You are on page 1of 27

The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Association between serum 25 (OH) vitamin D


level at birth and respiratory morbidities among
preterm neonates

Adham Mohamed El Tahry Hegazy, Dina Mohamed Shinkar, Noha Refaat


Mohamed & Hala Abdalla Gaber

To cite this article: Adham Mohamed El Tahry Hegazy, Dina Mohamed Shinkar, Noha Refaat
Mohamed & Hala Abdalla Gaber (2017): Association between serum 25 (OH) vitamin D level
at birth and respiratory morbidities among preterm neonates, The Journal of Maternal-Fetal &
Neonatal Medicine, DOI: 10.1080/14767058.2017.1350162

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1350162

Accepted author version posted online: 02


Jul 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at


http://www.tandfonline.com/action/journalInformation?journalCode=ijmf20

Download by: [Cornell University Library] Date: 04 July 2017, At: 03:44
Association between serum 25 (OH) vitamin D level at
birth and respiratory morbidities among preterm
neonates

D
Prof. Dr. Adham Mohamed El Tahry Hegazy M.D.
Professor of Pediatrics.

TE
Faculty of Medicine-Ain Shams University-Cairo-Egypt.

Dr. Dina Mohamed Shinkar M.D.


Lecturer of Pediatrics.

EP
Faculty of Medicine-Ain Shams University-Cairo-Egypt.

Dr. Noha Refaat Mohamed .M.D.


Lecturer of Clinical Pathology-Cairo-Egypt.
C
Faculty of Medicine-Ain Shams University- Cairo-Egypt

Hala Abdalla Gaber M.B.B.CH.


AC

Ministry of health- Egypt.

Correspondent author: Dr. Dina Mohamed Shinkar M.D.


62 Dr.Abdel Shafie Mohamed Street-7 th district-Nasr City-Cairo-Egypt.
ST

Tel: +201112636097
Email: drdodi28@gmail.com.
JU

Short title: Vitamin D level at birth and respiratory morbidities.


Key words: Vitamin D; Prematurity; Respiratory distress syndrome; Bronchopulmonary
dysplasia.

There is no financial assistance or potential conflicts of interest.

Abstract:
Objectives:

To determine the association between 25-hydroxyvitamin D [25(OH)D] levels on first

day of life with respiratory distress syndrome (RDS), need and duration of mechanical

ventilation and subsequent development of bronchopulmonary dysplasia (BPD) among

D
preterm neonates.

TE
Study design:

In this case control study, serum 25(OH)D was measured on first day of life in 65

preterm neonates < 34 weeks: 40 with RDS and 25 without RDS and compared between

insufficiency: (20- 30 ng/mL),


EP
them. Serum 25(OH)D levels were categorized into; normal : above 30 ng/mL ,

moderate deficiency (10 – 20 ng/mL) and severe

deficiency (< 10 ng/mL). Neonates with different 25(OH)D levels were compared as
C
regard grade of RDS, initial pH, initial CO2, need and duration of mechanical ventilation,
AC

development of BPD and mortality.

Results:

Only one of 65 studied preterm neonates had normal vitamin D level. Neonates with RDS
ST

had significantly lower mean serum 25(OH)D level than controls (10.6 ng/dl vs 13.9

ng/dl) (P value =0.028). Neonates with severe 25(OH)D deficiency developed more BPD

than those with moderate deficiency (29.4% vs 8.7%) but did not reach significant level
JU

(P value =0.08). There is no correlation between serum 25(OH)D level and duration of

mechanical ventilation. Logistic regression analysis shows that low serum 25(OH)D level

is an independent risk factor for RDS.

Conclusion:
Low 25(OH)D level is far frequent among Egyptian preterm neonates. Vitamin D

deficiency is an independent risk factor for development of RDS in preterm neonates.

Key words: Vitamin D; Prematurity; Respiratory distress syndrome; Bronchopulmonary

D
dysplasia.

Abbreviations: [25(OH)D]:25-hydroxyvitamin D; RDS: Respiratory distress syndrome;

TE
BPD: bronchopulmonary dysplasia; VDR:Vitamin D receptor; AT2C :Alveolar type 2

cell; nCPAP :Nasal continuous positive air pressure; VDRE:vitamin D response

EP
elements.

Introduction:
C
Respiratory distress syndrome (RDS) is leading cause of mortality and mortality in
AC

premature babies (1).

Bronchopulmonary dysplasia (BPD) is the most prevalent long-term morbidity among

surviving extremely preterm infants (2) .BPD affects ~20% of preterm infants, and up to
ST

60% of extremely preterm infants who are born before 26 completed weeks of gestation

(3).Early preterm infants are likely at risk of low vitamin D status because of high

prevalence of vitamin D deficiency in pregnancy, lack of sunlight exposure during


JU

hospitalization and difficulty in ensuring adequate enteral nutrition (4).

Animal and laboratory studies showed substantial positive effects of vitamin D on the

alveolar type II cell, fibroblast proliferation, surfactant synthesis and alveolarization (5).

Vitamin D and the vitamin D receptor (VDR) have important roles inperinatal lung

development (6,7).
Vitamin D may play a role in the embryogenesis and in cellular growth and

differentiation, including lung development and regulation of lung maturation in the fetus

(8, 9).

Vitamin D has anti-inflammatory properties and modulates lung growth. It directly

D
increase fetal alveolar type 2 cell (AT2C) growth by 26% And enhanced AT2C growth

by 73% (10).Several epidemiological studies have described an association between

TE
maternal vitamin D deficiency and the development of early childhood respiratory

infections, wheezing, and asthma later in life (11,12).

EP
The impact of vitamin D on early lung development and maturation and lung diseases of

early life is an emerging field of research.

We aimed at determining the association between 25-hydroxyvitamin D [25(OH) D]


C
levels at birth with RDS and subsequent development of BPD in Egyptian preterm
AC

neonates.

Patients and methods:


This prospective case control study was carried out in the level III Neonatal Intensive
ST

Care Unit of Ain Shams University Maternity and Children Hospital, Cairo, Egypt. It was

conducted in the period between November 2015 and May 2016.

Study Population:
JU

A total of 65 preterm neonates < 34 weeks gestational age were enrolled in the study, 40

preterm neonates with RDS and 25 preterm neonates without RDS. The required sample

size has been calculated using the G*Power software version 3.1.7 (Universitat

Dusseldorf, Germany). The sample size was calculated as 60 for α = 0.05 and power

0.90.Neonates whose mothers have parathyroid hormone and/or calcium metabolism


problems, those with major congenital abnormalities and/or chromosomal disorder and

babies with blood culture proven sepsis were excluded.

Methods:

The study protocol was approved by Ain Shams University NICU Ethical Committee.

D
Informed consent was taken from mother or legal guardians of included neonates in the

TE
study. Detailed history was taken for all neonates including maternal history of PROM,

diabetes mellitus, preeclampsia, antenatal steroid use and history and doses of maternal

intake of vitamin D during pregnancy. Also Apgar score was recorded (13).Diagnosis of

EP
RDS was based on presence of respiratory distress in conjugation with chest X ray.

Grading of respiratory distress was done by Downes score (14).


C
Capillary blood gases analysis was done on admission and repeated as needed. Serum
AC

level of vitamin D (25(OH)D) was measured in venous blood sample in all included

neonates on day one of life using 25(OH) D ELISA kit Immundiagnostik AG, Germany.

Serum Ca was measured on first day of life.


ST

We considered vitamin D “deficiency” if 25(OH) D value below 20 ng/ml and

“insufficiency” if 25(OH) D value between 20 and 30 ng/ml.


JU

Vitamin D deficiency was further classified as severe deficiency < 10 ng/ mL and

moderate deficiency10 – 20 ng/mL (15).

All included neonates were followed up for need and duration of mechanical ventilation,

development of BPD using the National Institutes of Health consensus definition of BPD

(16) and fate (died or alive).


Management strategy:

All infants were followed on nasal continuous positive air pressure (nCPAP) as an initial

respiratory support and mechanical ventilation was started if fraction of inspired oxygen

of > 0.4 and mean airway pressure > 7 cm H2O. Surfactant was given as early rescue if

D
mechanical ventilation was needed.

TE
Outcome measures:

The primary outcome was to determine the association between 25-hydroxyvitamin D

EP
[25(OH)D] levels on day one of life with RDS and subsequent development of BPD.

Statistical analysis:
C
Data were analyzed using SPSS version 20 computer software (SPSS, Chicago, IL). The
AC

qualitative data were presented as number and percentages while quantitative data were

presented as mean, standard deviations, and ranges when parametric and presented as

median with interquartile ranges (IQR) when non parametric. The comparison between
ST

groups regarding qualitative data were done by using Chi-square test and/or Fisher exact

test when the expected count in any cell found less than 5.
JU

The comparison between two groups regarding quantitative data with parametric

distribution were done by using Independent t-test while the comparison between two

groups regarding quantitative data with non parametric distribution were done by using

Mann-Whitney test.
The comparison between more than two groups regarding quantitative data with

parametric distribution were done by using One Way ANOVA while the comparison

between more than two groups regarding quantitative data with non parametric

distribution were done by using Kruskall-Wallis test. Spearman correlation coefficients

D
were used to assess the correlation between two quantitative parameters in the same

group.

TE
Logistic regression analysis was used to assess the risk factors of RDS. A two-tailed p

value was considered significant if < 0.05.

Results:
EP
C
From November 2015 to May 2016, we enrolled 65 preterm infants in this study; 40

neonates with RDS and 25 control neonates. The mean gestational age of neonates with
AC

RDS was 31.4 ± 2.25 wks versus 32.4 ± 1.76 wks in control group and mean birth weight

was 1.55 ± 0.63 kg in RDS group versus 1.72 ± 0.52 kg in control group(non- significant

difference). There was no significant difference between neonates in RDS group and Commented [M1]: There is no significant difference .
ST

control group as regard sex, mode of delivery, maternal age, antenatal steroid intake,

vitamin D supplementation during pregnancy ,PROM, DM and preeclampsia (Table 1).

47.5% of mothers of RDS neonates received vitamin D supplementation during


JU

pregnancy while 60% of control neonates received vitamin D supplementation( P =

0.326). Most of these mothers reported that their vitamin D intake was not regular and the

dose was not fixed due to lack of adherence to antenatal care. Although mean S.Ca level

in neonates in RDS group was lower than in the control group (8.7 mg/dl vs 9.0 mg/dl),

this difference is statistically non-significant (P=0.07).


Only one out of 65 studied preterm neonates had normal serum 25(OH)D level. None of

RDS neonates had 25(OH)D insufficiency, 23 (57.5%) had moderate 25(OH)D

deficiency and 17 (42.5%) had severe deficiency while, 3 (12.0%) of control group had

25(OH)D insufficiency, 12 (48.0%) had moderate deficiency and 10 (40.0%) had severe

D
deficiency

TE
Neonates in RDS group had significantly lower mean serum 25(OH)D level than the

control group (10.6 ng/dl Versus 13.9 ng/dl; P = 0.028) (Figure 1).

EP
Five out of 17 neonates with severe 25(OH)D deficiency developed BPD (29.4%) while 2

out of 23 neonates with moderate deficiency developed BPD (8.7%) (P value =0.08)

(Figure 2).
C
As regard demographic and maternal clinical data, there is no significant difference
AC

between neonates with moderate and severe 25(OH)D deficiency in RDS group. Males

had significantly more severe 25(OH)D deficiency than females (64.7% versus 35.3%; P

= 0.015) (Table 2).


ST

Also, there is no significant difference between neonates with moderate and severe

vitamin D deficiency in RDS group as regard Apgar score, grade of RDS, initial pH,
JU

initial CO2 and maximum PIP. Although neonates with severe 25(OH)D deficiency had

longer days on mechanical ventilation (16.53 ± 13.46 versus 12.09 ± 9.46 days; P=

0.227) and higher mortality (23.5% versus 8.7%; P=0.194), these differences are

statistically non-significant (Table 3 ). There is no statistically significant correlation

between serum 25(OH)D level and birth weight (r =,-0.013; P=0.935) and gestational age

(r =0.042 ; P=0.797) and serum Ca level (r =-0.013; P=0.935). Also, There is no Commented [M2]: There is no correlation with birth weight and
gestational ae
statistically significant correlation between serum 25(OH)D level and duration of

mechanical ventilation (r = 0.061; P = 0.710) (Table 4).

Logistic regression analysis shows that low serum 25(OH)D level on first day of life is

an independent risk factor for RDS (P=0.036), Odds

D
ratio (OR) : 0.904, 95% CI (0.82- 0.94) .As we chose both our groups gestational age

TE
matched, gestational age was not the independent risk factor in our patients (Table 5) .

Discussion:

EP
Preterm infants have increased risk of developing vitamin D deficiency compared with

full-term infants (17) as they miss the late gestation transfer of vitamin D from mother to

fetus (18).
C
The impact of vitamin D on early lung development and maturation and lung diseases of
AC

early life is an emerging field of research.

The purpose of our study was to assess the relation between vitamin D status at birth and

development of RDS and subsequent BPD in Egyptian preterm neonates.


ST

In our study, only one of 65 studied Egyptian preterm neonates had normal serum

25(OH)D level. This reflects poor vitamin D status of Egyptian women due to poor diet
JU

lacking sources of vitamin D as Fish, more prevalence of dark skin colored skin,

multiparity and lack of adequate supplementation during pregnancy.

Vitamin D freely crosses the placenta during pregnancy. Thus, levels of neonates at birth

depend entirely on that of the mother ()(19). Neonatal serum 25(OH)D level differed

significantly between the groups of mothers with different serum 25(OH)D levels
(P<0.001). Maternal 25(O.H) D level is positively correlated with neonatal vitamin D

level (r=0.914, P<0.001) (20). This occurs as the fetus has no endogenous production of

25(OH)D and depends on transplacental transfer (21). Maternal vitamin D level can help

to predict neonatal vitamin D deficiency.

D
Transplacental transfer occurs mainly in the third trimester and therefore, preterm infant s

TE
are at increased risk of vitamin D deficiency (22).

In our study, neonates in RDS group had significantly lower mean serum25(OH)D level

EP
than the control group (10.6 ng/dl vs 13.9 ng/dl) (P value =0.028). Logistic regression

analysis shows that low day 1 serum 25(OH)D level is independent risk factors for RDS.
C
It was demonstrated that in type 2 pneumocytes, 1,25(OH)D increased surfactant

synthesis by increasing intracellular phosphatidylcholine and phosphatidylglycerol and


AC

increased surfactant secretion by providing migration of newly formed osmophilic

lamellar bodies to the apex of the cell (8).

Sakurai et al. (2009) stated that 1,25(OH)D and its metabolite C-3 epimer play key role
ST

in alveolar epithelial–mesenchymal interaction, lipofibroblast proliferation, and apoptosis

of lung fibroblasts, which have critical roles in perinatal lung maturation (5).
JU

It has been demonstrated in experimental studies that vitamin D receptors are found in

type II pneumocytes, and that vitamin D plays a role in the morphogenesis of lung and

surfactant production (23).

Data from human and animal studies suggest that vitamin D may have a role in lung

development. The biological effects of metabolically active form of vitamin D,


1,25(OH)2D3, are mediated by the vitamin D receptor (VDR), It has been reported that

over 3000 genes have VDRE, many of which are involved in lung development. Vitamin

D pathway genes have been reported to be upregulated during the pseudoglandular and

saccular stages of lung development where proximal and distal airways are formed,

D
respectively (24).

TE
We could not demonstrate any correlation between gestational age and vitamin D status.

Also, Park et al. reported that the serum 25-OHD concentrations were not significantly

correlated to gestational age (r=-0.034, P=0.573). There were no significant differences in

EP
serum 25-OHD concentrations and incidence of severe vitamin D deficiency among

early, moderate, and late preterm infants (19).


C
Also Ataseven et al, in their study demonstrated that Vitamin D status was not correlated

with gestational age [r = 0.039; p = 0.634](25). Commented [M3]: another study showing no correlation with
AC

gestational age.
Ataseven F, Aygun C ,Okuyucu A ,im Bedir A, Kucuk Y, and
Kucukoduk S: Is Vitamin D Defi ciency a Risk Factor for
In RDS group, 57.5% had moderate 25(OH)D deficiency and 42.5% had severe 25(OH)D Respiratory
Distress Syndrome?
Int. J. Vitam. Nutr. Res. 83 (4)
deficiency. In control group, 12% of neonates had 25(OH)D insufficiency, 48% had
ST

moderate 25(OH)D deficiency, and 40% had severe 25(OH)D deficiency.

In study on 278 preterm infants, the incidence of vitamin D deficiency or insufficiency


JU

was 91.7% and 7.2%, respectively, and 51.1% of preterm infants were classified as

having severe vitamin D deficiency. Only 3 preterm infants were on sufficient vitamin D

status (26).

BPD is the most prevalent long-term morbidity among surviving extremely preterm

infants and has a multifactorial etiology. BPD is associated with later risk of reactive
airways disease, such as asthma, post neonatal mortality and adverse neuro-

developmental outcomes (27).

In our study more neonates with severe 25(OH)D deficiency developed BPD than those

with moderate deficiency (29.4% vs 8.7%) but the difference is not significant (P value

D
=0.08). The lack of statistically significant relation between vitamin D status and

TE
development of BPD may be explained by genetic predisposition to BPD in addition to

oxygen toxicity, barotrauma and volutrauma. A study by Koroglu et al. examined the role

of the VDR variant Fok 1 in BPD risk among 109 preterm neonates but did not find a

significant relation (28).

EP
Fettah et al. reported that 36.8% were diagnosed with BPD in vitamin D deficient group,
C
and 8.3% were diagnosed with BPD in neonates with normal vitamin D level (P 0.014)
AC

(23).

Cetinkaya et al. reported that by univariate analysis lower cord blood 25(OH) levels were

associated with BPD in a cohort of 100 preterm infants (32 weeks) (29) .In contrary,
ST

Joung et al., reported that among 44 infants born before 29 weeks, median 25(OH)D

levels at birth were 30.4 ng/ ml in preterm infants who subsequently died or developed

BPD and 33.8 ng ml in infants who survived without BPD, and there were no statistically
JU

significant differences between these two groups (P= 0.6) (27).

There is no statistically significant correlation between serum 25(OH)D level and

duration of mechanical ventilation . In a study by Onwuneme et al., low 25OHD level

(<30 nmol/L) in preterm infants at birth was associated with increased oxygen

requirement (P=.008), increased duration of intermittent positive-pressure ventilation


during resuscitation at delivery (P=.032), and greater need for assisted ventilation

(P=.013) (30).

On contrary, Fettah et al. reported that when groups with deficient and normal vitamin D

levels were compared, duration of mechanical ventilation did not differ between both

D
groups.

TE
Vitamin D supplementation during pregnancy in the United States (31) and Europe (32)

showed trends but no significant decreases in the incidence of childhood wheezing and

EP
asthma in the first 3 years of life among the offspring. However, these studies did not

analyze the role of vitamin D status in RDS or BPD among preterm infants.

American Academy of Pediatrics guidelines recommend vitamin D intake of 400 IU per


C
day for all infants (33). Fort et al. suggested that vitamin D deficiency among preterm
AC

infants can be prevented by supplementation with 800 units of vitamin D daily (34).

At Ain Shams University Hospital, we provide 400 IU vitamin D daily for exclusively

human milk-fed infants. For infants with a combination of human milk and formula also
ST

400 units is added until the infant is consuming a volume adequate to provide 400 units

per day.
JU

We conclude that that low 25(OH)D level is universal among Egyptian preterm neonates

at birth and it is independent risk factor for development of RDS . However, we did not

detect a statistically association between vitamin D status and BPD.

Limitations in our study included small sample size, risk and lack of data on prenatal

maternal 25(OH)D levels. Further studies on larger population of preterm neonates are
needed to assess the relation of maternal and neonatal vitamin D status with subsequent

development of BPD. Interventional trials of vitamin D supplementation are also needed.

We recommend regular supplementation of Egyptian pregnant women with vitamin D to

avoid development of RDS.

D
References:

TE
1) Jackson JC. Respiratory distress in the preterm infant. In: Averys diseases of the

new born.(Gleason, C.A. and Devaskar, S.U., EDS)8th ed. 2012; p:633, Elsevier

Saunders, Philadelphia.

EP
2) Jain D, Bancalari E. Bronchopulmonary dysplasia clinical perspective. Birth Defects
C
Res A Clin Mol Teratol.2014; 100(3): 134–144.
AC

3) Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC et al.

Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research

Network. Pediatrics (2010); 126(3): 443–456.


ST

4) Monangi N, Slaughter JL, Dawodu A, Smith C and Akinbi HT. Vitamin D status

of early preterm infants and the effects of vitamin D intake during hospital stay. Arch
JU

Dis Child Fetal Neonatal Ed. 2014; 99:F166–F168.

5) Sakurai R, Shin E, Fonseca S, Sakurai T, Litonjua AA and Weiss ST. (1alpha,

25(OH)2D3 and its 3-epimer promote rat lung alveolar epithelial–mesenchymal

interactions and inhibit lipofibroblast apoptosis. Am J Physiol Lung Cell Mol Physiol

2009; 297: L496–L505.


6) Mandell E, Seedorf GJ, Ryan SL, Gien J, Cramer SD, Abman SH. Antenatal

endotoxin disrupts lung vitamin D receptor and 25-hydroxyvitamin D 1-alpha

hydroxylase expression in the developing rat. Am J Physiol Lung Cell Mol

Physiol 2015; 309(9): L1018–L1026.

D
TE
7) Mandell E, Seedorf G, Gien J, Abman SH. Vitamin D treatment improves survival

EP
and infant lung structure after intra-amniotic endotoxin exposure in rats: potential role

for the prevention of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol

Physiol 2014; 306(5): L420–L428.


C
8) Nguyen M, Trubert CL, Rizk-Rabin M, Rehan VK, Besançon F and Cayre YE.
AC

1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR

expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase. J

Steroid Biochem Mol Biol 2004; 89-90: 93–97.


ST

9) Sutherland, E.R., Goleva, E., Jackson, L.P., Stevens, A.D and Leung, D.Y

.Vitamin D levels, lung function and steroid response in adult asthma. Am. J. Respir.
JU

Crit. Care Med 1010; 181, 699.

10) Mandell E, Seedorf G, Gien J and Abman SH. Lung cellular and molecular

physiology-American Journal of Physiology 2014; 306(5).

11) Camargo CAJ, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST,

Gold DR, Kleinman K, Gillman MW Maternal intake of vitamin D during


pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr

2007; 85: 788–795.

12) Camargo CA, Ingham T, Wickens K, Thadhani R, Silvers KM, Epton MJ, Town

GI, Pattemore PK, Espinola JA and Crane J. Cord-blood 25-hydroxyvitamin D

D
levels and risk of respiratory infection, wheezing, and asthma. Paediatrics 2011; 127:

e180–e187.

TE
13) Apgar V .A proposal for a new method of evaluation of the newborn. Classic Papers

in Critical Care1952; 32(449): 97.

EP
14) Downes JJ and Raphaely RC. Pediatric intensive care. The Journal of the American

Society of Anesthesiologists 1975; 43(2): 238-250.

15) Aly H and AbdelHady H (2015): Vitamin D and the neonate: An update. J Clin
C
Neonatol; 4:1-7.21
AC

16) Jobe AH and Bancalari EBronchopulmonary dysplasia. Am J Respir Crit Care

Med. 2001 ; 163(7): 1723–1729

17) Monangi N, Slaughter JL, Dawodu A, Smith C and Akinbi HT .Vitamin D status
ST

of early preterm infants and the effects of vitamin D intake during hospital stay. Arch

Dis Child Fetal Neonatal Ed 2014; 99:F166–F168.

18) Alan H .Vitamin D for extremely preterm infants. Journal of Pediatrics 2016;
JU

(174):1-3.

19) Seto TL, Tabangin ME, Langdon G, Mangeot C, Dawodu A, Steinhoff

M and Narendran V.Racial disparities in cord blood vitamin D levels and its

association with small-for-gestational-age infants. J Perinatol 2016; 36(8): 623–628.


20) Wang C, Gao JS, Yu SL, Qiu L, Zeng L andWang DH Correlation

between neonatal vitamin D level and maternal vitamin D level. Zhongguo Dang Dai

Er Ke Za Zhi. 2016.; 18(1):20-3.

21) Weisman Y. Maternal, fetal and neonatal vitamin D and calcium metabolism during

D
pregnancy and lactation. Endocr Dev 2003; 6: 34–49.

22) Burris HH, Van Marter LJ, McElrath TF, Tabatabai P, Litonjua AA, Weiss

TE
ST et al. Vitamin D status among preterm and full-term infants at birth. Pediatr

Res 2014; 75(1-1): 75–80.

EP
23) Fettah ND, Zenciroglu A, Dilli D, Beken S and Okumus N .Is Higher 25-

Hydroxyvitamin D Level Preventive for Respiratory Distress Syndrome in Preterm

Infants? Am J Perinatol 2015; 32:247–250.


C
24) Kho AT, Bhattacharya S, Tantisira KG, Carey VJ, Gaedigk R and Leeder JS
AC

Transcriptomic analysis of human lung development. Am J Resp Crit Care Med

2010; 181: 54–63.

25) Ataseven F, Aygun C ,Okuyucu A ,im Bedir A, Kucuk Y and Kucukoduk S. Is


ST

Vitamin D Defi ciency a Risk Factor for Respiratory Distress Syndrome? Int. J.

Vitam. Nutr. Res 2013; 83 (4). 232 – 237.

26) Lykkedegn S, Sorensen GL, Beck-Nielsen SS and Christesen HT The impact of


JU

vitamin D on fetal and neonatal lung maturation. A systematic review. Am J Physiol

Lung Cell Mol Physiol 2015; 308: L587–L602.

27) Joung KE, Burris HH, Van Marter LJ, McElrath TF, Michael Z, Tabatabai P,

Litonjua AA, Weiss ST and Christou H .Vitamin D and bronchopulmonary

dysplasia in preterm infants; Journal of perinatology 2016; 36, 878–882.


28) Koroglu OA, Onay H, Cakmak B, Bilgin B, Yalaz M, Tunc S et al. Association of

vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia. Pediatr

Res 2014;76 (2): 171–176.

29) Cetinkaya M, Cekmez F, Buyukkale G, Erener-Ercan T, Demir F, Tunc T, Aydın

D
FN and Aydemir G .Lower vitamin D levels are associated with increased risk of

early-onset neonatal sepsis in term infants. Journal of Perinatology 2015; 35: 39–45.

TE
30) Onwuneme C, Martin F, McCarthy R, Carroll A, Segurado R, Murphy J,

Twomey A, Murphy N, Kilbane M, McKenna M and Molloy E. The Association

EP
of Vitamin D Status with Acute Respiratory Morbidity in Preterm Infants. J Pediatr

2015; 166(5):1175-1180.
C
31) Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O'Connor

GT et al .Effect of prenatal supplementation with vitamin D on asthma or recurrent


AC

wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA

2016 ; 315(4): 362–370.


ST

32) Chawes BL, Bonnelykke K, Stokholm J, Vissing NH, Bjarnadottir E, Schoos

AM et al .Effect of vitamin D3 supplementation during pregnancy on risk of

persistent wheeze in the offspring: a randomized clinical trial. JAMA 2016; 315(4):
JU

353–361.

33) Abrams SA .Dietary guidelines for calcium and vitamin D.a new era. Pediatrics

2011; 127(3): 566–568.


34) Fort P, Salas AA, Nicola T, Craig CM, Carlo WA and Ambalavanan N .A

comparison of 3 vitamin D dosing regimens in extremely preterm infants: a

randomized controlled trial. J Pediatr. 2016; 174: 132–138.

D
TE
EP
C
Serum 25(OH)D (ng/ml)
AC

13.92

10.65
14
12
10
8
ST

6
4
2
0
JU

RDS group Control group

Fig. (1): Comparison between neonates in RDS group and control group as regard mean
serum 25(OH)D level.
D
TE
Moderate deficiency Severe deficiency

91.30%

EP
100%
70.60%
80%

60%
29.40%
40%
8.70%
C
20%

0%
AC

Negative Positive
BPD

Fig. (2): Comparison between neonates with moderate and severe 25(OH)D deficiency in
ST

RDS group as regards BPD.


JU
D
Table (1): Descriptive demographic data of neonates of RDS group and

TE
control group:
RDS group Control group Independent t-test
No. = 40 No. = 25 t/X²* P-value

EP
Gestational age (weeks) Mean ± SD 31.4 ± 2.25 32.44 ± 1.76 -1.964 0.054

Birth weight(kg) Mean ± SD 1.55 ± 0.63 1.72 ± 0.52 -1.121 0.267


C
Sex no (%) Female 23 (57.5) 13 (52) 0.188* 0.664
Male 17 (42.5) 12 (48)
AC

Mode Of delivery no (%) LSCS 33 (82) 19 (76) 0.406* 0.524


VD 7 (17.5) 6 (24)
IUGR no (%) Negative 34 (85) 23 (92) 0.698* 0.403
Positive 6 (15) 2 (8)
Maternal age (years) Median (IQR) 29 (24 – 31.5) 27 (26 – 29) -1.258 0.208
Range 18 – 36 19 – 33
ST

Antenatal steroid no (%) Negative 36 (90) 23 (92) 0.073* 0.786


Positive 4 (10) 2 (8)
Vitamin D Negative 21 (52.5) 10 (40) 0.964* 0.326
supplementation
Positive 19 (47.5) 15 (60)
JU

during pregnancy no (%)


PROM no (%) Negative 21 (52.5) 8 (32) 2.616* 0.106
Positive 19 (47.5) 17 (68)
DM with pregnancy no Negative 38 (95) 25 (100) 1.290* 0.256
(%) Positive 2 (5) 0 (0)
Preeclampsia no (%) Negative 34 (85) 24 (96) 1.937* 0.164
Positive 6 (15) 1 (4)

*: Chi-square test
D
TE
Commented [M4]: Table deleted as it is mentioned in results

EP
C
AC
ST
JU

Table (2): Comparison between neonates with moderate and severe


25(OH)D deficiency in RDS group as regards demographic and maternal
clinical data:
Moderate Severe Independent t-
deficiency(No=23) deficiency(No=17) test
t/X²* P-value

Birth weight (kg) Mean ± 1.49 ± 0.51 1.64 ± 0.78 -0.771 0.446 Commented [M5]: This demonstrate that the degree of vitamin
SD D deficiency is not related to birth weight

Range 0.8 – 2.8 0.94 – 4


Gestational age Mean ± 31.43 ± 2.29 31.35 ± 2.26 0.112 0.911 Commented [M6]: This demonstrate that that the degree of
(weeks) SD vitamin D deficiency is not related to gestational age

D
Range 26 – 34 26 – 34
Mode of delivery no LSCS 20 (87) 13 (76.5) 0.744* 0.388

TE
(%) VD 3 (13) 4 (23.5)
Sex no (%) Female 17 (73.9) 6 (35.3) 5.966* 0.015
Male 6 (26.1) 11 (64.7)
Vitamin D Negative 11 (47.8) 10 (58.8) 0.474* 0.491
supplementation Positive 12 (52.2) 7 (41.2)

EP
during pregnancy no
(%)
Antenatal steroid no Negative 21 (91.3) 15 (88.2) 0.102* 0.749
(%) Positive 2 (8.7) 2 (11.8)
Preeclampsia no (%) Negative 19 (82.6) 15 (88.2) 0.243* 0.622
C
Positive 4 (17.4 2 (11.8)
DM no (%) Negative 22 (95.7) 16 (94.1) 0.048* 0.826
Positive 1 (4.3) 1 (5.9)
AC

PROM no (%) Negative 12 (52.2) 9 (52.9) 0.002* 0.962


Positive 11 (47.8) 8 (47.1)

*: Chi-square test
ST
JU

Table (3) Comparison between neonates with moderate and severe


25(OH)D deficiency in RDS group as regard respiratory parameters:
Moderate Severe Mann-Whitney
deficiency(No=23) deficiency(No=17) test
Z/t*/X²• P-
value
Apgar 1 Median 5 (4 – 6) 5 (4 – 6) -0.155 0.877
(IQR)
Range 0–7 2–6

D
Apgar 5 Median 7 (6 – 7) 7 (7 – 7) -0.032 0.975
(IQR)
2–9 5–9

TE
Range
Grade of RDS Grade I-2 9 (39.1) 7 (41.2) 0.017• 0.896
no (%) Grade 3-4 14 (60.9) 10 (58.8)
Initial pH Mean ± SD 7.32 ± 0.09 7.30 ± 0.10 0.746* 0.460
7.15 – 7.48 7 – 7.46

EP
Range
Initial CO2 Mean ± SD 47.94 ± 14.37 51.89 ± 15.94 -0.819* 0.418
Range 26.4 – 80.3 26.8 – 91.6
Mechanical Negative 1 (4.3) 0 (0) 0.758 0.384
ventilation Positive 22 (95.7) 17 (100)
C
no (%)
Maximum PIP (Cm Mean ± SD 12.74 ± 8.05 13.12 ± 9.23 -0.138* 0.891
H2O) Range 0 – 20 0 – 25
AC

Duration of Mean ± SD 12.09 ± 9.46 16.53 ± 13.46 -1.227* 0.227


mechanical
Range 2 – 40 2 – 40
ventilation (days)
Days of NICU Mean ± SD 25.83 ± 17.29 28.53 ± 13.69 -0.532* 0.598
admission (days) Range 7 – 52 3 – 46
Mortality no (%) Alive 21 (91.3) 13 (76.5) 1.687 0.194
ST

Died 2 (8.7) 4 (23.5)

*: Independent t-test

: Chi-square tes
JU
Commented [M7]: New table
Table (4): Correlation between serum vitamin D level and demographic,
respiratory and laboratory parameters of neonates in RDS group:

Serum vitamin D (ng)

D
r P-value

Gestational age -0.013 0.935

TE
Birth weight 0.042 0.797

Apgar 1 -0.020 0.904

EP
Apgar 5 -0.009 0.958

Initial pH -0.269 0.093

Initial CO2 0.072 0.658


C
Maximum PIP 0.047 0.774
AC

Days of mechanical ventilation (days) -0.061 0.710

Days of NICU admission (days) -0.161 0.320

Serum Ca (mg/dl) -0.013 0.935


ST
JU
Table (5): Logistic regression analysis of risk factors of RDS in our
patients:

D
B S.E. Wald Sig. Odds 95% CI for OR
ratio (OR)
Lower Upper

TE
Gestational age (weeks) -0.261 0.138 3.550 0.060 0.770 0.587 1.011

Serum vitamin D (ng/dl) -0.101 0.048 4.375 0.036 0.904 0.822 0.994

birth is independent risk factor for RDS. EP


Logistic regression analysis shows that low serum vitamin D level at
Commented [M8]: Added this table to highlight that low vitamin
D level independently from low gestational age a risk factor for RDS
in our patients as both our groups are almost gestational age
C
matched.

28
AC
ST
JU