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Is Vitamin D Deficiency a Risk Factor for Respiratory Distress Syndrome?

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 Vol. 83 · Number 4
ISSN 0300-9831

International Journal for

Vitamin and
Nutrition Research

4 13
/
www.verlag-hanshuber.com/IJVNR

Editor-in-Chief
R. F. Hurrell
Associate Editors
T. Bohn · M. Eggersdorfer · M. Reddy
 International Journal for
Vitamin and Nutrition Research
Volume 83, Number 4

Contents

Original Nissensohn M., Sánchez-Villegas A., Fuentes Lugo D., Henríquez Sánchez P.,
Communications Doreste Alonso J., Skinner A. L., Warthon Medina M., Lowe N. L., Hall
Moran V., and Serra-Majem L.:
Effect of Zinc Intake on Mental and Motor Development in Infants:
A Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Ofner M., Tomaschitz A., Wonisch M., and Litscher G.:
Complementary Treatment of Obesity and Overweight with
Salacia Reticulata and Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Root M. M. and Dawson H. R.:
DASH-Like Diets High in Protein or Monounsaturated Fats Improve
Metabolic Syndrome and Calculated Vascular Risk . . . . . . . . . . . . . . . . . . . . . . 224
Ataseven, F., Aygün C., Okuyucu A., Bedir A., Kücük Y., and
Kücüködük, S.:
Is Vitamin D Deficiency a Risk Factor for Respiratory Distress Syndrome? . . 232
Faizan M., Stubhaug I., Menoyo D., Esatbeyoglu T., Wagner A. E.,
Struksnæs G., Koppe W., and Rimbach G.:
Dietary Alpha-Tocopheral Affects Tissue Vitamin E and Malondialdehyde Levels
but Does not Change Antioxidant Enzymes and Fatty Acid Composition in Farmed
Atlantic Salmon (Salmo salar L.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Roncero-Ramos I., Pastoriza S., Navarro M. P., and Delgado-Andrade, C.:
Consumption of Model Maillard Reaction Products has no Significant Impact
on Ca and Mg Retention or on Tissue Distribution in Rats . . . . . . . . . . . . . . . . . . 246
Research Note Chevallereau G., Gleyses X., Roussel L., Hamdan S., Beauchet O.,
and Annweiler C.:
Proposal and Validation of a Quick Question to Rate the Influence of Diet in
Geriatric Epidemiological Studies on Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . 254

Int. J. Vitam. Nutr. Res. 83 (4) © 2013 Hans Huber Publishers, Hogrefe AG, Bern
International Journal for
Vitamin and
Nutrition Research
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232 Int. J. Vitam. Nutr. Res., 83 (4), 2013, 232 – 237

Original Communication

Is Vitamin D Deficiency
a Risk Factor for Respiratory
Distress Syndrome?
Fevzi Ataseven1, Canan Aygün2, Ali Okuyucu3, Abdulkerim Bedir4,
Yasemin Kücük5, and Şükrü Kücüködük6
1
Specialist, Ondokuz Mayıs University Medical Faculty, Division of Neonatology Department of Pediatrics, Samsun, Turkey
2
Associate Professor, Ondokuz Mayıs University Medical Faculty, Division of Neonatology Department of Pediatrics, Samsun, Turkey
3
Specialist, Ondokuz Mayıs University Medical Faculty, Department of Medical Biochemistry, Samsun, Turkey
4
Associate Professor, Ondokuz Mayıs University Medical Faculty, Department of Medical Biochemistry, Samsun, Turkey
5
Assistant, Ondokuz Mayıs University Medical Faculty, Department of Medical Biochemistry, Samsun, Turkey
6
Associate Professor, Ondokuz Mayıs University Medical Faculty, Division of Neonatology Department of Pediatrics, Samsun, Turkey

Received: September 4, 2013; Accepted: January 31, 2014

Abstract: Background: Previous studies have shown the relationship between in utero lung development
and vitamin D [25(OH)D], but there have been no studies to investigate whether vitamin D deficiency
is a risk factor for respiratory distress syndrome (RDS) in preterm babies. Objectives: In this study, we
investigated if 25(OH)D deficiency is a risk factor for RDS. Methods: One hundred fifty-two preterm
newborns, born at 29 – 35 weeks gestational age, were included in the study following informed consent
from the parents. Peripheral blood samples were collected within the first 24 hours of life and 25(OH)D
levels were measured by liquid chromatography-tandem mass spectrometry. Demographic characteristics
of the babies and the diagnosis of RDS were recorded. Results: In 64 % of preterm infants, 25(OH)D levels
were compatible with severe deficiency (≤ 10 ng/mL), 33 % with moderate deficiency (10 – 20 ng/mL), and
3 % with mild deficiency (20 – 30 ng/mL). In none of the babies was a normal 25(OH)D level observed.
Serum 25(OH)D levels were not correlated with gestational age. Respiratory distress syndrome was
more common in preterm babies with severe (28 %) compared to mild-moderate 25(OH)D deficiency
(14 %) (p < 0.05). Conclusions: None of the preterm infants in this study had normal vitamin D level,
which underlined the burden of vitamin D deficiency in pregnant women and their offspring. RDS
was more common in severely vitamin D-deficient preterms. Determination of vitamin D status of the
mothers and appropriate supplementation might be a valuable strategy to reduce RDS, in addition to
antenatal steroids. Besides, since vitamin D is a regulatory factor in many organs during fetal develop-
ment, long-term effects of in utero vitamin D deficiency warrant further studies.

Key words: respiratory distress syndrome, premature, Vitamin D

Int. J. Vitam. Nutr. Res. 83 (4) © 2013 Hans Huber Publishers, Hogrefe AG, Bern DOI 10.1024/0300 – 9831/a000165
 Author's personal copy (e-offprint)

F. Ataseven et al.: Vitamin D Deficiency in RDS 233

Table I: Comparison of Babies According to Serum VitD Levels.

Serum VitD Concentration

Characteristic < 10 ng/mL (n = 97) ≥ 10 ng/mL (n = 55) p

Girl, n (%) 51 (53) 30 (55) 0,86
Birth weight, [mean ± SD], g 1900 ± 603 1908 ± 545 0,93
Gestational age at birth,
median (min – max) 33 (29 – 35) 33 (29 – 35) 0,73
Maternal age, [mean ± SD] 29 ± 5,8 30 ± 5,7 0,73
Preeclampsia (%)   26 (26) 14 (25) 1,00
Antenatal corticosteroids, n (%)  26 (26) 19 (35) 0,35
Premature rupture of membranes (%)    16 (16) 5 (9) 0,23
Early-onset sepsis 4 (4) 2 (4) 1,00
Cesarean delivery, n (%) 93 (95) 52 (94) 0,70
Multiple births, n (%) 13 (13) 3 (5) 0,17
CRIB, median (min – max) 0 (0-2)  0 (0-8) 0,01
Apgar scores
1. min. median (min – max) 7 (3 – 8) 6 (3 – 8) 0,23
5. min. median (min – max) 8 (5 – 9) 8 (5 – 9) 0,06
SD: Standard deviation; CRIB: Critical Risk Index for Babies.

Introduction
RDS is the leading cause of mortality and morbid-
ity in premature babies [1], caused by the immature
anatomical development of the lungs and surfactant
deficiency. Animal experiments have demonstrated
that 25(OH)D plays an important role in pulmo-
nary maturation and also enhances steroid activity
[2, 3]. Several in vitro studies have shown that the
addition of 25(OH)D decreases the effective dose
of dexamethasone up to 10 times, and that 25(OH)
D improves the dose-dependent efficacy of dexa-
methasone and its immunosuppressive function in
the steroid-resistant cell pattern [3, 4]. Some studies
have also revealed that 25(OH)D improves the matu-
ration of Type II pneumocytes and the synthesis of
surfactant [5, 6]. There are studies investigating the
relationship between the 25(OH)D levels in babies
and newborns with sepsis, bronchopulmonary dys-
plasia, atopic dermatitis, and asthma [7, 8]. However,
there are no human studies in the literature investi-
gating the relationship between the 25(OH)D status
of newborns and development of RDS. The purpose
of this study was to investigate whether 25(OH)D
deficiency is a risk factor for RDS.
Methods
Study design and data collection
The study was performed in the Ondokuz Mayıs Uni-
versity Faculty of Medicine, located in Samsun, Tur-
key (latitude 41° N). One-hundred ninety newborn
preterms with a gestational age of 29 to 35 weeks,
delivered between October 2012 and June 2013 and
followed in the Neonatal Intensive Care Unit (NICU),
were included in the study, following informed con-
sent from the families. Babies with major congenital
abnormalities and/or chromosomal disorders, whose
mothers had diabetes mellitus, parathyroid hormone,
and/or calcium metabolism problems, were excluded.
The local Ethics Committee for Clinical Research
approved the study[No: 2012/79]. The study was sup-
ported by the Ondokuz Mayıs University Research
Fund (PYO.TIP.1901.13.015). The diagnosis of RDS
was based on clinical and radiological data and blood
gas analysis. Data on gender, gestational age, body
weight, Apgar scores, premature rupture of mem-
branes, antenatal steroid use, type of delivery, and
antenatal problems and Critical Risk Index for Ba-
bies (CRIB) scores were recorded [9]. Total calcium
levels were measured at hour 12 of life, according to
the NICU protocol. Babies with serum calcium level
< 7 ng/dL were considered to have hypocalcemia [10].

Int. J. Vitam. Nutr. Res. 83 (4) © 2013 Hans Huber Publishers, Hogrefe AG, Bern
 Author's personal copy (e-offprint)

234 F. Ataseven et al.: Vitamin D Deficiency in RDS

Determination of 25-hydroxyvitamin D3 were compared using the chi-square or Fisher’s Ex-

levels
Samples were drawn from a peripheral vein in the
first 24 hours of life and were placed in freezers at 70 °C
for long-term storage. 25(OH)D levels were measured
by liquid chromatography-tandem mass spectrometry
[LC-MS] method.
Vitamin D deficiency was classified according to
serum 25(OH)D levels as follows:
act test. A linear regression model was used to ana-
lyze the relationship between 25(OH)D levels and
gestational age. For variables that could affect the
development of RDS [sex, gestational age, way of
birth, birth weight, maternal age, premature rup-
ture of membranes, early neonatal sepsis, antenatal
steroid use, and 25(OH)D levels], Logistic regres-
sion analysis was performed. A p value of < 0.05 was
considered significant.

< 10 ng/mL: Severe

10 – 20 ng/mL: Moderate
21 – 30 ng/mL: Mild vitamin D deficiency
> 30 ng/mL: Normal [11, 12]
Statistical Analyses
The sample size was calculated as 140 for α = 0.05 and
power 0.99. Data were analyzed using SPSS version
21.0 computer software. The Kolmogorov–Smirnov
test was used to evaluate the distribution of vari-
ables. For normally distributed variables, values are
given average standard deviation, whereas values
not normally distributed were expressed as median
(minimum-maximum). Student’s t-test was used for
continuous variables with normal distribution and
the Mann–Whitney U test was used for continuous
variables without normal distribution. Frequencies
Results
During the study period, 190 babies eligible for the
study were admitted to the NICU. Thirty patients
were excluded because they did not meet the study
criteria (infants of diabetic mothers: 7; Down syn-
drome: 3, congenital anomalies: 13; perinatal as-
phyxia: 2; traumatic delivery: 2; died before blood
sampling: 2; hydrops fetalis: 1). Eight families re-
jected informed consent. In the end 152 patients were
included; whose demographic data is presented in
Tables I and II.
Vitamin D status was not correlated with gesta-
tional age [r = 0.039; p = 0.634]. There were 81 (53.3 %)
girls and 71 (46.7 %) boys in the study group. Average
25(OH)D levels of girls (9.4 ± 5.3 ng/mL) were similar
with the boys (8.9 ± 5.8 ng/mL) [p = 0.391].

Table II: Comparison of Babies With and Without RDS.

RDS

Characteristic (+) (n = 35) (-) (n = 117) p

Girl, n (%) 18 (51)  63 (54) 0.84
Birth weight, [mean ± SD], g 1667 ± 505 1974 ± 585 0.01
Gestational age median (min – max) 32 (29 – 35)  33 (29 – 35) 0.00
Maternal age, [mean ± SD] 30 ± 6.3 29 ± 5.6 0.44
Preeclampsia (%) 13 (37) 26 (22) 0.08
Antenatal corticosteroids, n (%) 8 (23) 37 (32) 0.40
Premature rupture of membranes (%) 3 (9) 18 (15) 0.40
Early-onset sepsis 2 (6)  4 (3) 0.62
Cesarean delivery, n (%) 35 (100)   110 (94) 0.35
CRIB score, median (min – max) 0 (0 – 5)  0 (0 – 8) 0.17
Apgar scores
1. min. median (min – max) 6 (3 – 8) 7 (3 – 8) 0.10
5. min. median (min – max) 7 (5 – 9)  8 (5 – 9) 0.19
25 (OH) vitamin D (ng/mL) 7.5 ± 4.9 9.6 ± 5.7 0.06

Int. J. Vitam. Nutr. Res. 83 (4) © 2013 Hans Huber Publishers, Hogrefe AG, Bern
 Author's personal copy (e-offprint)
F. Ataseven et al.: Vitamin D Deficiency in RDS
Table III: Logistic regression analysis of the factors lea-
ding to RDS
95 % C.I.
Variables p Exp(B)
lower upper
25(OH)D 0.017 0.299 0.111 0.808
Gestational age 0.000 1.840 1.361 2.487
Ninety-seven (63 %) of preterms had severe, 50
(34 %) had moderate, and 5 (3 %) had mild vitamin D
deficiency. There was no baby in the study with a nor-
mal 25(OH)D level. Five babies in the mildly deficient
group were also included in the moderately deficient
group and two groups were designed. There were 97 ba-
bies with 25 (OH) vitamin D level < 10 ng/mL (Group 1)
and 57 babies with 25 (OH) vitamin D level 10 – 30 ng/
mL (Group 2). Twenty-seven patients (28 %) were
diagnosed as RDS in the first group, while eight (14 %)
patients had RDS in the second group. RDS was more
frequent in babies with severe 25(OH)D deficiency
(p = 0.017). The risk of RDS was reduced 3.34 times
in babies with higher vitamin D levels (Table III).
When vitamin D-deficient groups were compared
regarding the incidence of hypocalcemia, Group 1 had
15 (15.5 %) and Group 2 had 7 (12.3 %) patients with
hypocalcemia [no statistical significance (p = 0.54)].
The average 25(OH)D value in babies born to
pre-eclamptic mothers was 8.2 ± 1.2 ng/mL, and
7.7 ± 1.5 ng/mL in infants of mothers without pre-
eclampsia. The difference was not statistically signifi-
cant (p = 0.63).
Discussion
In the present study, 64 % of preterms had severe,
33 % had moderate, and 3 % had mild 25(OH)D defi-
ciency. RDS was more frequent in babies with severe
vitamin D deficiency (28 % of babies with severe and
14 % of babies with mild/moderate deficiency had
RDS). When these two groups were compared, it was
observed that RDS was reduced 3.34 times in babies
with higher vitamin D levels.
Studies on rats have shown that 25(OH)D plays
an important role in fetal pulmonary maturity in the
antenatal period, especially between days 18 and 22.
This effect remains at the maximum level for several
hours after birth, then decreases and becomes unde-
tectable within several days [3]. 25(OH)D receptors
have been identified in type II pneumocytes in the
pulmonary culture of fetal rats. Type II pneumocytes
Int. J. Vitam. Nutr. Res. 83 (4) © 2013 Hans Huber Publishers, Hogrefe AG, Bern
235
responded to low-dose 25(OH)D with increased syn-
thesis of surfactants and their release, and decreased
glycogen content. In in vitro studies, 25(OH)D also
induced the synthesis of compounds related to surfac-
tant, phosphatidylcholine and phosphatidylglycerol [3,
4]. 25(OH)D seems as a good candidate for promoting
the development of epithelial mesenchymal cells in fetal
lungs and an adjunct for the prophylaxis of RDS [2]. In
another study it was reported that 25(OH)D induces
alveolar septal thinning and the synthesis of surfactant
[13]. The results of the present study, showing that RDS
is more frequent in severely vitamin D-deficient babies,
also support the data derived from animal studies.
There was no baby in the study with a normal vita-
min D level. Higher levels of 25(OH)D in the mother
facilitate the maternal-fetal transport of 25(OH)D [14].
Studies have demonstrated that there is a strong cor-
relation between the 25(OH)D level of the mother and
fetus [15, 16]. Therefore, near to the ground 25(OH)D
levels observed in the present study are most probably
due to maternal 25(OH)D deficiency. Low 25(OH)D
levels in pregnant women could be due to failure to take
a 25(OH)D supplement regularly during pregnancy,
and/or lack of adequate sunlight related to the use of
traditional and religious clothes (gown and veils), which
prevents sunlight from reaching the body. In addition,
low 25(OH)D levels could be related to the location
of the NICU (latitude 41° N of northern hemisphere),
where weather is rainy most days and exposure to sun-
light is limited. In addition, most of the samples (62 %)
were obtained in winter months, which might also have
contributed to lower vitamin D levels.
Previous studies from different parts of the world
have demonstrated very low 25(OH)D levels in
mother-infant pairs, similar to our results [17 – 20].
Lee et al. from the US reported that 65 % of moth-
ers had 25(OH)D levels < 30 ng/mL and Zeghoud
et al. from France detected that 63.7 % of infants
had 25(OH)D concentrations ≤ 30 nmol/L at birth.
Bowyer et al. from Australia reported that 11 % of
babies had 25(OH)D levels < 10 ng/mL and 29 %
between 10 – 20 ng/mL in the cord blood. In the study
by Maghbooli et al. from Iran, 25(OH)D levels were
< 14 ng/dL in 94 % of cord blood samples. Studies
from Turkey have also shown that 25(OH)D levels
were < 15 ng/mL in 66 % and 15 – 20 ng/mL in 15 %
of children aged 0 – 16 years [21]. Halıcıoglu et al.
has reported very low 25(OH)D levels in pregnant
women (11.5 ± 5.4 ng/mL). Interestingly, that study
was directed in a region of Turkey with > 80 % sunny
days/year [22]. Similarly, in the study by Pehlivan et
al., the average 25(OH)D level was 17.5 ± 10.3 nmol/L
in pregnant women [23].
 Author's personal copy (e-offprint)
236 F. Ataseven et al.: Vitamin D Deficiency in RDS
Furthermore, studies have demonstrated that there
is a correlation between 25(OH)D deficiency in the
mother and preterm birth [24, 25]. Since all patients
in our study were preterms, low levels of 25(OH)D in
the infants could be the result of the predilection of
25(OH)D deficient mothers to preterm birth.
We could not demonstrate any correlation be-
tween gestational age and vitamin D status. 25(OH)
D is transferred to the fetus depending on its level in
circulation during pregnancy [14, 26]. Since nearly all
the samples had hardly detectable vitamin D levels,
such correlation might not have been observed.
Zeghoud et al. compared two groups of babies with
25(OH)D levels of ≤ 15 nmol/L and 16 – 30 nmol/L and
found no difference regarding hypocalcemia. How-
ever, those infants whose mothers took 25(OH)D
supplements had a lower incidence of hypocalcemia
[18]. We could not find any significant relationship
between 25(OH)D levels and hypocalcemia.
Albeit previous studies have shown a correlation
between lower 25(OH)D levels and the incidence of
pre-eclampsia, such an association was not observed
in the present study [25, 27].
Recent reports from different parts of the world
point out that 25(OH)D deficiency occurs more com-
monly in women of reproductive age, pregnant wom-
en, and nursing mothers, which poses a great risk for
mothers, newborns, and infants [28, 29]. Many studies
have shown that antenatal vitamin D supplementa-
tion increases neonatal 25(OH)D levels [12, 30]. The
present study reveals that premature newborns in our
country are at great risk for vitamin D deficiency. A
higher incidence of RDS in the group of infants with
lower 25(OH)D levels presents the importance of
monitoring 25(OH)D intake and levels during preg-
nancy in order to prevent RDS. Besides, 25(OH)D
might be a promising agent in addition to antenatal
steroids for the prevention of RDS.
Furthermore, since vitamin D is a regulatory fac-
tor in many organs including the lung during fetal
development, long term effects of in utero vitamin D
deficiency warrants newer studies on that topic.
We are grateful to Prof. Yüksel Bek for his help in
statistical analysis.
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Fevzi Ataseven, Specialist
Ondokuz Mayıs University Medical Faculty
Division of Neonatology
Department of Pediatrics
55200 Samsun
Turkey
fevziataseven@gmail.com