What is neonatal hypocalcemia?

Neonatal Hypocalcemia

Definition and Pathophysiology

Neonatal hypocalcemia is a common metabolic disorder occurring when serum calcium drops below critical thresholds due to interruption of placental calcium transfer at birth, combined with immature hormonal regulation (delayed parathyroid hormone surge). 1

Diagnostic Thresholds

• Term infants and preterm >1500g: Total serum calcium <8 mg/dL (2 mmol/L) or ionized calcium <4.4 mg/dL (1.1 mmol/L) 2
• Very low birth weight infants (<1500g): Total serum calcium <7 mg/dL (1.75 mmol/L) or ionized calcium <4 mg/dL (1 mmol/L) 2

Calcium Homeostasis in Newborns

Blood calcium exists in three fractions: ionized calcium (50%), protein-bound calcium (40%), and a small amount complexed with citrate and phosphate. 1 Calcium homeostasis is controlled by parathyroid hormone (PTH), calcitonin, and 1,25(OH)₂-vitamin D, with the main regulatory mechanism being deposition in or release from bone. 1

Classification and Timing

Early-Onset Hypocalcemia (First 24-72 hours)

Early neonatal hypocalcemia occurs rapidly within the first 24-48 hours of life due to relative immaturity of hormonal control (delayed PTH surge) following interruption of placental calcium transfer at birth. 1

• Generally asymptomatic and not associated with obvious clinical problems such as tetany 1
• Requires screening at 24 and 48 hours after birth in high-risk infants 2

Late-Onset Hypocalcemia (After 72 hours to end of first week)

Late-onset hypocalcemia develops after the first 72 hours and is generally symptomatic. 2 Common causes include:

• Excessive phosphate intake 2, 3
• Hypomagnesemia 2, 3
• Hypoparathyroidism 2, 3
• Vitamin D deficiency 2, 3

High-Risk Populations Requiring Screening

Serum calcium levels must be monitored in the following populations: 2

• Preterm infants with gestational age <32 weeks 2
• Small for gestational age (SGA) infants 2
• Infants of diabetic mothers (IDM) - prevalence 10-40% in infants of mothers with type 1 diabetes 4, 5, 6, 7
• Infants with severe perinatal asphyxia (1-minute Apgar score <4) 2, 3, 6
• Large for gestational age infants 4

Predictive Factors in Infants of Diabetic Mothers

In IDMs, the lowest serum calcium can be predicted using: Lowest Ca (mg/dL) = 34.05 - 3.22 (cord Ca) - 0.84 (GA) + 0.10 (GA)(cord Ca), with 72% sensitivity and 75% specificity for predicting hypocalcemia. 7 Cord blood calcium and gestational age are the dominant predictive factors. 7

Clinical Presentation

Asymptomatic Hypocalcemia

Most infants with early-onset hypocalcemia are asymptomatic, making screening essential in at-risk populations. 1, 2, 6

Symptomatic Hypocalcemia

When symptomatic, hypocalcemia can present with: 1, 2

• Neuromuscular excitability and tetany 1, 2
• Generalized seizures 1, 2
• Cardiac arrhythmias and QT prolongation 1
• Jitteriness and irritability 2

Critical caveat: Hypocalcemia can trigger seizures at any age, even in patients with no prior history of hypocalcemia or seizures, due to underlying parathyroid dysfunction. 1

Treatment Algorithm

Asymptomatic Hypocalcemia

Elementary calcium replacement of 40-80 mg/kg/day is recommended for asymptomatic newborns. 2 Treatment should be initiated immediately while investigating the etiology. 2

Symptomatic Hypocalcemia (Tetany or Seizures)

For acute symptomatic hypocalcemia: 2

• Elementary calcium 10-20 mg/kg (1-2 mL/kg/dose of 10% calcium gluconate) given as slow intravenous infusion 2
• Continue treatment for at least 72 hours in early-onset hypocalcemia 6
• Late-onset hypocalcemia requires longer-term therapy 6

Calcium Infusion for Prevention and Treatment

Calcium infusion may be used for prevention and treatment of early neonatal hypocalcemia (ESPGHAN/ESPEN/ESPR/CSPEN conditional recommendation, strong consensus). 1 Calcium infusion will usually prevent or treat early neonatal hypocalcemia. 1

Additional Considerations

• Evaluate and correct hypomagnesemia if present, as it can perpetuate hypocalcemia 2, 3
• Reduce excessive phosphate intake in cases of late-onset hypocalcemia 2, 3
• Consider vitamin D metabolites for vitamin D-related disorders 3

Special Situations

Transfusion-Associated Hypocalcemia

Large volume blood transfusions are associated with hypocalcemia due to citrate (a chelating agent in RBC additives) binding calcium ions. 1 Renal and liver immaturity in neonates aggravates citrate toxicity. 1 Mild, asymptomatic hypocalcemia is common in preterm neonates, but blood transfusions can aggravate pre-existing hypocalcemia, causing high calcium requirements. 1

Parenteral Nutrition Considerations

In parenteral nutrition, calcium supplies may be limited due to risk of calcium-phosphate salt precipitation, but this can be prevented by using organic phosphorus compounds such as glycerophosphate. 1

Monitoring

• Track serum calcium levels at 24 and 48 hours in high-risk infants 2
• Monitor both total and ionized calcium concentrations 2
• Continue monitoring until stable 4
• Maintain blood glucose ≥2.5 mmol/L (45 mg/dL) as hypoglycemia often coexists in the same at-risk populations 4