Further evaluation – Additional testing to identify the cause of hypocalcemia (algorithm 1) and direct further treatment is warranted if the neonate has any of the following (see 'Additional testing' above and 'Correction of underlying disease' above):

•Persistent early (days 0 to 3 after birth) hypocalcemia that does not respond to dietary treatment

•Late hypocalcemia (≥4 days after birth)

•Symptomatic hypocalcemia (eg, seizures)

●Management of hypocalcemia

•Asymptomatic neonates – Asymptomatic neonates generally do not require acute parenteral repletion. Management focuses on ensuring adequate Ca intake by initiating early feedings, if possible, or parenteral nutrition (algorithm 1). In addition, any underlying disorder (eg, hypomagnesemia, hyperphosphatemia) resulting in a low Ca value should be corrected. (See 'Asymptomatic neonates' above.)

•Symptomatic neonates – Symptomatic patients require parenteral Ca repletion, which is provided with 10 percent Ca gluconate solution at a dose of 100 mg/kg (1 mL/kg). Further Ca supplementation is provided either parenterally or orally if enteral feeds are tolerated. As for asymptomatic neonates, the underlying cause of hypocalcemia should be addressed (algorithm 1). (See 'Symptomatic neonates' above.)