Pediatric Neurology 48 (2013) 469e471

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Pediatric Neurology
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Case Report

Neonatal Hypocalcemic Seizures Due to Excessive Maternal Calcium Ingestion

Jenna F. Borkenhagen BS a, Ellen L. Connor MD b, Carl E. Stafstrom MD, PhD c, *
a

University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Pediatric Endocrinology, University of Wisconsin School of Medicine and Public Health and American Family Childrens Hospital, Madison, Wisconsin
c
Pediatric Neurology, University of Wisconsin School of Medicine and Public Health and American Family Childrens Hospital, Madison, Wisconsin
b

article information

abstract

Article history:
Received 17 January 2013
Accepted 15 February 2013

Hypocalcemia is a common, treatable cause of neonatal seizures. A term girl neonate with no
apparent risk factors developed seizures on day 5 of life, consisting of rhythmic twitching of
all extremities in a migrating pattern. Physical examination was normal except for jitteriness.
Laboratory evaluation was unremarkable except for decreased total and ionized serum
calcium levels and an elevated serum phosphorus level. The mother had ingested 3-6 g of
calcium carbonate daily during the nal 4 months of pregnancy to control morning sickness.
The babys electroencephalogram showed multifocal interictal sharp waves and intermittent
electrographic seizures consisting of focal spikes in the left hemisphere accompanied by
rhythmic jerking of the right arm and leg. Treatment with intravenous calcium gluconate over
several days resulted in cessation of seizures and normalization of serum calcium. The child
has remained seizure free and is normal developmentally at 9 years of age. Hypocalcemic
seizures in this newborn were likely secondary to excessive maternal calcium ingestion,
which led to transient neonatal hypoparathyroidism and hypocalcemia. Inquiry about
perinatal maternal medication use should include a search for over-the-counter agents that
might not be thought of as drugs, as in this case, antacids.
2013 Elsevier Inc. All rights reserved.

Introduction

Newborns with seizures usually have identiable seizure

risk factors, including hypoxic-ischemic injury, hemorrhage, and metabolic disturbances. Hypocalcemia is
a frequent and treatable cause of neonatal seizures, with
numerous possible etiologies, typically categorized by
postnatal age (Table) [1,2]. This article presents an otherwise healthy newborn who developed hypocalcemic
seizures on day 5 of life caused by excessive maternal
calcium ingestion during pregnancy.
Case Report
A 5-day-old girl presented with episodes of choking and gagging with
feedings, followed by rhythmic independent twitching of both arms and
legs. There was no loss of consciousness, fever, cyanosis, or abnormal eye
* Communications should be addressed to: Dr. Stafstrom; Department
of Neurology; University of Wisconsin; UWMF Centennial Building;
1685 Highland Avenue; Madison, WI 53705.
E-mail address: stafstrom@neurology.wisc.edu
0887-8994/$ - see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2013.02.010

movements. She had not received any medications at home. In the

emergency department, she had seven witnessed seizures, lasting from
30 seconds to 6 minutes; the longer seizures were associated with
oxygen desaturation to 70-80%. Between seizures, she was alert and
appeared normal.
Prenatal ultrasound was normal. Pregnancy was complicated by dietcontrolled gestational diabetes and severe morning sickness during all
trimesters. The mother reported that her only medication was prenatal
vitamins. The infant was born vaginally at 41 weeks gestation weighing
4400 g (>95th percentile for gestational age). Delivery was complicated
by mild meconium staining, without need for suction or resuscitation.
Apgar scores were 7 at 1 minute and 8 at 5 minutes. The Wisconsin
Newborn Screen was normal. The baby was discharged home on day 2 of
life and she initially fed well, taking 3-4 oz of Similac with Iron every 3
hours. There was no fever or other signs of illness.
Family history was negative for epilepsy (including neonatal
seizures), birth defects, renal disease, hypoparathyroidism, and metabolic disorders, including hypoglycemia and hypocalcemia. Three older
siblings were healthy.
Initial physical examination revealed an alert, vigorous, slightly
jittery but easily consolable infant. Weight was 4.8 kg (>95th percentile)
and head circumference was 37.2 cm (95th percentile). She was afebrile
with normal vital signs. Fontanels were soft and at. There was no
dysmorphism or jaundice. The remainder of the general physical

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J.F. Borkenhagen et al. / Pediatric Neurology 48 (2013) 469e471

Table. Common causes of neonatal hypocalcemia by age

Early (days 1-3)

Late (days 4-10)

Congenital

Perinatal asphyxia, stress

Prematurity
Low birth weight
Maternal diabetes
Maternal hyperparathyroidism

Vitamin D insufciency
Increased phosphate load
Hypomagnesemia
Hypoparathyroidism
Parathyroid hormone resistance

Parathyroid gland hypoplasia including DiGeorge and other

velocardiofacial syndromes
Metabolic syndromes

Kearns-Sayre syndrome and other mitochondrial disorders

Kenny-Caffey syndrome (tubulin folding mutation)

Iatrogenic causes

examination was normal. Likewise, her neurologic examination was

normal except for intermittent jitteriness.
Initial laboratory ndings revealed total calcium 7.2 mg/dL (normal,
8.5-10.2), ionized calcium 3.96 mg/dL (normal, 4.9-5.6), magnesium 1.4
mg/dL (normal, 1.3-2.0), and phosphorus 7.7 mg/dL (normal, 3.9-6.9).
Electrolytes, glucose, serum urea nitrogen, creatinine, albumin, alkaline
phosphatase, total and direct bilirubin, liver transaminases, amylase,
ammonia, hemogram, and venous blood gas were normal. Urine toxin
screen was negative for amphetamines, barbiturates, benzodiazepines,
cocaine metabolites, phencyclidine, and opiates. A head computerized
tomography scan was normal.
Initial electroencephalogram revealed interictal sharp transients
independently in the left frontal, right frontal, left central, and left
midtemporal regions. During sleep, an 8-minute electroclinical seizure
occurred, with high-voltage, rhythmic spike-wave discharges beginning
in the left central vertex region with spread into the left posterior
temporal, left parietal, and right parietal regions. The seizure semiology
began as right foot jerking with subsequent rhythmic jerks of each arm
and leg independently.
On further inquiry, the mother admitted ingesting a large quantity of
Tums E-X (calcium carbonate) to treat her morning sickness. Specically,
she took 10-15 tablets each day during months 5-8 of gestation, and 1520 tablets each day during the nal month of pregnancy. Each calcium
carbonate tablet contains 750 mg of calcium carbonate, or 300 mg of
elemental calcium. Therefore, her estimated daily calcium intake was 3-6
g (the tolerable upper limit for calcium intake is 2.5 g [3]).
The proximate cause of this infants seizures was considered to be
hypocalcemia. Antiepileptic drugs were not administered. A lumbar
puncture was not performed and a more comprehensive search for an
inborn error of metabolism was deferred, but additional studies were
obtained to evaluate hypocalcemia. On hospital day 2, the babys 25hydroxy vitamin D level was 31 ng/mL and the 1,25-dihydroxy vitamin
D level was 8 pg/mL (both normal). The mother had a serum calcium of
9.0 mg/dL, phosphorus of 3.9 mg/dL, and intact parathyroid hormone
(PTH) of 27 pg/mL (she had not ingested any calcium carbonate since
giving birth 5 days previously). The infants rst available intact PTH, on
hospital day 3, was 36 pg/mL (normal), at which time the ionized
calcium was 5.20 mg/dL. Brain magnetic resonance imaging on the baby
was normal. Two subsequent electroencephalograms and a 24-hour
video electroencephalogram were normal, with no interictal or ictal
abnormalities. An electrocardiogram was normal.
Calcium gluconate 10% was administered intravenously for 3 days to
normalize serum calcium. The infant was also supplemented with
magnesium, which is needed for adequate secretion of PTH. Over the rst
48 hours, the infant continued to have intermittent brief focal seizures,
with ionized calcium uctuating between 4.5 and 5.3 mg/dL. She remained
afebrile and vigorous and fed without difculty. Her serum calcium gradually normalized, and her jitteriness, seizures, and tetany episodes declined
and then resolved. Calcium supplementation was switched to an oral
preparation, calcitriol was added to improve the intestinal absorption of the
oral calcium, and her formula was switched to PM 60/40, a low-phosphorus
formula, owing to a persistent elevation of serum phosphorus. The calcium
supplements and PM 60/40 were discontinued when the child was 4
months old, at which time her total calcium was 11.2 mg/dL and

Citrated blood products

Lipids
Glucocorticoids
Alkalosis
Diuretics

phosphorus was 6.5 mg/dL. The baby had no seizures after the perinatal
period. She is now 9 years old with normal development and cognition.

Discussion

Seizures occur in up to 1.5% of newborns, depending on

gestational age. Neonatal seizures usually reect signicant
nervous system pathology or metabolic derangement, and an
extensive search for an etiology is warranted [4]. The most
common causes of neonatal seizures are hypoxic-ischemic
encephalopathy and intracranial hemorrhage or thrombosis. Other etiologies include central nervous system
infection; acute metabolic disorders such as hypocalcemia,
hypoglycemia, hypomagnesemia, and hypo- or hypernatremia; genetic conditions including inborn errors of
metabolism; mitochondrial disorders; neurocutaneous
disorders; and toxins. Diagnoses of exclusion include benign
familial neonatal convulsions and benign idiopathic neonatal
convulsions, the latter termed fth-day ts because of their
propensity to present on the fth postnatal day.
Based on the age of seizure presentation in the neonate in
this study, day 5 of life, the most likely etiologies were
central nervous system infection, hemorrhage, inborn
error of metabolism, hypocalcemia, and benign neonatal
convulsions. As the baby was afebrile and well appearing,
with a normal brain magnetic resonance image and normal
newborn screening, the rst three etiologies were unlikely.
There was no family or clinical history to suggest the familial
or idiopathic types of benign neonatal seizures. Laboratory
results and the striking maternal history of calcium ingestion in the third trimester implicated hypocalcemia as the
most probable seizure etiology in this infant.
Hypocalcemia in the newborn can present with a variety
of symptoms, including tetany, laryngeal spasm, seizures,
myocardial dysfunction, and apnea. In the patient in this
study, the episodes of choking or gagging prior to the
seizures were consistent with tetany of the vocal cords,
causing laryngeal spasms. Infants of diabetic mothers are at
increased risk for hypocalcemia, although in this case, the
mothers gestational diabetes was easily controlled with
diet. Hypocalcemic seizures are often clonic, as in the patient
in this study, with shifting focality [5]. Despite hypocalcemia
being a diffuse metabolic derangement, hypocalcemic
seizures are often multifocal (not generalized), possibly
related to the neonatal brains underdeveloped neural
pathways that prevent seizure generalization. In addition,
areas of the developing brain might be differentially prone to
hyperexcitability.

J.F. Borkenhagen et al. / Pediatric Neurology 48 (2013) 469e471

The differential diagnosis of neonatal hypocalcemia is

broad, with etiologies categorized according to time of
onset (Table 1) [1,6]. In the past, infant formula as well as
an unmodied cows milk diet contained signicantly
elevated levels of phosphorus, which was a frequent
cause of neonatal hypocalcemia and subsequent seizures
[1]. The ratio of calcium to phosphorus in modern infant
formula more closely resembles breast milk, dramatically
reducing this cause of neonatal hypocalcemia. In addition
to the iatrogenic causes listed in the Table, excessive
prenatal calcium intake by the mother can cause neonatal
hypocalcemia.
In this instance, the hypocalcemia was probably
secondary to transient neonatal hypoparathyroidism in
response to maternal calcium excess, but this hypothesis
lacks denitive proof, because there was no laboratory
documentation of maternal hypercalcemia, maternal
hyperparathyroidism, or infantile hypoparathyroidism. The
fetus was exposed to high calcium levels because of
maternal hypercalcemia combined with active transplacental transport of calcium, resulting in suppression of
fetal parathyroid gland function. The transient hypoparathyroidism in the infant subsequently exacerbated the expected postnatal decline in the babys serum calcium and an
elevation in the serum phosphorus by 4 to 5 days of life.
Although there was no verication of maternal hypercalcemia or altered PTH (the mother had ingested no calcium
carbonate since delivery), there are ample case reports of
calcium carbonateeinduced hypercalcemia [7]. In a similar
clinical case [8], a mother ingested 10-14 Tums E-X daily
from the midrst trimester until the onset of labor. That
infant, who presented with seizures on day 8 of life, had an
initial total serum calcium of 6.3 mg/dL. Other causes of
neonatal hypocalcemia were excluded. The maternal
calcium level as well as phosphorus and parathyroid
hormone levels were normal by the time that infant presented with hypocalcemic seizures [8]. The babys hypocalcemia and seizures resolved with intravenous calcium
gluconate. Therefore, neonatal hypocalcemia caused by
maternal prenatal calcium ingestion may be more common
than realized, warranting direct questioning about all
ingested products, both prescribed and over the counter.
The mechanism by which hypocalcemia causes seizures
is unclear. Calcium is necessary for numerous cellular
functions and plays a pivotal role in neurotransmitter
release and membrane excitability. Lowering extracellular
calcium would be predicted to decrease the release of both
excitatory and inhibitory neurotransmitters, and low
calcium causes epileptic discharges in hippocampal slices in
the absence of synaptic transmission [9], so calciums effect
on transmitter release is insufcient to explain seizure
occurrence. Likewise, inux of calcium through neuronal
voltage-dependent channels causes membrane depolarization, so a reduction of extracellular calcium might be
predicted to decrease rather than increase excitability. A
plausible explanation as to why hypocalcemia causes
seizures is decreased membrane surface charge screening;
a local decit of positive charges from calcium ions at the
external membrane surface reduces the transmembrane
voltage gradient and thus decreases the threshold for
depolarization. In addition, calcium ion accumulation at the
mouths of sodium channels might independently increase

471

excitability and lead to seizures [10]. Other mechanisms by

which low extracellular calcium can increase neuronal
excitability include induction of neuronal burst ring due to
enhancement of the persistent sodium current [11,12];
reduction in neuronal after hyperpolarizations, leading to
more rapid action potential ring [13]; and increased activation of sodium leak channels [14].
Conclusions

This report emphasizes the need to carefully assess all

ingested drugs, both prescription and nonprescription.
Hypocalcemic neonatal seizures respond readily to calcium
replacement, and if uncomplicated hypocalcemia is documented, an extensive search for infectious, structural, and
rare metabolic causes may not be necessary. Fortunately, as
in this case, the prognosis for hypocalcemic seizures is
usually excellent [15].
We dedicate this article to the memory of Todd S. Varness, MD, colleague and friend.

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