Neonatal Hypercalcaemia

Neonatal hypercalcaemia is a total serum calcium over 2.75 mmol/L (11 mg/dL) or an ionised calcium over 1.4 mmol/L in the newborn period. Levels over 3.5 mmol/L are severe and need urgent treatment.

It is rare. Presentation is often late in the first weeks of life, with poor feeding and failure to thrive.

Causes include subcutaneous fat necrosis (after perinatal asphyxia or therapeutic hypothermia), Williams syndrome, excess calcium or vitamin D intake (including parenteral nutrition), maternal hypocalcaemia or hypoparathyroidism, neonatal severe hyperparathyroidism and familial hypocalciuric hypercalcaemia from CASR variants, hypophosphatasia, and CYP24A1 variants. Phosphate depletion in preterm infants and thyrotoxicosis are other causes.

Pathophysiology.

In fat necrosis, macrophage granulomas convert 25-hydroxyvitamin D to its active form, increasing gut calcium absorption and bone resorption. In Williams syndrome, sensitivity to vitamin D may be raised.

Hypercalcaemia causes nephrogenic diabetes insipidus with polyuria and dehydration, smooth muscle hypotonia with constipation and vomiting, and deposition of calcium in the kidneys.

• Poor feeding, vomiting, constipation, polyuria, dehydration, irritability, lethargy, hypotonia and failure to thrive.
• Seizures and coma in severe cases. Short QT interval and arrhythmia.
• Firm subcutaneous nodules over the back, buttocks and limbs (fat necrosis), or distinctive facial features, supravalvar aortic stenosis and a friendly manner (Williams syndrome).

Red flags.

• Calcium over 3.5 mmol/L, with lethargy, seizures or arrhythmia.
• Renal impairment or nephrocalcinosis.
• Neonatal severe hyperparathyroidism: marked hypotonia, bone demineralisation and respiratory distress.

• Total and ionised calcium, phosphate, magnesium, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, creatinine and urine calcium to creatinine ratio.
• Parental calcium and urine calcium excretion to identify familial hypocalciuric hypercalcaemia.
• Renal ultrasound for nephrocalcinosis and skeletal survey for demineralisation or fractures. ECG for short QT interval.
• Genetic testing for CASR, CYP24A1, the 7q11.23 deletion of Williams syndrome and ALPL.

Differential diagnosis. Excess vitamin D or calcium, hyperparathyroidism, familial hypocalciuric hypercalcaemia, Williams syndrome, hypophosphatasia, thyrotoxicosis, adrenal insufficiency and malignancy.

General measures.

• Stop all calcium and vitamin D supplements and review medicines. Change to a low calcium, vitamin D-free formula. Ensure adequate phosphate in preterm infants.
• Rehydrate with 0.9% sodium chloride 10 to 20 mL/kg IV, then 1.5 to 2 times maintenance fluid to promote calciuresis.
• Furosemide 1 mg/kg IV every 6 to 12 hours after rehydration, with electrolytes, magnesium and urine output monitored.

Severe or persistent hypercalcaemia.

• Prednisolone 1 to 2 mg/kg/day orally for vitamin D-mediated causes, including fat necrosis.
• Pamidronate 0.5 to 1 mg/kg IV over 4 hours as a single dose in severe or refractory disease, under specialist direction, with calcium monitored for hypocalcaemia.
• Calcitonin 4 units/kg SC every 12 hours is a short term option.
• Parathyroidectomy for neonatal severe hyperparathyroidism that does not respond to treatment.

Monitoring. Calcium daily until normal, then weekly. In fat necrosis, calcium can rise for 6 to 8 weeks after onset, so measure weekly for at least 6 weeks. Repeat renal ultrasound for nephrocalcinosis.

Referral and escalation. Refer to paediatric endocrinology for calcium over 3.0 mmol/L, renal involvement or an unclear cause. Refer to genetics for Williams syndrome and CASR disorders.