The Journal of Maternal-Fetal & Neonatal Medicine

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Vitamin D levels in newborns and association with

neonatal hypocalcemia

Büşra Yılmaz, Canan Aygün & Erhan Çetinoğlu

To cite this article: Büşra Yılmaz, Canan Aygün & Erhan Çetinoğlu (2017): Vitamin D levels in
newborns and association with neonatal hypocalcemia, The Journal of Maternal-Fetal & Neonatal
Medicine, DOI: 10.1080/14767058.2017.1331430

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Published online: 14 Jun 2017.

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THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017
https://doi.org/10.1080/14767058.2017.1331430

ORIGINAL ARTICLE

Vitamin D levels in newborns and association with neonatal hypocalcemia

€şra Yılmaza, Canan Aygu
Bu  lub
€na and Erhan Çetinog
a
Faculty of Medicine Neonatology Unit, Ondokuz Mayıs University, Samsun, Turkey; bB€
uy€
uk Anadolu Hastanesi, Samsun, Turkey

ABSTRACT ARTICLE HISTORY

Objective: Vitamin D has many important functions in our body. Especially in intrauterine and Received 22 February 2017
early infancy periods, Vitamin D plays a major role in bone development, growth, and the matur- Revised 2 May 2017
ation of tissues such as lung and brain. Fetus is dependent on the mother in terms of Vitamin D Accepted 14 May 2017
and maternal Vitamin D deficiency results in a Vitamin D deficient newborn. The purpose of this
study was to determine the levels of Vitamin D in newborns and to investigate the association KEYWORDS
between Vitamin D status of the baby and neonatal hypocalcemia. Hypocalcemia; vitamin D;
Method: Vitamin D, calcium, and parathyroid hormone levels of 750 infants, born between preterm; newborn; maternal
1 January 2014 and 30 June 2015 and followed in Ondokuz Mayıs University Neonatal Intensive diabetes
Care Unit were analyzed retrospectively. Blood levels of Vitamin D were checked within 3 days
after birth. A 25(OH)D3 level of <10 ng/ml indicated severe, levels between 10 and 20 ng/ml,
which indicated moderate and levels between 20 and 30 ng/ml indicated mild Vitamin D defi-
ciency. Serum calcium levels below 8 mg/dl in term infants and below 7 mg/dl in preterm infants
were accepted as hypocalcemia. Hypocalcemia that developed within the first week after birth
was defined as early, while hypocalcemia after one week were defined as late hypocalcemia.
Results: A total of 44% of the infants in the study were girls, while 56% were boys; 38% were
term and 62% were preterm. Average 25(OH)D3 level of all infants was 11.4 ± 10.2 (0–153)
ng/ml. Only 30 (4%) infants had normal (>30 ng/ml) 25(OH)D3 levels; 68 (9%) had mild, 234
(31%) had moderate and 418 (56%) had severe vitamin D deficiency. No correlation was found
between Vitamin D levels and gender, mother’s age, gestational week or birth weight. In 79
(17.2%) preterms, neonatal hypocalcemia was observed. Vitamin D levels of the premature
infants who had early neonatal hypocalcemia were statistically significantly lower when com-
pared with those who did not have early neonatal hypocalcemia (p ¼ .02). No significant differ-
ence was found between the Vitamin D levels of the term infants who had early neonatal
hypocalcemia and those who did not (p¼ .29). No significant difference was found between the
Vitamin D levels of the infants who had late neonatal hypocalcemia and those who did not (in
preterm p ¼ .27; in term p ¼ .29).
Conclusions: Although lack of Vitamin D is preventable and curable, it is an important health
problem for newborns in Turkey. In our study, 56% of the infants were found to have severe
lack of Vitamin D and lack of Vitamin D was found to be associated with early neonatal hypocal-
cemia in preterm newborns. However, long-term effects of lack of Vitamin D in infancy are not
fully known. In order to be able to prevent neonatal Vitamin D deficiency, 1200 IU/day vitamin D
was supplemented to mothers from the 12th gestational week to 6th month of the birth, which
was put into effect by the Ministry of Health in 2011, and should be applied by all health
workers.

Introduction Vitamin D affects both prenatal and postnatal

Vitamin D, a key molecule in calcium and phosphorus
metabolism, has also roles in cell proliferation and
membrane stabilization, nerve conduction, anti-inflam-
matory, and anti-infective processes and insulin syn-
thesis via autocrine and paracrine effects [1,2]. It can
be considered as a hormone not only due to its ster-
oid structure and nuclear receptor, but also due to its
synthesis in human body and participation in critical
processes [3–8].
health. It takes part in fetal bone development via
fetal calcium metabolism and supports the growth
and stability of bones [9–11]. Since Vitamin D recep-
tors has been shown in many areas of the central ner-
vous system and 1-alpha-hydroxylase activity has been
demonstrated in the brain tissue, it is closely related
with neurological development [12].
The best indicator of Vitamin D status of the body
is serum 25(OH)D3 level, reflecting both Vitamin D
ingested by the diet and produced endogenously in

CONTACT B€
uşra Yılmaz busra_akyurt@hotmail.com Faculty of Medicine Neonatology Unit, Ondokuz Mayıs University, Samsun, Turkey
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 B. YILMAZ ET AL.
the skin [3]. 25(OH)D3 is the metabolite of Vitamin D
with the longest (12–19 days) and most stable half-life
[13,14]. Fetus is dependent on the mother for Vitamin
D. 25(OH)D3 passes through the placenta and cord
blood levels 50–60% of maternal levels [9,15].
Vitamin D deficiency (VDD) in perinatal period has
been linked with gestational diabetes [16], preeclamp-
sia [17], intrauterine growth retardation (IUGR) [18,19],
and preterm or low weight birth [20]. Vitamin D defi-
cient newborns might present with hypocalcemic con-
vulsions, hypocalcemic dilated cardiomyopathy,
osteomalacia and eventually childhood rickets [21].
A recent literature suggests an association of VDD
even with respiratory distress syndrome [22]. These
findings show that Vitamin D plays a significant role in
the growth and development of children, starting from
the perinatal period [23].
Although hypocalcemia is frequently asymptomatic
in the first days of life, it can be life-threatening [24].
Prematurity itself is a reason for neonatal hypocalce-
mia. Hypocalcemia can be observed in approximately
1/3 of preterms and in most of the very low birth
weight (VLBW) infants in the first two days of life.
Decreased parathyroid hormone (PTH) sensitivity,
increased calcitonin levels and high renal sodium
excretion might lead to hypocalcemia in these vulner-
able babies. Other reported etiological factors for early
neonatal hypocalcemia (ENH) are maternal VDD,
maternal diabetes, perinatal asphyxia, IUGR, maternal
and/or neonatal hypoparathyroidism, and hypomag-
nesemia [24].
In the present study, we aimed to:
 To monitor Vitamin D levels in infants admitted to
neonatal intensive care unit (NICU) and to find
whether VDD is a problem for the region.
 To examine whether there is an association
between VDD and neonatal hypocalcemia.
Methods
A total of 750 newborns born between 1 January 2014
and 30 June 2015 and admitted to Ondokuz Mayıs
University (OMU) Faculty of Medicine NICU were
included in the study. Mothers and babies with known
or suspected calcium metabolism or PTH problems,
whose mothers had renal failure or whose Vitamin D
samples could not be obtained were excluded from
the study.
Vitamin D and calcium status of babies were
recorded retrospectively from NICU computer data-
base. According to the NICU protocol, all hypocalcemic
babies underwent diagnostic work-up with serum
phosphorus, ALP and PTH levels. Local ethical board
approved the study (26.02.2015, No: OMU € KAEK 2015/
85 B.30.2.ODM.0.20.08/1029). 25(OH)D3 levels were
studied by high-performance liquid chromatography.
Values <10 ng/ml was accepted as severe, 10–19 ng/ml
as moderate, and 20–29 ng/ml as mild VDD [3].
Hypocalcemia was defined as serum calcium
<8 mg/dl in term and <7 mg/dl in preterm infants.
Hypocalcemia within the first week of birth was
defined as early, afterwards as late hypocalcemia [25].
Serum PTH level 65 pg/ml was accepted as normal,
while >65 pg/ml was accepted as high.
The data were transferred to SPSS 20.0 (Chicago, IL)
package program. Quantitative data were expressed in
average ± standard deviation while qualitative data
were expressed in numbers and percentages.
Kolmogorov–Smirnov test was used to show whether
the qualitative data were normally distributed.
Mann–Whitney U test was used for the comparison
between groups. Spearman’s Correlation test was used
to show the association of Vitamin D level with other
parameters and Chi-square test was used for the com-
parison of data obtained with numbers. A p values
<.05 was considered as statistically significant.
Results
Clinical characteristics of the infants included in the
study are presented in Table 1. Average 25(OH)D3
level of all infants in the study was 11.4 ± 10.2 (0–153).
Only 30 (4%) babies had a 25(OH)D3 level >30 ng/ml.
68 (9%) had mild, 234 (31%) had moderate and 418
(56%) had severe VDD. 423 (56%) of the study group
were boys, and 327 (44%) were girls. Average
25(OH)D3 level of girls was 11.29 ± 11.1 (0–153) while
the average level in boys was 11.54 ± 9.3 (0–65); with-
out a significant difference (p ¼ .98). 61.4% of the
study population was preterm, and 38.6% was term.
The average 25(OH)D3 level of term infants was
10.9 ± 7.8 (0–59.9) while it was 11.7 ± 11.3 (0–153) in
preterms; without a statistically significant difference
(p ¼ .95). No correlation was found between Vitamin D
levels of the babies and maternal age, gestational
Table 1. Clinical characteristics of the study group.
Female/Male (%) 44/56
Gestational age (weeks) 35.8 ± 3.4 (25–42)
Birth weight (grams) 2572.7 ± 841.7 (590–4770)
Maternal age (years) 28.8 ± 6.2 (18–50)
Term/Preterm (%) 38.6/61.4
Serum 25(OH)D3 level (ng/ml) 11.4 ± 10.2 (0–153)
Hypocalcemia n (%) 138 (18.4)
Early Neonatal Hypocalcemia n (%) 130 (17.3)
Late Neonatal Hypocalcemia n (%) 8 (1.1)
Maternal diabetes n (%) 74 (9.8)
Values were given as average þ SD (minimum–maximum).

week, nor birth weight; neither in term nor in preterm
babies.
Neonatal hypocalcemia
Hypocalcemia was observed in 138 (19%) of the
babies: 130 (95%) early and 8 (5%) late. 79 (60.7%) of
the early hypocalcemic babies were preterm and 14
(10.7%) were VLBW. Four (50%) of the late hypocalce-
mic babies were preterm. The average birth weight
and gestational age of preterm babies with early and
late neonatal hypocalcemia were not statistically differ-
ent (p ¼ .38 and .57, respectively). The average
25(OH)D3 level of preterms without hypocalcemia was
12.4 ± 12.1 (0–153), while this was 8.3 ± 5 (0–65) in
hypocalcemic ones; with a statistically significant dif-
ference (p ¼ .002). The average 25(OH)D3 level of term
infants with hypocalcemia was 9.4 ± 6.6 (0–59), while it
was 11.3 ± 8.1 (0–136) in normocalcemic terms
(p > .05). All babies (except one) with ENH had VDD.
Of these, 83 (63.8%) had severe, 43 (33.1%) had mod-
erate, and four (3.1%) had mild deficiencies. Overall,
137 (19%) of the infants with mild and moderate
(10–29 ng/ml) VDD had hypocalcemia, whereas 99
(23.6%) of the infants with severe VDD were hypocal-
cemic (p ¼ .14).
Seventy-four (9.8%) of the 750 infants had a history
of maternal pre-gestational or gestational diabetes. 17
(22.9%) of the infants of diabetic mothers was diag-
nosed as ENH. In 13% of the ENH cases, there was a
history of maternal diabetes. The average Vitamin D
levels of the infants with and without maternal dia-
betes were not statistically different [12.4 ± 19.3 versus
11.3 ± 8.6 ng/ml, (p ¼ .157)].
Discussion
There are different opinions on normal Vitamin D
values. At the start of the present study, the literature
considered a 25(OH)D3 level >30 ng/ml as normal;
<10 ng/ml as severe, 10–20 ng/ml as moderate, and
21–30 ng/ml as mild VDD [4]. However, in parallel with
the global increase in very low values of 25(OH)D3, in
the consensus report published in February 2016 the
threshold for definition of VDD was scaled down from
30 ng/ml to 20 ng/ml (<50 nmol/L) [3].
There are limited studies on neonatal Vitamin D lev-
els in our country; most data obtained from studies in
children. Andıran et al. from Ankara showed that [26],
in 0- to 16-year-old children, Vitamin D levels were
<15 ng/ml in 66%, and 15% had levels 15–20 ng/ml.
Kirel et al. [27] reported Vitamin D levels of 171 chil-
dren admitted to a Pediatric Endocrinology outpatient
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 3
clinic: 72% were <15 ng/ml, 14.6% were 15–20 ng/ml,
and 13.4% were >20 ng/ml.
Ataseven et al. from Middle Black Sea [22] exam-
ined 152 preterms with gestational ages 29–35 weeks.
They found severe VDD in 64%, moderate VDD in 33%
and mild VDD in 3%. None of the infants had normal
Vitamin D levels. Vitamin D levels and deficiency sever-
ity observed in that study are in close correlation with
the present one.
Studies throughout the world show similar results
in terms of low Vitamin D levels in newborns.
Zeghoud et al. [28] from France, showed that Vitamin
D levels at birth was <30 ng/ml in 63.7% of the
infants. In a study from Australia, Vitamin D levels in
cord blood was <10 ng/ml in 11% of infants, while in
29% it was 10–20 ng/ml [29]. Similarly, a study from
Iran, showed that cord blood Vitamin D levels were
<14 ng/ml in 94% of the infants [30].
In our study, a correlation was shown between low
Vitamin D levels and ENH in premature infants. In a
study conducted in Iran, when the Vitamin D levels of
100 infants and mothers who were hypocalcemic after
the third day of life were considered, 85% of the
infants and 74% of the mothers were Vitamin D defi-
cient [31]. However, VDD frequency can be higher
since only hypocalcemic infants were included in that
study.
One limitation of the present study was the
absence of maternal Vitamin D levels. We argue that
the low Vitamin D levels observed in the newborns
are a reflection of maternal VDD since the only known
Vitamin D source of the fetus is the mother. Studies
from different latitudes of Turkey have shown that
VDD is very common among pregnant woman
[3,12,32,33]. Halicioglu et al. [32] reported normal val-
ues (>30 mg/ml) only in 0.4% of 256 pregnant women.
A study conducted at Ankara on 6- to 17-month-old
children and their mothers found that 81.7% of the
mothers had Vitamin D levels <20 ng/ml [34].
In our study, normal Vitamin D level was observed
only in 4% of the infants, showing that VDD is an
important health problem in our country. Our study is
a guide in terms of its largest number of cases and
the data obtained.
Some studies have shown that Vitamin D supple-
ments during pregnancy have a positive effect on
both height and childhood bone mass [14,35], but
some showed no difference [36]. Although we have
found an association between VDD and ENH in pre-
terms, long-term effects of Vitamin D deficiency are
obscure. In Turkey, Ministry of Health has a program
that supports pregnant women with 1200 IU/day
Vitamin D starting from 12th week of pregnancy until
4 B. YILMAZ ET AL.
6th month after birth, irrespective of Vitamin D status
[37]. However, our results imply that, the suggestion
was not taken up by the mothers.
We conclude that VDD is very common in new-
borns and is associated with ENH in preterms. Since
VDD is preventable, Vitamin D supplements are
advised for pregnant women and babies after birth.
Disclosure statement
No potential conflict of interest was reported by the authors.
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