Transient Neonatal Hypocalcemia

A 7-day-old girl presented to the emergency department (ED) with concern for seizure-like activity. The mother stated that patient had awakened early that morning with a loud cry followed by jerking of her right arm and leg, lasting about 10 seconds. Immediately after the episode had occurred, the newborn was sleepy but arousable. About 12 hours later, a second episode had occurred, lasting about 25 seconds, at which time the mother brought the newborn to the ED.

History

The mother denied any fever, fussiness, inconsolable crying, emesis, diarrhea, or upper respiratory infection symptoms in the girl. The neonate had been feeding well, taking 30 mL of formula every 2 to 3 hours, and producing 6 to 8 wet diapers per day.

The patient had been born to a 24-year-old mother at 39 weeks and 5 days of gestation via spontaneous vaginal delivery with vacuum assist for nonreassuring fetal heart tones. She was small for gestational age with intrauterine tobacco exposure; the maternal history was significant for poor weight gain during pregnancy. Results of prenatal screening, including for group B streptococcus, HIV, rubella, gonorrhea/chlamydia, and syphilis, were negative.

Measurements at birth included the following: weight, 2570 g (6th percentile); head circumference, 34 cm (31st percentile); and length, 46 cm (3rd percentile).

The girl had had an uncomplicated nursery course and had been discharged home with her mother 2 days after delivery.

Physical Examination

In the ED, examination demonstrated an afebrile newborn with stable vital signs, a weight of 2740 g (11th percentile), and no change in head circumference or length from birth. She was well appearing and resting comfortably in her mother’s arms. The head was atraumatic, and the anterior fontanelle was soft and flat. She had good suck, good tone, a normal Moro reflex, and a positive Babinski sign bilaterally. The rest of the physical examination findings were unremarkable.

Laboratory Tests

Laboratory evaluation showed the following values: total calcium, of 6.5 mg/dL; ionized calcium, 0.8 mmol/L; serum phosphate, greater than 12 mg/dL; glucose, 79 mg/dL; and sodium, 138 mEq/L. The rest of the chemistry panel findings were unremarkable. Results of a liver function panel were within normal limits, with an albumin level of 3.4 g/dL.

The patient was admitted to the general pediatric floor, where she had another episode of generalized convulsions lasting about 10 seconds. Levels of intact parathyroid hormone (PTH) and magnesium were within normal range (32.1 pg/mL and 1.5 mg/dL, respectively). Intravenous (IV) calcium gluconate, 100 mg/kg, was administered twice while on a cardiorespiratory monitor in an attempt to replace her calcium. She then was started on oral calcium supplements at a dose of 100 mg/kg/d.

Her vitamin D level was found to be low at 14 ng/mL, and she was started on replacement vitamin D, 8000 IU daily. Once stable, she was allowed to take an oral electrolyte solution, and then was transitioned to an infant formula with a high calcium content and a low phosphorus content.

A consultant endocrinologist recommended serial monitoring of her calcium and phosphate levels. A neurologist was consulted, and the results of 24-hour video electroencephalography were normal. No other imaging studies were indicated.

The patient received a diagnosis of transient neonatal hypocalcemia.

Discussion

Calcium circulates within the plasma in 3 different forms. Approximately 40% is bound to serum proteins, approximately 10% is complexed with anions such as citrate, and approximately 50% circulates as the active, free ionized form.

Neonatal hypocalcemia is defined as a total calcium level of less than 8 mg/dL in full-term newborns or less than 7 mg/dL in preterm newborns, and an ionized calcium level from less than 1.0 mmol/L to 1.3 mmol/L in both full-term and preterm newborns. Neonatal hypocalcemia often presents asymptomatically, and therefore its prevalence is believed to be underreported.^1,2 When neonatal hypocalcemia is symptomatic, as in the case of the newborn described here, patients often present with neuromuscular excitability, resulting in myoclonic jerks that are referred to as tetany or drug-resistant seizures, as well as apnea, cyanosis, or cardiac arrhythmias.³

During pregnancy, calcium is transferred from maternal circulation to the fetus, resulting in higher fetal calcium levels. Postnatally, after the placental supply of calcium has been removed, calcium levels decline naturally in the neonate, and hypocalcemia self-resolves in the first week of life.⁴ An exaggeration of this hypocalcemia in the first 3 to 4 days of life is believed to be the cause of early neonatal hypocalcemia. It often occurs in preterm infants, infants of diabetic mothers, infants with asphyxia, and infants with intrauterine growth restriction.⁵

Late hypocalcemia occurs after the third or fourth day of life, usually toward the end of the first week. The most common cause is immature parathyroid glands, which results in intolerance of the phosphorus content in milk-based formula. This condition is suggested by an elevated phosphate level and low or inappropriately normal PTH levels, as observed in our patient’s case.

Differential Diagnosis

The differential diagnosis of transient neonatal hypocalcemia includes PTH resistance, vitamin D deficiency, and DiGeorge syndrome.⁵

PTH increases calcium circulation by targeting kidneys and bone. PTH acts on the renal distal tubules to increase calcium reabsorption and stimulates 1α-hydroxylase, which helps convert vitamin D to its active form. Vitamin D then increases the absorption of calcium via the gastrointestinal tract. PTH also mobilizes calcium from the bone. In PTH resistance, also known as pseudohypoparathyroidism, genetic mutations cause the target organs to be unresponsive to the circulating PTH, resulting in an elevated PTH level in relation to the amount of hypocalcemia.⁶

Vitamin D is an essential nutrient that has an important role in calcium homeostasis, affecting bone growth and development. It promotes calcium and phosphorus absorption via the gastrointestinal tract. One study⁷ found the prevalence of vitamin D deficiency among infants and toddlers to be approximately 12%, with exclusive breastfeeding without supplementation in infants and decreased milk intake in toddlers as the leading related predictors. A recent study⁵ of 78 severely hypocalcemic and hyperphosphatemic infants found vitamin D levels deficient or insufficient in all 42 infants whose vitamin D level was evaluated. This may suggest that higher vitamin D levels might be protective against hypocalcemia.⁵

DiGeorge syndrome is associated with a chromosomal deletion at 22q11.2, affecting the development of the pharyngeal pouch system. This results in hypoplasia of the thymus and parathyroid glands; a series of structural anomalies of the great vessels; esophageal atresia; bifid uvula; congenital heart disease; mandibular hypoplasia; and low-set, notched ears. Children with the syndrome often present in the neonatal period with hypocalcemic seizures. Aside from hypocalcemia and tetany, our patient did not display any dysmorphic features suggestive of DiGeorge syndrome.⁶

Management

The treatment of late neonatal hypocalcemia depends on its etiology. No established protocol currently exists outlining the treatment of acute hypocalcemia in neonates. In symptomatic infants, it is essential to administer IV calcium to establish a calcium concentration above symptom threshold. Common treatment includes IV administration of calcium gluconate, 10% (100 mg/kg or 1 mL/kg IV), infused over 5 to 10 minutes, while the patient is maintained on a cardiorespiratory monitor to evaluate for arrhythmias, and the infusion site is closely monitored. An IV calcium infusion should be considered in order to maintain appropriate calcium levels.^3,5

Outcome of the Case

The newborn’s calcium and phosphate levels normalized, and oral calcium supplements were discontinued. She was observed for another 24 hours off calcium supplements, during which time she remained seizure free, and her calcium and phosphate levels normalized (at discharge, her calcium level was 8.8 mg/dL and her phosphate level was 8.7 mg/dL). She was discharged home on a multivitamin and regular formula, with close follow-up.

Karolina Maksimowski, MD, is a resident in the Department of Pediatrics at MetroHealth Medical Center in Cleveland, Ohio.

David Effron, MD, is an assistant professor of emergency medicine at Case Western Reserve University, an attending physician in the Department of Emergency Medicine at MetroHealth Medical Center, and a consultant emergency physician at the Cleveland Clinic Foundation, all in Cleveland, Ohio.

References:

1. Wandrup J. Critical analytical and clinical aspects of ionized calcium in neonates. Clin Chem. 1989;35(10):2027-2033.
2. Brown DM, Boen J, Bernstein A. Serum ionized calcium in newborn infants. Pediatrics. 1972;49(6):841-846.
3. Zhou P, Markowitz M. Hypocalcemia in infants and children. Pediatr Rev. 2009;30(5):190-192.
4. McKay CP. Disorders of calcium metabolism. In: Feld LG, Kaskel FJ, eds. Fluid and Electrolytes in Pediatrics: A Comprehensive Handbook. New York, NY: Humana Press; 2010:105-147.
5. Thomas TC, Smith JM, White PC, Adhikari S. Transient neonatal hypocalcemia: presentation and outcomes. Pediatrics. 2012;129(6):e1461-e1467.
6. Kliegman RM, ed. Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders Elsevier, 2007:884-886,2344-2345.
7. Gordon CM, Feldman HA, Sinclair L, Williams AL, Kleinman PK, Perez-Rossello J, Cox JE. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008;162(6):505-512.