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Clin Pediatr EndocrinolClin Pediatr EndocrinolCPEClinical Pediatric Endocrinology0918-57391347-7358The Japanese Society for Pediatric Endocrinology 2018-000510.1297/cpe.27.187Case ReportVitamin D deficiency associated with dilated cardiomyopathy in early infancy
caused by maternal cholestasis Omotobara-Yabe Tomona 
1
Kuga Shuji 
1
Takeguchi Masahiro 
1
Ihara Kenji 
1
1  Department of Pediatrics, Oita University Faculty of
Medicine, Oita, JapanCorresponding author: Tomona Omotobara-Yabe, M.D., Department of Pediatrics, Oita
University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593,
JapanE-mail omotobara@oita-u.ac.jp31 7 2018 2018 27 3 187 192 08 2 2018 05 4 2018 2018©The Japanese Society for Pediatric
Endocrinology2018This is an open-access article distributed under the terms of the Creative
Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0:

http://creativecommons.org/licenses/by-nc-nd/4.0/）. Abstract.
Breast feeding is known to be a major cause of vitamin D deficiency in infants because
the content of vitamin D in breast milk is significantly lower than that in formula. We
report a case of a 1-mo-old boy who developed hypocalcemic seizures and dilated
cardiomyopathy caused by vitamin D deficiency despite being fed a sufficient amount of
regular formula. The cause of vitamin D deficiency in this case was maternal vitamin
deficiency due to severe hyperemesis and insufficient sunlight exposure, induced mainly by
the malabsorption of fat-soluble vitamins caused by maternal cholestasis. We should
carefully consider maternal conditions during pregnancy and the postpartum period to
detect and prevent vitamin D deficiency in the fetus and infant.

vitamin D deficiencyhypocalcemiaformuladilated cardiomyopathycholestasis
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Introduction
Vitamin D deficiency during pregnancy is sometimes observed and is mainly attributed to
decreased maternal intake of vitamin-D-containing foods and skin protection from sunlight
(1). Consequently, low vitamin D levels are
sometimes detected in the blood of pregnant women and in newborn cord blood as well.
Critical consequences of vitamin D deficiency in early infancy are rare when babies are fed
a formula containing vitamins. The content of vitamin D in formula ranges from 6.5 to 9.3 μg
in 100 g, which is 20 times more than that in breast milk (0.3 μg in 100 g) (2). Although the vitamin D content in formula in Japan is
lower than that recommended by Western guidelines, severe phenotypes of vitamin D deficiency
rarely develop in infants fed with regular formula.

We herein report a 1-mo-old boy who developed severe vitamin D deficiency, complicated by
hypocalcemic seizures and dilated cardiomyopathy, despite self-demand feeding with Japanese
regular formula. Extensive medical history-taking revealed that maternal cholestasis during
pregnancy played a critical role in the development of severe vitamin D deficiency in the
fetus and subsequent clinical symptoms in infancy.

Case Report
A Japanese boy was born at 37 wk 4 d of gestation by caesarean section. The neonate was
born without asphyxia but with a low birth weight (1,830 g) and was admitted to the neonatal
intensive-care unit. He was managed with regular formula and had appropriate weight gain.
Hypocalcemia was not detected during admission, and he was discharged at 24 d of age. The
laboratory and echocardiogram data at discharge were as follows: serum calcium, 9.2 mg/dl;
ionized calcium, 2.57 mEq/l, and normal wall motion with a left ventricular ejection
fraction of 78%. After discharge, he consumed regular formula well, and had appropriate
weight gain. However, he did not receive enough sunlight at home for about 1 mo.

At 48 d of age, he developed an afebrile seizure and was transferred to the pediatric
clinic of the regional emergency center. The blood test revealed hypocalcemia (Ca 5.5
mg/dl), and he was then transferred to our hospital. At the time of admission, he had
intermittent convulsions and continuous irritability. His measurements were as follows:
height, 48.0 cm (–2.18 standard deviations [SD]); weight, 3,700 g (Kaup index 16.1); and
head circumference, 38.0 cm (–0.71 SD). His body temperature was 36.5°C, with blood pressure
98/64 mmHg, heart rate 156/min, and percutaneous oxygen saturation 99%. Laboratory findings
demonstrated hypocalcemia (Ca 6.13 mg/dl), and high levels of alkaline phosphatase (ALP) and
intact PTH (ALP, 2,137 IU/l; intact PTH, 306 pg/ml). Further evaluation revealed severe
hypovitaminosis D, below the detection levels of serum vitamin D2 and D3 (Table 1Table
1 Laboratory data on admission at 48 days of
age
). Chest X-ray revealed no pulmonary congestion or
cardiomegaly, with a cardiothoracic ratio of 52% (Fig.
1aFig. 1. Chest X-ray. (a) At hospitalization (48 d of age).
(b) At 17 d of hospitalization (65 d of age): Cardiomegaly (cardiothoracic ratio 66%)
and pulmonary congestion were observed. (c) At 170 d of age. The cardiothoracic ratio
was almost normal (56%), and the permeability of both lung fields was
normalized.

). Wrist X-ray
showed no signs of rickets. Intravenous administration of calcium gluconate at 5 ml/kg/d
followed by oral calcium supplementation at 35 mg/kg/d and alfacalcidol at 0.15 μg/kg/d soon
stabilized his hypocalcemia. Serum intact PTH and phosphorus levels were normalized in a few
months (Fig. 2Fig. 2. Clinical
course of the infant. Convulsions manifested several times during the first week of
admission. At about 60 d of age, tachypnea gradually appeared, and dilated
cardiomyopathy was diagnosed; a diuretic and an angiotensin-converting enzyme
inhibitor were started. The acute heart failure was stabilized within about 2 wk (74 d
of age).

).

After taking an intensive family medical history, we noted important information about his
mother. At 36 yr of age, she developed hyperemesis during early pregnancy and stayed in bed
most of the day without adequate intake of food, resulting in severe weight loss. During
late pregnancy, she developed hypertension, and received oral methyldopa starting at 35 wk
of gestation. Two weeks later, at 36 wk and 6 d of gestation, jaundice appeared, and a blood
test detected the presence of cholestasis with marked elevation of serum bilirubin and
leucine aminopeptidase (LAP; 632 U/l). The total and direct bilirubin levels were 8.37 mg/dl
and 5.69 mg/dl, respectively. Drug-induced cholestasis was suspected, and methyldopa
treatment was discontinued. The jaundice and liver dysfunction (with peak aspartate
transaminase [AST] and alanine transaminase [ALT] levels of 108.0 IU/l and 119.5 IU/l,
respectively) spontaneously recovered. During this event, fetal growth retardation was
observed, and caesarean section was carried out at 37 wk 4 d of gestation.

Intensive treatment of hypocalcemia due to vitamin D deficiency successfully stabilized his
clinical and biological condition. However, at 12 d of hospitalization (60 d of age),
tachypnea gradually appeared, and echocardiography revealed depressed LV function with a
dilated LV. Chest radiography showed apparent cardiomegaly with a cardiothoracic ratio at
66% and the presence of a butterfly shadow in the lung fields (Fig. 1b). The level of N-terminal prohormone of brain natriuretic
peptide was markedly high (3,242 pg/ml). He was diagnosed with congestive heart failure due
to dilated cardiomyopathy. Treatment with furosemide and an angiotensin-converting enzyme
inhibitor was immediately started, and the cardiac condition gradually improved after 1 wk.
At 26 d of hospitalization, oral calcium was discontinued, and he was discharged at day 30
of hospitalization. Alfacalcidol was discontinued at 100 d of age. At 170 d of age, cardiac
function had recovered to almost normal, with normal findings of wall motion on
echocardiography and a cardiothoracic ratio of 56% without congestion in the lung fields on
chest X-ray (Fig. 1c). Diuretic therapy was
discontinued at this time (Fig. 2). The laboratory
data of the mother (at 72 d of age for her infant) showed improvement in cholestasis, but
hypovitaminosis D was still observed: 25(OH)D2, < 4.0 ng/ml; 25(OH)D3, 14.0 ng/ml.

Discussion
The present case demonstrated several key findings of vitamin D deficiency in infants.
First, cholestasis in the mother during late pregnancy was able to cause severe
malabsorption of lipophilic vitamins and typical clinical symptoms of vitamin D deficiency
in her infant as late as 1 mo of age, even when the infant was fed a regular formula.
Second, dilated cardiomyopathy appeared gradually, even after starting calcium and vitamin D
supplementation, and recovered within several months of supplementation with medical
treatment for heart failure.

A review of cases of infants with vitamin D deficiency showed that this condition occurred
mostly in breast-fed infants of mothers with or without vitamin D deficiency during
pregnancy and lactation periods. The onset of an afebrile seizure with hypocalcemia due to
vitamin D deficiency seems rare for formula-fed infants; however, cases of maternal
hyperparathyroidism, distinct restriction of sunlight exposure, severe hyperemesis during
pregnancy, and twin or multiple pregnancy were reported causes (3,4,5).

In the present case, the combination of insufficient intake due to pregnancy hyperemesis,
lack of sunlight exposure in both the mother and infant and —probably the major cause—
drug-induced cholestasis causing malabsorption of fat-soluble vitamins induced severe
vitamin D deficiency in the baby during the fetal and neonatal periods. Our findings
indicate that carefully taking a prenatal maternal medical history and noting issues such as
hyperemesis, a lack of sunlight exposure, any history of jaundice, and postnatal factors,
including breast milk or formula nutrition and restriction of sunlight exposure, is
important for the early detection of vitamin D deficiency and early supplementation. In
addition, this case showed that clinical manifestations of seizure due to hypocalcemia could
occur as late as 1 mo of age, even with persistent vitamin D deficiency in the fetal and
neonatal periods.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus with an onset in
the second or third trimester of pregnancy or elevated serum aminotransferases and bile acid
levels, and by the spontaneous relief of signs and symptoms within several weeks after
delivery (6). ICP is observed in 0.1–1.5% of
pregnancies in most areas of Central and Western Europe and North America but is rarely
found in Asian countries, including Japan (7). Cases
of drug-induced cholestasis, in contrast, may increase in number as new drugs are developed
and used. Drug-induced cholestasis is clinically difficult to distinguish from ICP in
pregnant women under medical treatment. Cholestasis typically causes malabsorption of
lipids, often resulting in lipid-soluble vitamin deficiencies, and can cause a critical
phenotype in the fetus and infant. Although whether the present case had drug-induced
cholestasis due to methyldopa or just ICP was unclear, underlying lipid-soluble vitamin
deficiencies in pregnant women with cholestasis should be carefully considered, and the
presence of a vitamin D deficiency should be monitored in cholestasis-affected women as well
as their babies.

The first clinical examination is especially important for the differential diagnosis of
hyperphosphatemic hypocalcemia, which is an unusual manifestation of vitamin D deficiency.
Meanwhile, previous reports had shown that serum phosphorous levels could increase in severe
vitamin D deficiency, presumably due to resistance to the phosphaturic effects of PTH from
autologous desensitization of the PTH receptor or insensitivity to PTH-induced signal
transduction in renal tubular cells. Although we did not evaluate the percentage of tubular
reabsorption of phosphate and urinary calcium excretion rate at the first presentation in
this case, laboratory data for the differential diagnosis of pseudohypoparathyroidism would
be clinically important for infants with hyperphosphatemic hypocalcemia (8, 9).

Previous reports have shown that dilated cardiomyopathy can be accompanied by hypocalcemia
due to vitamin D deficiency. Hypocalcemia caused by hypoparathyroidism, such as DiGeorge
syndrome, is also accompanied by cardiomyopathy in some cases (10). In a review of 59 cases with dilated cardiomyopathy due to
hypocalcemia, most cases showed a reversible course with a good prognosis using treatment
with calcium preparations (11). Cardiac function
normalized after a range of periods: 12.4 mo on average (12), 8 to 12 wk (13), or 2 to 5 mo (median,
3 mo) (14). On the other hand, 5 deaths were reported
(11). To our knowledge, detailed clinical data on
the course of cardiomyopathy associated with hypocalcemia have rarely been reported,
suggesting that dilated cardiomyopathy gradually develops despite normalization of calcium
concentration in the blood with vitamin D supplementation, and that cardiac dysfunction
gradually improves over several months. Further studies with more patients are needed to
clarify whether this clinical course was specific to this patient or typical of
cardiomyopathy induced by severe vitamin D deficiency.

In conclusion, maternal cholestasis should be considered a risk factor for lipid-soluble
vitamin deficiencies, especially vitamin D deficiency. Dilated cardiomyopathy due to vitamin
D deficiency may clinically appear, even after the successful treatment of calcium
metabolism.
==== Refs
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