Causes of Hypocalcemia in Infants
Temporal Classification
Hypocalcemia in infants occurs in two distinct temporal patterns: early-onset (first 24-48 hours) caused by interrupted placental calcium transfer and delayed parathyroid hormone surge, and late-onset (after 72 hours) primarily from excessive phosphate intake, maternal vitamin D deficiency, hypomagnesemia, or hypoparathyroidism. 1
Early-Onset Hypocalcemia (First 24-48 Hours)
Primary Mechanism
- Interruption of placental calcium transfer at birth combined with relative immaturity of hormonal control causes hypocalcemia in the first 24-48 hours of life 1, 2
- The delayed parathyroid hormone (PTH) surge is the key pathophysiologic mechanism—cord blood shows elevated calcium but undetectable or low PTH levels, and most infants maintain inappropriately low PTH during the first 48 hours despite falling calcium 3
- This form is generally asymptomatic and not associated with obvious clinical problems such as tetany 1, 2
High-Risk Populations for Early-Onset
- Preterm infants with gestational age <32 weeks require screening at 24 and 48 hours 4
- Infants of diabetic mothers have a 10-40% prevalence of hypocalcemia 2
- Small for gestational age infants are at increased risk 4
- Large for gestational age infants also demonstrate increased risk 2
- Infants with severe perinatal asphyxia (1-minute Apgar score <4) 4
- "Sick" infants have significantly lower calcium and ionized calcium levels compared to healthy newborns, though PTH patterns remain similar 3
Late-Onset Hypocalcemia (After 72 Hours)
Hypomagnesemia
- Magnesium deficiency impairs PTH secretion and creates PTH resistance 1
- Hypocalcemia will not resolve until magnesium levels are corrected—this is a critical clinical pitfall 1
- Depressed plasma magnesium is frequently present in hypocalcemic infants, and the interrelationship between hypomagnesemia and parathyroid insufficiency is bidirectional 3
Vitamin D Deficiency
- Maternal vitamin D deficiency is a significant cause, with 56.5% of hypocalcemic infants showing low 25-hydroxyvitamin D levels in one study 5
- Hispanic (69%) and African American (23%) infants are disproportionately affected 5
- Infantile serum vitamin D status directly reflects maternal levels in all measured cases 5
Excessive Phosphate Intake
- High phosphate intake from cow's milk-based formulas is a common cause of late-onset hypocalcemia 4
- However, hyperphosphatemia was uncommon and did not appear to be a major contributing factor in most hypocalcemic infants in physiologic studies 3
Hypoparathyroidism
- Primary hypoparathyroidism can present in the neonatal period, with genetic disorders, particularly 22q11.2 deletion syndrome, carrying an 80% lifetime prevalence of hypocalcemia 1
- Relative hypoparathyroidism is the etiology in the majority of cases of late-onset and early infantile hypocalcemia, characterized by inappropriately low PTH levels despite hypocalcemia 5, 3
- Maternal hyperparathyroidism causes transient neonatal hypoparathyroidism through chronic fetal parathyroid suppression—this presents as late-onset hypocalcemia with inappropriately normal PTH and should prompt maternal calcium evaluation 6
Special Clinical Situations
Parenteral Nutrition-Related
- Very low birth weight and small for gestational age infants are at risk for early hypophosphatemia due to high phosphorus needs for growth 7
- When phosphorus is deficient, calcium cannot be fixed in bone, inducing hypercalcemia, hypercalciuria, and if prolonged, bone demineralization and nephrocalcinosis 7
- Infants on long-term parenteral nutrition risk metabolic bone disease from calcium and/or phosphate deficiency, negative calcium balance, hyperparathyroidism, excessive vitamin D intake, or aluminum toxicity 7
Blood Transfusion-Related
- Large volume blood transfusions cause hypocalcemia because citrate (used as an anticoagulant) chelates calcium ions 2
- Mild, asymptomatic hypocalcemia is common in preterm neonates, but transfusions can aggravate pre-existing hypocalcemia, causing high calcium requirements 2
Critical Diagnostic Considerations
Laboratory Assessment
- Always measure pH-corrected ionized calcium (most accurate) rather than total calcium alone, as ionized calcium (~50% of total) is the physiologically active fraction 1, 8
- Infant laboratory calcium reference values are higher than adult values—applying adult ranges can miss diagnoses because the lower limit of normal is elevated due to rapid bone mineralization 8
- Check magnesium levels in all hypocalcemic neonates, as hypomagnesemia must be corrected first before calcium levels will normalize 1, 8