Case 1: Neonate with seizures and hypocalcemia

A 10-day-old boy born in September was admitted with new-onset focal seizures. In the previous six days, his parents had noted left-sided arm and leg twitching, right-sided head turning and lip smacking. These episodes lasted for approximately 30 s, and their frequency had increased to seven times per hour before admission. There was no history of fever, trauma, sick contacts or neonatal sepsis risk factors. The baby was breastfed and supplemented with formula.

The pregnancy was unremarkable and the baby was born at term by an uncomplicated caesarian section because of a previous caesarian section. His birth weight was 4.1 kg (75th to 95th percentile). The mother was originally from Ecuador. The boy’s family history was otherwise noncontributory.

On admission, focal seizures, as described, were witnessed. The baby’s weight was 4.1 kg. He was afebrile with normal vital signs. He had no dysmorphic features and his physical examination was otherwise unremarkable.

Initial blood work showed normal renal function and electrolytes, with hypocalcemia (total calcium 1.80 mmol/L [normal 1.96 mmol/L to 2.66 mmol/L] and ionized calcium 0.82 mmol/L [normal 1.14 mmol/L to 1.29 mmol/L]) and hyperphosphatemia 3.30 mmol/L (normal 1.62 mmol/L to 3.10 mmol/L). His blood glucose level was within normal limits at 4.3 mmol/L.

The diagnosis was revealed after further maternal history and blood tests.

CASE 1 DIAGNOSIS: HYPOCALCEMIC SEIZURES SECONDARY TO MATERNAL AND INFANT VITAMIN D DEFICIENCY

On further investigation, the mother was noted to have a diet low in calcium and she reported not taking any antenatal vitamin supplements. She also reported always wearing sunscreen when outdoors. The baby had not been started on vitamin D supplements.

Vitamin D deficiency in the infant was diagnosed on the basis of a low 25-hydroxy vitamin D level of 13 mmol/L (normal 27 mmol/L to 110 mmol/L), with a normal 1,25-hydroxy vitamin D level of 173 pmol/L (normal 39 pmol/L to 193 pmol/L). A low 25-hydroxy vitamin D level indicates that vitamin D stores are low, while a normal 1,25-hydroxy vitamin D level confirms that the child is able to convert vitamin D to its active form. The infant’s parathyroid hormone (PTH) level was appropriately elevated at 70 ng/L (normal 10 ng/L to 65 ng/L). Urine calcium to creatinine ratio, head ultrasound, electroencephalography and fluorescent in situ hybridization for 22q deletion were all normal. There was no clinical or radiological evidence of rickets.

Maternal investigations demonstrated a total calcium level of 2.27 mmol/L (normal 2.19 mmol/L to 2.60 mmol/L), 25-hydroxy vitamin D level of 16 nmol/L (normal 17 nmol/L to 95 nmol/L) and an elevated PTH level of 88 ng/L (normal 10 ng/L to 65 ng/L), confirming the diagnosis of vitamin D deficiency in the mother.

The baby was managed with an intravenous calcium gluconate infusion, oral calcium, vitamin D and calcitriol (1,25-dihydroxy vitamin D). The seizures resolved within 48 h of admission. The results of a full septic workup were negative.

The differential diagnosis of hypocalcemia presenting after the first week of life in term, normal weight neonates includes:

• Hypoparathyroidism (impaired synthesis [eg, 22q deletion syndrome] or secretion);

• Vitamin D deficiency (reduced intake or production);

• Maternal hyperparathyroidism (fetal hypercalcemia leads to infant suppression of PTH);

• Ill neonate;

• Hypomagnesemia (causes resistance to PTH); and

• High phosphate intake (antagonizes PTH).

Clinical manifestations of neonatal hypocalcemia include:

• Jitteriness;

• Muscle jerking;

• Generalized or focal seizures;

• Stridor (secondary to laryngospasm);

• Wheezing (secondary to bronchospasm);

• Vomiting (secondary to pylorospasm); and

• Prolonged QTc (QT interval corrected for rate) on electrocardiogram.

Initial investigations in the present scenario should include PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, and urine calcium to creatinine ratio. Other diagnostic investigations include renal function tests and plain x-rays (wrist or knee) looking for signs of rickets. Maternal calcium, 25-hydroxy vitamin D and PTH levels should also be obtained.

Vitamin D deficiency in infants and mothers is a re-emerging public health issue. In one Canadian study (1), 46% of healthy mothers and 36% of their newborn term infants were found to have plasma 25-hydroxy vitamin D levels consistent with deficiency. Our infant presented with symptomatic hypocalcemia at an unusually young age. This is likely due to the profound degree of maternal hypovitaminosis D. Although the mother was pale-skinned (believed to be protective in this condition), she reported always wearing sunscreen outdoors. Sunscreen with a sun protection factor of 8 reduces cutaneous production of vitamin D by 98%.

There is no current consensus for maternal vitamin D requirements during pregnancy and lactation; however, the Society of Obstetricians and Gynecologists of Canada recommends 400 U/day for pregnant women. For pregnant and breastfeeding mothers living above the 55th parallel, the Canadian Paediatric Society recommendation is to increase vitamin D intake to 800 U/day between October and April. One commonly used prenatal vitamin contains 400 U/day of vitamin D.

The infant was discharged home on oral calcium, calcitriol and vitamin D. At follow-up, two weeks after discharge, he remained clinically well and seizure-free. Total and ionized calcium were slightly elevated, but phosphate, magnesium, PTH and vitamin D levels were within normal limits. The calcium and calcitriol doses were weaned, while vitamin D supplements were continued.

Our infant, like others reported in the literature, presented with symptomatic hypocalcemia without evidence of rickets. Vitamin D replacement from birth would likely not have prevented the seizure, but maternal supplementation in the last trimester of pregnancy may have been effective. The long-term impact of vitamin D deficiency during fetal development, as well as the most appropriate dose of vitamin D supplementation for pregnant and breast-feeding mothers, remains an area of ongoing research (2).

CLINICAL PEARLS

• Symptomatic hypocalcemia without evidence of rickets may present in the early neonatal period.

• Risk factors for neonatal vitamin D deficiency secondary to maternal hypovitaminosis D include having a mother with dark skin, being born in the winter months, living at extremes of latitude, maternal diet low in vitamin D during pregnancy and lactation, and lack of maternal sun exposure.

• Initial investigations of infants at risk should include PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, and urine calcium to creatinine ratio. Maternal PTH, calcium and 25-hydroxy vitamin D levels should also be obtained.

• The current recommendation of vitamin D in pregnancy and for breastfeeding mothers is 400 U/day. For those residing above the 55th parallel, vitamin D intake should be increased to 800 U/day between October and April.

• The Canadian Paediatric Society guidelines recommend vitamin D supplements for all breastfed babies (400 U/day) to begin at birth and continue until the infant is 12 months of age. For those residing above the 55th parallel, vitamin D intake should be increased to 800 U/day between October and April.