Neonatal hypocalcemia is defined as serum total calcium concentration <2 mmol/L (8 mg/dL) or ionized calcium concentration <1.1 mmol/L (4.4 mg/dL) in full-term infants or preterm infants with a birth weight ≥1,500 g. For preterm infants with a birth weight <1,500 g, serum total calcium <1.75 mmol/L (7 mg/dL) or ionized calcium <0.8 mmol/L defines hypocalcemia. This condition is one of the common causes of neonatal seizures.
Etiology and Pathogenesis
During late pregnancy, maternal parathyroid hormone (PTH) levels are elevated, and both total and ionized calcium levels in fetal umbilical cord blood are higher than maternal levels at birth. As a result, neonatal parathyroid function is transiently suppressed (causing relatively low PTH levels). After birth, the abrupt cessation of maternal calcium supply, combined with insufficient exogenous calcium intake and low neonatal PTH levels, prevents calcium mobilization from the bones, ultimately leading to hypocalcemia.
Early-Onset Hypocalcemia
Early-onset hypocalcemia occurs within 72 hours after birth. It is often observed in preterm infants, small-for-gestational-age infants, and infants born to mothers with diabetes or hypertensive disorders of pregnancy. The severity of hypocalcemia in preterm infants generally correlates inversely with gestational age. A history of difficult delivery, asphyxia, infection, or birth trauma increases the likelihood of hypocalcemia, potentially due to cellular damage causing elevated phosphate levels, which bind to calcium. Hypomagnesemia, which impairs parathyroid function, may also contribute to hypocalcemia.
Late-Onset Hypocalcemia
Late-onset hypocalcemia occurs after the first 72 hours of life.
It is common in full-term infants who are fed cow's milk, primarily due to the high phosphate content of cow's milk, which leads to poor calcium absorption because of an inappropriate calcium-phosphorus ratio. Low neonatal glomerular filtration rates and enhanced tubular phosphate reabsorption result in hyperphosphatemia, calcium deposition in the bones, and subsequent hypocalcemia. Late-onset hypocalcemia may also occur in children with chronic malabsorption syndromes.
Persistent or recurrent hypocalcemia should prompt investigation for underlying conditions, such as:
- Maternal hyperparathyroidism, often due to parathyroid adenoma.
- Congenital transient idiopathic hypoparathyroidism, which is a benign self-limiting condition. In such cases, maternal parathyroid function is normal, and treatment involves calcium supplementation alongside vitamin D for several months.
- Congenital permanent hypoparathyroidism, caused by congenital absence or underdevelopment of the parathyroid gland. This condition is X-linked recessive and characterized by permanent hypoparathyroidism and hyperphosphatemia. If associated with thymic hypoplasia, immunodeficiency, mandibular deformities, and aortic arch anomalies, the condition is diagnosed as DiGeorge syndrome.
Other causes include respiratory alkalosis induced by excessive ventilation (e.g., improper ventilator settings) or the use of alkaline agents such as sodium bicarbonate, which can cause free calcium to bind and decrease serum ionized calcium. Exchange transfusions or blood transfusions containing citrate as an anticoagulant may also lead to reduced free calcium levels. Long-term use of loop diuretics like furosemide may cause hypercalciuria, leading to decreased serum calcium.
Clinical Manifestations
Most infants with neonatal hypocalcemia are asymptomatic. Symptoms vary in severity and may include apnea, irritability, restlessness, muscle twitching, tremors, and startle reflex. Severe cases may involve seizures. Carpopedal spasms and laryngospasms are rare in neonates. Between episodes, general condition is typically stable, although hypertonia, increased tendon reflexes, and a positive ankle clonus sign may be observed.
Preterm infants usually lack obvious symptoms, possibly due to immature development, low plasma protein levels, and relatively higher levels of ionized calcium under acidotic conditions. However, in extremely low and very low birth weight infants, hypocalcemia can disrupt calcium and phosphorus metabolism, leading to metabolic bone disease characterized by reduced bone mineral content, fewer trabeculae, thinner cortical bone, delayed growth, and, in severe cases, rickets-like symptoms or fractures.
Diagnostic Investigations
Hypocalcemia is defined as serum total calcium <1.75 mmol/L (7 mg/dL) or serum ionized calcium <1.0 mmol/L (4 mg/dL). Serum phosphate levels are often >2.6 mmol/L (8 mg/dL), while alkaline phosphatase levels are typically normal. Evaluations should include serum magnesium and PTH levels in the infant and, if necessary, maternal serum calcium, phosphate, and PTH levels. Electrocardiograms may reveal arrhythmias and prolonged QT intervals (>0.2 seconds in preterm infants and >0.19 seconds in full-term infants). For suspected DiGeorge syndrome, chest imaging and echocardiography should be performed.
Treatment
Early-onset hypocalcemia often resolves without intervention. For asymptomatic infants, supportive measures include early enteral feeding or parenteral nutrition to ensure adequate calcium intake, while addressing any underlying conditions that may contribute to hypocalcemia. Symptomatic infants require calcium supplementation.
Intravenous Calcium Supplementation
A slow infusion of 10% calcium gluconate solution (containing 9 mg elemental calcium per mL) at a dose of 1–2 mL/(kg·dose) over 10–15 minutes is recommended, with monitoring of heart rate and the infusion site. Repeat dosing may be administered after 10 minutes if symptoms persist. Maintenance calcium gluconate may be added to intravenous fluids. Enteral calcium supplementation can be introduced if oral feeding is tolerated.
Oral Calcium Supplementation
For asymptomatic preterm infants or those tolerating enteral feeding, oral calcium supplements at 50–60 mg elemental calcium/(kg·day) for 2–4 weeks are used to maintain serum calcium levels within 2–2.3 mmol/L (8.0–9.0 mg/dL).
Magnesium Supplementation
Seizures that do not resolve with calcium supplementation warrant evaluation of magnesium levels. If serum magnesium is <0.6 mmol/L, administer 25% magnesium sulfate intramuscularly at a dose of 0.4 mL/kg.
Vitamin D Supplementation
Infants with hypoparathyroidism on long-term calcium supplementation require vitamin D therapy, such as 10,000–25,000 IU/day of vitamin D2, 0.05–0.1 mg/day of dihydrotachysterol, or 0.25–0.5 μg/day of 1,25(OH)2D3 (calcitriol). Serum calcium levels should be monitored regularly, and vitamin D dosages adjusted as needed.
Dietary Adjustments
Cow's milk with high phosphate content should be replaced with breast milk or formula with an appropriate calcium-phosphorus ratio.