Neonatal hypocalcaemic seizures unmasking asymptomatic maternal primary hyperparathyroidism

Abstract

Hypocalcaemia is a common cause of neonatal seizures. Here, we present a breastfed neonate with smooth perinatal transition and no family history of seizures presenting at 3 weeks with recurrent multifocal clonic seizures. On evaluation, the neonate was found to have low iCa and total calcium. 25-hydroxy vitamin D (25(OH)D) level was low and intact parathyroid hormone (iPTH) was inappropriately normal. The maternal evaluation revealed high calcium and low phosphate levels. iPTH was very high and 25(OH)D was very low in the mother. Sestamibi scan showed a left inferior parathyroid adenoma in the mother. Maternal primary hyperparathyroidism causing hypercalcaemia can suppress parathyroid activity in the fetus, resulting in inappropriate parathyroid response to hypocalcaemia after birth causing recurrent hypocalcaemic seizures. So neonatal hypocalcaemic seizures need careful evaluation of the neonate and the mother at times and can help both mother and neonate.

Background

Primary hyperparathyroidism (PHP) during pregnancy is a very rare event that increases maternal and perinatal morbidity and mortality. The prevalence of PHP in women of childbearing age is estimated to be approximately eight cases per 100 000 per year.¹ Most cases are diagnosed during pregnancy.² Maternal PHP causing hypercalcaemia during pregnancy can suppress fetal and neonatal parathyroid hormone (PTH) secretion.³ Consequently, transient neonatal hypoparathyroidism can occur in a neonate born to a mother with untreated hyperparathyroidism. Transient suppression of fetal parathyroid development may result in severe neonatal hypocalcaemia that leads to seizures. As most affected mothers are asymptomatic, neonatal hypocalcaemic seizures may be the first manifestation of the underlying maternal PHP.⁴

Case presentation

A male neonate presented with 15 episodes of multifocal clonic seizures of the left upper and lower limb associated with eye blinking and lip-smacking movement lasting 1–2 min beginning on the 23rd day of life. It was not associated with fever, poor feeding or lethargy. Physical examination revealed an active, afebrile baby with a normal facial appearance. There was no history of trauma or clinical signs of infection.

He was born at 36+6 weeks following preterm premature rupture of membranes via vaginal delivery with a birth weight of 2256 g. The neonate had a smooth perinatal transition with APGAR scores of 8 and 9, had unconjugated hyperbilirubinaemia requiring phototherapy for 24 hours and was discharged on day 5 of life. The neonate was exclusively breast fed and was receiving 400 IU of vitamin D₃ from birth. The metabolic investigations for seizure revealed normal blood glucose 96 mg/dL (normal range: 60–180 mg/dL), low serum total calcium level 5.25 mg/dL (normal range: 8.5–10.5 mg/dL) with low ionised calcium (iCa) 0.7 mmol/L (normal range: 1.05–1.37 mmol/L), high serum phosphate 8.02 mg/dL (normal range: 2.7–4.5 mg/dL) and high alkaline phosphatase (ALP) 1005 U/L (48–406 U/L). On ECG, QTc (corrected QT interval) was prolonged to 0.55 s (normal <0.45 s). His PTH level was inappropriately normal at 48.3 pg/mL (normal range: 10–65 pg/mL) and 25(OH)D levels were low at 4.08 ng/mL (normal range: 20–50 ng/mL). Kidney function tests (blood urea/serum creatinine) were normal at 5/0.3 mg/dL (normal range blood urea: 3–18 mg/dL, serum creatinine: 0.2–0.9 mg/dL) (table 1). Mother, 25 years old was clinically asymptomatic. Neonatal hypocalcaemic seizures with abnormally normal iPTH levels guided us to go for maternal investigations. The mother’s evaluation revealed a high serum calcium level of 11.9 mg/dL (normal range: 8.8–10.3 mg/dL) with a low serum phosphate level of 2.1 mg/dL (normal range: 2.6–4.5 mg/dL) and serum ALP level was 217 U/L (normal range: 44–147 IU/L) (table 2). The urinary calcium creatinine ratio was elevated to 1.4 (normal range <0.14); however, no evidence of nephrocalcinosis on sonography was found. iPTH level was elevated to 498 pg/mL (normal range: 10–55 pg/mL), while the 25(OH)D level was low at 4 ng/mL (normal range: 20–40 ng/mL).

Table 1.

Infant’s investigations

	Day 24	Day 37 (discharge)	Day 72 (stopped supplement)	Day 96	1 year
C reactive protein (mg/dL)	1.3
Urea/serum creatinine (mg/dL)	5/0.33
Ionised calcium (mmol/L)/total calcium (mg/dL)	0.7/5.2	0.9/7.8	1.2/9.7	1.2/10.6	1.2/10.3
Phosphate (mg/dL)	8.02	8.5	5.04	6.13	5.6
Alkaline phosphatase (IU/L)	1005	954	552	423	308
25 Hydroxy vitamin D (ng/dL)	4.08	11.2	43.5	62.9	36.5
iPTH (pg/mL)	48.3	75.3	60.8	44.8	72.5
Ionised magnesium (mmol/L)	0.35
Total protein/albumin (gm/dL)	4.7/3.1
Urinary calcium (mg/dL)	0.95
Urinary creatinine (mg/dL)	6.09
Urinary calcium creatinine ratio	0.15
USG cranium	Normal

iPTH, intact parathyroid hormone.

Table 2.

Maternal investigations

	Day 25 post partum	1 Year post partum (pre-surgery)	Postsurgery at discharge
Urea/serum creatinine (mg/dL)	16/0.6
Total calcium (mg/dL)	11.9	13.77	8.97
Phosphate (mg/dL)	2.1	2.54	4.54
Alkaline phosphatase (IU/L)	217
25 Hydroxy vitamin D (ng/dL)	4		13.8
iPTH (pg/mL)	498.9	673.3	20.5
Total protein/albumin (gm/dL)	7.2/3.8
Urinary calcium (mg/dL)	8.94
Urinary creatinine (mg/dL)	39.06
Urinary calcium–creatinine ratio	1.4
USG neck	Normal
USG kidneys	No nephrocalcinosis

iPTH, intact parathyroid hormone.

Differential diagnosis

Before seizure episodes, the baby was well-looking and accepted breast feeding. The sepsis screen was negative; the clinical course and examination did not favour sepsis either. The blood culture was also sterile.

Baby did not have any associated anomaly, his chest X-ray (thymus shadow present) and Echo 2D (no cardiac anomaly) were normal, ruling out DiGeorge syndrome. Urinary calcium and creatinine ratio was normal at 0.15 (normal range: 0.013–1.17) and iPTH was normal in presence of hypocalcaemia, so possibility of autosomal dominant hypocalcaemia was also kept but was ruled out later as the baby had normal calcium levels after stopping supplements also.⁵ Vitamin D deficiency alone could not explain the picture as calcium was low while phosphate was high in the newborn, and both should be low in vitamin D deficiency. High phosphate load was ruled out as the baby was exclusively breast fed, and no phosphate supplement or animal milk was given. Hypomagnesaemia was ruled out as ionised magnesium levels were normal. The possibility of familial hypocalciuric hypercalcaemia (FHH) in mother was also considered but there was no family history, iPTH was very high as compared with mild elevation expected in FHH and urine calcium creatinine ratio was high (though postpartum).⁶

Treatment

The baby was initially managed with intravenous calcium gluconate 20 mg/kg bolus followed by 80 mg/kg/day for 2 days. As the baby remained seizure-free post 6 hours of admission (two episodes in hospital), so later shifted to oral calcium (calcium carbonate; 150 mg/kg/day) and oral 25(OH) vitamin D (cholecalciferol; 2000 IU OD) and discharged on oral supplements after 15 days as reports were in improving trend and baby remained seizure-free.

The mother was started on oral vitamin D 60 000 units/week and a sestamibi scan was planned for evaluation of suspected primary hyperparathyroidism.

Outcome and follow-up

For the baby: vitamin D and calcium were discontinued after 2 months as reports normalised. After stopping vitamin D and calcium supplements, the baby’s calcium, phosphate and vitamin D levels remained normal (Ca: 10.6 mg/dL, P: 6.13 mg/dL). The infant’s growth and development was appropriate for age at 1 year.

For the mother: the sestamibi scan showed a left inferior parathyroid adenoma (figure 1). She underwent left inferior parathyroid excision (1.5×1 cm) at 1 year post partum and is doing fine with normal calcium, phosphate and iPTH values postsurgery.

Figure 1.

Sestamibi parathyroid scan showing left inferior parathyroid adenoma in mother (arrow).

Discussion

The physiological nadir in neonatal serum calcium concentrations occurs 24–48 hours after birth.⁷ Early-onset hypocalcaemia occurs within 72 hours of life while late-onset hypocalcaemia develops after the first 72 hours and towards the end of the first week of life.⁷ Increased serum calcium levels in the mother due to unrecognised hyperparathyroidism result in fetal hypercalcaemia, which in turn leads to suppression of parathyroid gland activity in the fetus, resulting in impaired parathyroid responsiveness to hypocalcaemia after birth. This results in hypocalcaemia in the newborn, which may be severe and prolonged.⁴ The seizures can occur early with 24–48 hours nadir as well as late-onset when the metabolic demands of the baby for growth increase.⁸ Moreover, neonatal seizure is difficult to recognise at times, hence can result in a delay in reporting to the hospital. Vitamin D cannot be synthesised by fetus, so transfer from mother across placenta is essential. Vitamin D deficiency in newborn results from poor maternal vitamin D stores, exclusive breast feeding without supplements and limited sun exposure. Vitamin D deficiency can further exaggerate hypocalcaemia.⁹ Thus, this should be kept in mind while evaluating a healthy newborn with late-onset hypocalcaemic seizures. Maternal primary hyperparathyroidism is difficult to diagnose early in pregnancy as the symptoms are usually subtle.

Patient’s perspective.

I am happy that doctors could not only treat my baby’s seizures due to calcium deficiency but also diagnose my asymptomatic parathyroid tumor which could have affected my kidneys, bones etc. and future pregnancies over time. I was happy with the interdepartmental cooperation of doctors for my nuclear scan and surgery and also for my child being regularly followed up for growth and development (from mother).

Learning points.

• Healthy neonates can present as neonatal seizure due to hypocalcaemia.

• Neonatal hypocalcaemia evaluation should involve maternal investigations if hypoparathyroidism is suspected.

• Maternal vitamin D deficiency and calcium abnormalities should be addressed in antenatal visits as they can impact the fetus.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).