What are the causes of seizures due to hypocalcemia and failure to thrive in a neonate?

Neonatal Hypocalcemic Seizures and Failure to Thrive: Causes

In a neonate presenting with seizures due to hypocalcemia and failure to thrive, the most critical underlying cause to identify is maternal hyperparathyroidism, which suppresses fetal parathyroid function and leads to neonatal hypoparathyroidism—this requires immediate maternal evaluation with serum calcium, phosphate, and intact PTH levels. 1, 2, 3

Primary Maternal-Fetal Causes

Maternal Hyperparathyroidism (Most Critical)

• Maternal primary hyperparathyroidism causes chronic fetal hypercalcemia, which suppresses fetal parathyroid gland development and function 1, 2, 3
• After birth, the neonate loses the maternal calcium supply but has inadequate parathyroid response, resulting in severe hypocalcemia with seizures typically presenting at 2-4 weeks of age 2, 3
• The mother is often asymptomatic and undiagnosed during pregnancy, making this a frequently missed diagnosis 2, 3
• Maternal evaluation must include serum calcium, phosphate, intact PTH, and 25-hydroxyvitamin D levels in any neonate with late-onset hypocalcemic seizures 2, 3
• Maternal findings typically show: elevated calcium, low phosphate, markedly elevated iPTH, and often low vitamin D 2

Excessive Maternal Calcium Carbonate Ingestion

• Extremely high doses of calcium carbonate taken by the mother during the third trimester can suppress fetal parathyroid function 4
• This results in neonatal hypoparathyroidism with low calcium, low magnesium, low PTH, and elevated phosphate 4
• Always obtain a detailed maternal medication history, including over-the-counter antacids and calcium supplements 4

Genetic and Congenital Causes

22q11.2 Deletion Syndrome (DiGeorge Syndrome)

• This syndrome carries an 80% lifetime prevalence of hypocalcemia due to parathyroid hypoplasia or aplasia 5, 6, 7
• Hypocalcemia can present at any age, with the majority experiencing recurrence after initial neonatal hypocalcemia 5, 6
• Associated features include congenital heart disease (especially Tetralogy of Fallot), feeding difficulties, failure to thrive, immune deficiency, and characteristic facial features 7
• Screen all neonates with Tetralogy of Fallot or conotruncal cardiac defects for 22q11.2 deletion syndrome 7
• The American Heart Association recommends genetic testing in all patients with Tetralogy of Fallot 7

Primary Congenital Hypoparathyroidism

• Isolated parathyroid agenesis or hypoplasia can occur without 22q11.2 deletion 6, 8
• Presents with low calcium, low or inappropriately normal PTH, and elevated phosphate 2

Metabolic and Nutritional Causes

Vitamin D Deficiency

• Maternal vitamin D deficiency leads to neonatal vitamin D deficiency and impaired calcium absorption 8, 2
• This is particularly common in exclusively breastfed infants whose mothers have low vitamin D stores 2
• Measure 25-hydroxyvitamin D levels in both neonate and mother 8, 2

Hypomagnesemia

• Magnesium deficiency impairs PTH secretion and creates PTH resistance, preventing hypocalcemia correction 6, 8
• Hypocalcemia will not resolve until magnesium levels are corrected 6, 8
• Always check magnesium levels simultaneously with calcium and correct magnesium first if low 8, 7

Phosphate Overload

• Excessive phosphate intake (from high-phosphate formulas or cow's milk) can precipitate hypocalcemia 6
• Elevated phosphate binds calcium and suppresses vitamin D activation 6

Clinical Presentation and Diagnostic Approach

Key Clinical Features

• Seizures are often the first manifestation, ranging from subtle to status epilepticus 1, 9, 10
• Failure to thrive results from feeding difficulties, increased metabolic demands from seizures, and underlying cardiac dysfunction 7, 10
• Life-threatening dilated cardiomyopathy can occur with severe hypocalcemia and requires urgent recognition 10
• Other manifestations include neuromuscular irritability, apnea, cyanosis, and cardiac arrhythmias 1
• Prolonged QT interval on ECG is a critical finding that predisposes to ventricular arrhythmias 5, 8

Essential Initial Laboratory Evaluation

• Measure pH-corrected ionized calcium (most accurate), not just total calcium 6, 8, 7
• Obtain magnesium, phosphate, intact PTH, creatinine, and 25-hydroxyvitamin D levels 8, 7
• Perform ECG to assess QT interval and screen for cardiac arrhythmias 8, 7
• If neonatal hypoparathyroidism is confirmed, immediately evaluate the mother with calcium, phosphate, PTH, and vitamin D levels 2, 3

Timing Considerations

• Early neonatal hypocalcemia (first 72 hours) suggests birth asphyxia, prematurity, or maternal diabetes 4
• Late neonatal hypocalcemia (after 1 week) strongly suggests maternal hyperparathyroidism, vitamin D deficiency, or genetic causes 2, 3

Critical Management Pitfalls

• Never assume neonatal hypocalcemia is isolated—always evaluate the mother for hyperparathyroidism 2, 3
• Failure to correct hypomagnesemia will result in treatment-resistant hypocalcemia 6, 8
• Concomitant use of ceftriaxone and calcium gluconate is absolutely contraindicated in neonates ≤28 days due to fatal precipitation reactions 1
• Calcium gluconate contains aluminum (up to 400 mcg/mL) which is toxic to premature neonates with immature renal function 1
• Monitor calcium levels every 4 hours during acute treatment to avoid overcorrection and hypercalcemia 7, 1
• Screen for 22q11.2 deletion syndrome in all neonates with hypocalcemia and congenital heart disease, feeding difficulties, or dysmorphic features 7