Original Article
247
Is Higher 25-Hydroxyvitamin D Level Preventive for Respiratory Distress Syndrome in Preterm Infants? Nurdan Dinlen Fettah, MD1 Nurullah Okumuş, MD1
Ayşegül Zenciroğlu, MD1
1 Neonatal Intensive Care Unit, Dr. Sami Ulus Maternity and Children
Research and Training Hospital, Ankara, Turkey
Dilek Dilli, MD1
Serdar Beken, MD1
Address for correspondence Nurdan Dinlen Fettah, MD, Dr. Sami Ulus Hastanesi, Ankara, Turkey (e-mail: [email protected]).
Abstract
Keywords
► 25-hydroxyvitamin D ► respiratory distress syndrome ► prematurity ► infant
Objective The objective of this study was to investigate the relationship between cord blood 25-hydroxyvitamin D (25(OH)D) levels and respiratory distress syndrome (RDS) development in preterm infants. Study Design Between January 2012 and January 2013, 81 preterm infants, gestational age below 32 weeks, were prospectively enrolled into the study. Cord bloods of these newborns were tested for 25(OH)D levels. Low level was defined as 15 ng/mL (Group 1) and normal level as > 15 ng/mL (Group 2). Patients in Group 1 were also divided further into two subgroups as severe deficiency (Group 1a, 5 ng/mL) and mild deficiency (Group 1b, 5–15 ng/mL). Results In this study, 57 infants had low 25(OH)D levels (Group 1, median 8.0 ng/mL [interquartile range, IQR, 5–10]; Group 2, median 21 ng/mL [IQR, 19–24.7]). RDS rate was significantly higher in Group 1a (n ¼ 18, 32.7%) and Group 1b (n ¼ 34, 61.8%) compared with Group 2 (n ¼ 3, 5.4%) (p ¼ 0.001). There were no difference of having RDS between Group 1a (94.7%) and Group1b (89.5) (p ¼ 0.512). Multivariate analysis showed that higher 25(OH)D level can be preventive for the development of RDS (odds ratio, 0.6; 95% confidence interval (0.5–0.8); p ¼ 0.001). Conclusion Lower cord blood 25(OH)D levels might be associated with increased risk of RDS in preterm infants with very low birth weight.
Vitamin D is a steroidal hormone that has important roles in bone metabolism and neuromuscular functions. Understanding the extraosseous effects such as antiproliferative, prodifferentiative, proapoptotic, and immunomodulator functions of vitamin D has caused this hormone to be examined for its different aspects.1 In the past 20 years, attention has concentrated on vitamin D deficiency, a common problem of mother and child, based on the biological association with the mother and the child, and in this context, the identification of perinatal vitamin D deficiency has come into prominence. The pregnancy period has been emphasized as a critical period, especially in terms of extraosseous effects of vitamin D and the
effects of vitamin D deficiency during pregnancy on the fetus may continue throughout infancy.2 Respiratory distress syndrome (RDS) is the most common respiratory disorder in preterm infants.3 The most important role in the pathophysiology of RDS is thought to be due to surfactant deficiency and lung immaturity. Surfactant synthesis is regulated by many hormones, growth factor, and cytokines. It is already known that corticosteroids play a role in surfactant synthesis and lung maturation.4 In animal studies, it has been demonstrated that another steroid hormone, 25-hydroxyvitamin D (1,25(OH)D), affects fetal lung development and has role in lung morphogenesis and
received February 28, 2014 accepted after revision May 8, 2014 published online September 14, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1383849. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Am J Perinatol 2015;32:247–250.
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
surfactant production.5 This study aimed to demonstrate whether there is any relation between 25(OH)D levels of umbilical cord blood of preterm infants with very low birth weight and the risk of RDS development.
Outcome Measures The primary outcome of the study was to investigate the relationship between cord blood 25(OH)D levels and RDS development in preterm infants.
Ethics and Consent
Methods Design This was a prospective cohort study.
This study was approved by the institutional review board and strictly followed the institution’s ethical guidelines. This trial has been registered at www.clinicaltrials.gov (identifier NCT01812681).
Setting and Year of the Study The study was conducted in the level III Neonatal Intensive Care Unit of Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey, between January 2012 and January 2013.
Study Population A total of 81 Caucasian preterm infants with gestational age (GA) of < 32 weeks were prospectively enrolled into the study. Infants with severe birth asphyxia (Apgar score of 3 at 5 minutes), cyanotic congenital heart disease, major congenital anomalies, maternal history of suspected infection during pregnancy, premature rupture of membranes, chorioamnionitis, preeclampsia, gestational diabetes, coronary artery disease, and goiter or known thyroid diseases were excluded. Infants without parental consent were also not included. RDS diagnosis was based on radiological classification of pulmonary X-ray findings for RDS and clinical findings such as cyanosis, intercostal retraction with Silverman score. All infants were followed on nasal continuous positive airflow pressure (nCPAP) as an initial respiratory support and poractant alfa (Curosurf, Chiesi Pharmaceuticals, Italy) was given as an “early rescue therapy” when requirement of mechanical ventilation with a fraction of inspired oxygen of > 0.4 and mean airway pressure > 7 cm H2O to obtain arterial pressure of oxygen between 70 and 80 mm Hg needed. No improvement in clinical status, with over 40% of the oxygen requirements and blood gas partial pressure of carbon dioxide in patients over 60, second surfactant therapy applied 6 hours after the first dose. Recorded data included length of hospital stay and survival rate. Umbilical cord blood samples of the subjects were tested for 25(OH)D levels by Vit. D3-Ria-CT kits (BioSource Europe SA Rue de I’Industrie, 8, B-1400 Nivelles, Belgium). The investigators were blinded for vitamin D results. The detection limit (sensitivity) of the assay was 1.5 nmol/L (0.6 ng/mL) and cross-reactivity for 25(OH) ergocalciferol (specificity) was 0.6%. The normal range for 25(OH)D was stated as 28 to 175 nmol/L (11.2–70 ng/mL) and the intra- and interassay coefficients of variance (CVs) were 7 and 7.7%, respectively. Our laboratory range for 25(OH)D was 10 to 80 ng/mL and intra- and interassay CVs were 7.1, and 7.9%, respectively. The patients were divided into two groups according to their 25(OH)D status. Low level was defined as 15 ng/mL (Group 1) and normal group as > 15 ng/mL (Group 2).6 The vitamin D deficient group was further divided into two subgroups as severely deficient ( 5 ng/mL; Group 1a) and mildly deficient (5–15 ng/mL; Group 1b). American Journal of Perinatology
Vol. 32
No. 3/2015
Sample Size Calculation and Statistics SPSS 16.0 (SPSS, Chicago, IL) was used for statistical analysis. Data were expressed as mean (standard deviation) or medians (interquartile range, IQR) as appropriate. Differences among the two groups were analyzed by Student t-test or Mann–Whitney U test, where appropriate. Chi-square test was performed for categorical variables. Pearson or Spearman test was used to analyze correlation between variables. Wilcoxon and Friedman tests were used to analyze paired samples. A two-tailed p value of < 0.05 was accepted as significant. The diagnostic cutoff values were defined using the receiver operating curve (ROC) curve analysis. Sensitivity, specificity, and positive and negative predictive values of the diagnostic tests were also calculated.
Results The mean GA of the patients was 28.4 2.3 weeks, and mean birth weight (BW) was 1,138 260 g. The GA distributions of the patients were as follows: 23 (28.4%) were born in the 24th–27th, 31 (38.2%) were born in the 28th–30th, and 27 (33.4%) were born in the 31st–32nd gestational weeks. When patients are divided according to their vitamin D status, there were no significant differences between the groups for demographic and perinatal characteristics including BW, GA, gender, ethnicity, mode of delivery, and use of antenatal steroid as well (►Table 1). RDS developed in 18 patients (94.7%) in Group 1a, 34 patients (89.5%) in Group 1b, and 3 patients (12.5%) in Group 2. While 25(OH)D level of patients who developed RDS was 8.31 4.68 ng/mL (median, 8 ng/ mL), this value was 19.46 5.63 ng/mL (median, 21 ng/mL) in patients who did not develop RDS. Distribution of 25(OH)D levels and GA of infants with and without RDS are given in ►Fig. 1. It was observed that the development of RDS in the vitamin D deficient group (Group 1) was higher than the group with normal vitamin D levels (Group 2) (p ¼ 0.001) (►Fig. 2). There were no difference with regard to having RDS between Group 1a (94.7%) and Group1b (89.5%) (p ¼ 0.512); 19.2% of patients in Group 1b received additional dose of surfactant. When groups with deficient and normal vitamin D levels were compared in terms of duration of hospitalization, it was detected that median length of hospital stay for patients with low (32 days [IQR, 21–55]) vitamin D levels was longer than patients with normal (20 days [IQR, 15.2–35]) vitamin D levels (p ¼ 0.02). Duration of mechanical ventilation did not differ between Groups 1 and 2 (4 days [IQR, 1–29] vs.
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248
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
249
Table 1 Demographic data of the patients depending on their vitamin D status
Birth weight (g) (mean SD) Gestationel age Gender, n %
Group 1b (n: 38)b
Group 2 (n: 24)c
p
1,061 277
1,139 286
1,198 187
0.257
Mean SD
27,9 2,4
28,3 2,3
29,2 1,8
0.229
median, IQR
28/25–30
28/27–31
29/28–31
Female
13 (68.4)
20 (52.6)
12 (50)
Male
6 (31.6)
18 (47.4)
12 (50)
Mode of delivery, n %
Vaginal
8 (42.1)
14 (36.8)
7 (29.2)
CS
11(57.9)
24 (63.2)
17 (70.8)
Antenatal steroid, n %
Yes
15 (78.9)
26 (68.4)
22 (91.7)
No
4 (21.1)
12 (31.6)
2 (8.3)
0.426 0.668 0.102
Abbreviations: CS, cesarean section; IQR, interquartile range; SD, standard deviation. a 25(OH)D 5 ng/mL. b 25(OH)D 5–15 mg/mL. c 25(OH)D > 15 ng/mL.
4 days [IQR, 2–10], p ¼ 0.9). Twenty-one patients (36.8%) were diagnosed with bronchopulmonary dysplasia (BPD) in Group 1, and 2 patients (8.3%) were diagnosed with BPD in Group 2 (p ¼ 0.014). Four deaths occurred, three in Group 1a due to septicemia and one in Group 1b. There were no differences between groups in inclusion rate between summer and winter according to their vitamin D levels. When the gestational week, BW, gender, antenatal steroid use, mode of delivery, and 25(OH)D level of umbilical cord blood were accepted as possible independent risk variables in the multiple regression analysis, it was observed that low 25(OH)D levels of umbilical cord blood (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2–1.7; p ¼ 0.001) and GA (OR, 2.6; 95% CI, 1.3–5.5; p ¼ 0.001) increased the risk of RDS development. ROC analysis identified vitamin D cutoff value of 12.5 mg/dL (area under the curve 0.91) with a sensitivity of 88.5% and specificity of 83.6%.
Fig. 1 Distribution of 25-hydroxyvitamin D levels and gestational age of infants with and without respiratory distress syndrome.
Discussion 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.7–9 The normal range of 25(OH)D is not precise in defining vitamin D insufficiency and deficiency. The borderline of the sufficient and insufficient levels of vitamin D has yet to be clearly defined. In the current study, according to the American Academy of Pediatrics, a vitamin D level 15 ng/mL is determined as deficiency, and a vitamin D level 5 ng/mL as severe deficiency.6 Surfactant synthesis is regulated by many hormones, growth factors, and cytokines. Corticosteroids and thyroid hormones play a role in both surfactant synthesis and lung maturation. In animal studies, it has been found that a steroidal hormone 1,25(OH)D affects fetal lung development.10,11 In a study performed by Nguyen et al,12 the activation of receptors on Type 2 pneumocyte surfaces in rat lungs for 1,25(OH)D binding at the same time
Fig. 2 25-hydroxyvitamin D levels in patients with and without respiratory distress syndrome (RDS). American Journal of Perinatology
Vol. 32
No. 3/2015
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Group 1a (n: 19)a
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
with the beginning of differentiation of Type 2 pneumocytes and surfactant secretion has been shown with the monoclonal antibody method. In the same study, it was demonstrated that in Type 2 pneumocytes, 1,25(OH)D increased surfactant synthesis by increasing intracellular phosphatidylcholine and phosphatidylglycerol and increased surfactant secretion by providing migration of newly formed osmophilic lamellar bodies to the apex of the cell. Vitamin D not only plays a role in the regulation of the proliferation, differentiation, and apoptosis of different cells but also regulates the homeostasis of the extracellular matrix in specific extraosseous tissues, such as lung and skin tissue, by direct and indirect control of transforming growth factor-β, matrix metalloproteinase, and plasminogen activator systems.13 Sakurai et al7 stated that 1,25(OH)D and its metabolite C-3 epimer play key role in alveolar epithelial–mesenchymal interaction, lipofibroblast proliferation, and apoptosis of lung fibroblasts, which have critical roles in perinatal lung maturation. In the current study, it was seen that RDS developed in 52 patients (91.2%) out of 57 patients with vitamin D deficiency and in 18 patients (94.7%) out of 19 patients with severe vitamin D deficiency. When GA, BW, gender, antenatal steroid use, mode of delivery, and level of 25(OH)D in umbilical cord blood were considered as possible independent risk variables, it was seen that low levels of 25(OH)D in umbilical cord blood increased the risk of RDS development. Interestingly, a significance difference in having RDS was not shown between severe (Group 1a) and mild Group 1b) 25(OH)D deficient groups in this study. Considering the fact that the borderline of the sufficient and insufficient levels of vitamin D has yet to be clearly defined, we also speculated that a vitamin D level 15 ng/mL might be acceptable as deficiency for low-birth-weight preterm infants as well. In their study, Burris et al revealed that infants born before 32 weeks of GA had lower 25(OH)D levels compared with infants born during 32 to 37 weeks of GA and full-term infants.14 The vitamin D levels of umbilical cord blood are closely related to maternal serum levels of 25(OH)D. It has been detected that the concentration of 25(OH)D in umbilical cord blood was 50 to 60% of the concentration of 25(OH)D in maternal circulation. It was detected that this relation was linear and was also valid for the intake of pharmacological doses of vitamin D.15–17 It has been reported that the umbilical cord blood levels of 25(OH)D are correlated with maternal vitamin D levels in preterm infants, as well as full-term infants.16,17 In the current study, the maternal 25(OH)D levels could not examined unfortunately. Limitation of our study is that sample size in each group is small and not stratified properly. Although there were no differences between groups according to their GA, it is seen that lowest vitamin D levels were seen in the lower GA infants. On the contrary, there is still insufficient data about normal levels of vitamin D level during each gestational week and also about levels seemed normal or low. To the best of our knowledge, this is the first report of an association between vitamin D and RDS. In conclusion, it is to be further determined whether higher cord vitamin D may be a reflection of higher gestation infants with less RDS risk, or that the higher levels were protective of RDS. Further studies are necessary on this subject. American Journal of Perinatology
Vol. 32
No. 3/2015
Note The clinical trials registration number of this study is NCT01812681.
Conflict of Interest The authors declare that they have no conflict of interest.
References 1 Özkan B, Döneray H. Non-skeletal effects of vitamin D. Çocuk
Sağılığı ve Hastalıkları Dergisı 2011;54:99–119 2 Thandrayen K, Pettifor JM. Maternal vitamin D status: implications
3 4
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for the development of infantile nutritional rickets. Endocrinol Metab Clin North Am 2010;39(2):303–320 Rodriguez RJ. Management of respiratory distress syndrome: an update. Respir Care 2003;48(3):279–286, discussion 286–287 Mendelson CR. Role of transcription factors in fetal lung development and surfactant protein gene expression. Annu Rev Physiol 2000;62:875–915 Nguyen TM, Guillozo H, Marin L, Tordet C, Koite S, Garabedian M. Evidence for a vitamin D paracrine system regulating maturation of developing rat lung epithelium. Am J Physiol 1996;271(3 Pt 1): L392–L399 Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M. Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 2008;122(2):398–417 Sakurai R, Shin E, Fonseca S, et al. 1alpha,25(OH)2D3 and its 3epimer promote rat lung alveolar epithelial-mesenchymal interactions and inhibit lipofibroblast apoptosis. Am J Physiol Lung Cell Mol Physiol 2009;297(3):L496–L505 Marin L, Dufour ME, Tordet C, Nguyen M. 1,25(OH)2D3 stimulates phospholipid biosynthesis and surfactant release in fetal rat lung explants. Biol Neonate 1990;57(3-4):257–260 Phokela SS, Peleg S, Moya FR, Alcorn JL. Regulation of human pulmonary surfactant protein gene expression by 1alpha,25-dihydroxyvitamin D3. Am J Physiol Lung Cell Mol Physiol 2005; 289(4):L617–L626 Ballard PL, Ertsey R, Gonzales LW, Gonzales J. Transcriptional regulation of human pulmonary surfactant proteins SP-B and SP-C by glucocorticoids. Am J Respir Cell Mol Biol 1996;14(6): 599–607 Beers MF, Shuman H, Liley HG, et al. Surfactant protein B in human fetal lung: developmental and glucocorticoid regulation. Pediatr Res 1995;38(5):668–675 Nguyen M, Trubert CL, Rizk-Rabin M, et al. 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(1-5):93–97 Zasloff M. Fighting infections with vitamin D. Nat Med 2006;12(4): 388–390 Burris HH, Van Marter LJ, McElrath TF, et al. Vitamin D status among preterm and full-term infants at birth. Pediatr Res 2014; 75(1-1):75–80 Yorifuji J, Yorifuji T, Tachibana K, et al. Craniotabes in normal newborns: the earliest sign of subclinical vitamin D deficiency. J Clin Endocrinol Metab 2008;93(5):1784–1788 Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr 2004;79(5): 717–726 Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH. Perinatal metabolism of vitamin D. Am J Clin Nutr 2000;71(5, Suppl):1317S–1324S
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250
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
247
Is Higher 25-Hydroxyvitamin D Level Preventive for Respiratory Distress Syndrome in Preterm Infants? Nurdan Dinlen Fettah, MD1 Nurullah Okumuş, MD1
Ayşegül Zenciroğlu, MD1
1 Neonatal Intensive Care Unit, Dr. Sami Ulus Maternity and Children
Research and Training Hospital, Ankara, Turkey
Dilek Dilli, MD1
Serdar Beken, MD1
Address for correspondence Nurdan Dinlen Fettah, MD, Dr. Sami Ulus Hastanesi, Ankara, Turkey (e-mail: [email protected]).
Abstract
Keywords
► 25-hydroxyvitamin D ► respiratory distress syndrome ► prematurity ► infant
Objective The objective of this study was to investigate the relationship between cord blood 25-hydroxyvitamin D (25(OH)D) levels and respiratory distress syndrome (RDS) development in preterm infants. Study Design Between January 2012 and January 2013, 81 preterm infants, gestational age below 32 weeks, were prospectively enrolled into the study. Cord bloods of these newborns were tested for 25(OH)D levels. Low level was defined as 15 ng/mL (Group 1) and normal level as > 15 ng/mL (Group 2). Patients in Group 1 were also divided further into two subgroups as severe deficiency (Group 1a, 5 ng/mL) and mild deficiency (Group 1b, 5–15 ng/mL). Results In this study, 57 infants had low 25(OH)D levels (Group 1, median 8.0 ng/mL [interquartile range, IQR, 5–10]; Group 2, median 21 ng/mL [IQR, 19–24.7]). RDS rate was significantly higher in Group 1a (n ¼ 18, 32.7%) and Group 1b (n ¼ 34, 61.8%) compared with Group 2 (n ¼ 3, 5.4%) (p ¼ 0.001). There were no difference of having RDS between Group 1a (94.7%) and Group1b (89.5) (p ¼ 0.512). Multivariate analysis showed that higher 25(OH)D level can be preventive for the development of RDS (odds ratio, 0.6; 95% confidence interval (0.5–0.8); p ¼ 0.001). Conclusion Lower cord blood 25(OH)D levels might be associated with increased risk of RDS in preterm infants with very low birth weight.
Vitamin D is a steroidal hormone that has important roles in bone metabolism and neuromuscular functions. Understanding the extraosseous effects such as antiproliferative, prodifferentiative, proapoptotic, and immunomodulator functions of vitamin D has caused this hormone to be examined for its different aspects.1 In the past 20 years, attention has concentrated on vitamin D deficiency, a common problem of mother and child, based on the biological association with the mother and the child, and in this context, the identification of perinatal vitamin D deficiency has come into prominence. The pregnancy period has been emphasized as a critical period, especially in terms of extraosseous effects of vitamin D and the
effects of vitamin D deficiency during pregnancy on the fetus may continue throughout infancy.2 Respiratory distress syndrome (RDS) is the most common respiratory disorder in preterm infants.3 The most important role in the pathophysiology of RDS is thought to be due to surfactant deficiency and lung immaturity. Surfactant synthesis is regulated by many hormones, growth factor, and cytokines. It is already known that corticosteroids play a role in surfactant synthesis and lung maturation.4 In animal studies, it has been demonstrated that another steroid hormone, 25-hydroxyvitamin D (1,25(OH)D), affects fetal lung development and has role in lung morphogenesis and
received February 28, 2014 accepted after revision May 8, 2014 published online September 14, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1383849. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Am J Perinatol 2015;32:247–250.
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
surfactant production.5 This study aimed to demonstrate whether there is any relation between 25(OH)D levels of umbilical cord blood of preterm infants with very low birth weight and the risk of RDS development.
Outcome Measures The primary outcome of the study was to investigate the relationship between cord blood 25(OH)D levels and RDS development in preterm infants.
Ethics and Consent
Methods Design This was a prospective cohort study.
This study was approved by the institutional review board and strictly followed the institution’s ethical guidelines. This trial has been registered at www.clinicaltrials.gov (identifier NCT01812681).
Setting and Year of the Study The study was conducted in the level III Neonatal Intensive Care Unit of Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey, between January 2012 and January 2013.
Study Population A total of 81 Caucasian preterm infants with gestational age (GA) of < 32 weeks were prospectively enrolled into the study. Infants with severe birth asphyxia (Apgar score of 3 at 5 minutes), cyanotic congenital heart disease, major congenital anomalies, maternal history of suspected infection during pregnancy, premature rupture of membranes, chorioamnionitis, preeclampsia, gestational diabetes, coronary artery disease, and goiter or known thyroid diseases were excluded. Infants without parental consent were also not included. RDS diagnosis was based on radiological classification of pulmonary X-ray findings for RDS and clinical findings such as cyanosis, intercostal retraction with Silverman score. All infants were followed on nasal continuous positive airflow pressure (nCPAP) as an initial respiratory support and poractant alfa (Curosurf, Chiesi Pharmaceuticals, Italy) was given as an “early rescue therapy” when requirement of mechanical ventilation with a fraction of inspired oxygen of > 0.4 and mean airway pressure > 7 cm H2O to obtain arterial pressure of oxygen between 70 and 80 mm Hg needed. No improvement in clinical status, with over 40% of the oxygen requirements and blood gas partial pressure of carbon dioxide in patients over 60, second surfactant therapy applied 6 hours after the first dose. Recorded data included length of hospital stay and survival rate. Umbilical cord blood samples of the subjects were tested for 25(OH)D levels by Vit. D3-Ria-CT kits (BioSource Europe SA Rue de I’Industrie, 8, B-1400 Nivelles, Belgium). The investigators were blinded for vitamin D results. The detection limit (sensitivity) of the assay was 1.5 nmol/L (0.6 ng/mL) and cross-reactivity for 25(OH) ergocalciferol (specificity) was 0.6%. The normal range for 25(OH)D was stated as 28 to 175 nmol/L (11.2–70 ng/mL) and the intra- and interassay coefficients of variance (CVs) were 7 and 7.7%, respectively. Our laboratory range for 25(OH)D was 10 to 80 ng/mL and intra- and interassay CVs were 7.1, and 7.9%, respectively. The patients were divided into two groups according to their 25(OH)D status. Low level was defined as 15 ng/mL (Group 1) and normal group as > 15 ng/mL (Group 2).6 The vitamin D deficient group was further divided into two subgroups as severely deficient ( 5 ng/mL; Group 1a) and mildly deficient (5–15 ng/mL; Group 1b). American Journal of Perinatology
Vol. 32
No. 3/2015
Sample Size Calculation and Statistics SPSS 16.0 (SPSS, Chicago, IL) was used for statistical analysis. Data were expressed as mean (standard deviation) or medians (interquartile range, IQR) as appropriate. Differences among the two groups were analyzed by Student t-test or Mann–Whitney U test, where appropriate. Chi-square test was performed for categorical variables. Pearson or Spearman test was used to analyze correlation between variables. Wilcoxon and Friedman tests were used to analyze paired samples. A two-tailed p value of < 0.05 was accepted as significant. The diagnostic cutoff values were defined using the receiver operating curve (ROC) curve analysis. Sensitivity, specificity, and positive and negative predictive values of the diagnostic tests were also calculated.
Results The mean GA of the patients was 28.4 2.3 weeks, and mean birth weight (BW) was 1,138 260 g. The GA distributions of the patients were as follows: 23 (28.4%) were born in the 24th–27th, 31 (38.2%) were born in the 28th–30th, and 27 (33.4%) were born in the 31st–32nd gestational weeks. When patients are divided according to their vitamin D status, there were no significant differences between the groups for demographic and perinatal characteristics including BW, GA, gender, ethnicity, mode of delivery, and use of antenatal steroid as well (►Table 1). RDS developed in 18 patients (94.7%) in Group 1a, 34 patients (89.5%) in Group 1b, and 3 patients (12.5%) in Group 2. While 25(OH)D level of patients who developed RDS was 8.31 4.68 ng/mL (median, 8 ng/ mL), this value was 19.46 5.63 ng/mL (median, 21 ng/mL) in patients who did not develop RDS. Distribution of 25(OH)D levels and GA of infants with and without RDS are given in ►Fig. 1. It was observed that the development of RDS in the vitamin D deficient group (Group 1) was higher than the group with normal vitamin D levels (Group 2) (p ¼ 0.001) (►Fig. 2). There were no difference with regard to having RDS between Group 1a (94.7%) and Group1b (89.5%) (p ¼ 0.512); 19.2% of patients in Group 1b received additional dose of surfactant. When groups with deficient and normal vitamin D levels were compared in terms of duration of hospitalization, it was detected that median length of hospital stay for patients with low (32 days [IQR, 21–55]) vitamin D levels was longer than patients with normal (20 days [IQR, 15.2–35]) vitamin D levels (p ¼ 0.02). Duration of mechanical ventilation did not differ between Groups 1 and 2 (4 days [IQR, 1–29] vs.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
248
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
249
Table 1 Demographic data of the patients depending on their vitamin D status
Birth weight (g) (mean SD) Gestationel age Gender, n %
Group 1b (n: 38)b
Group 2 (n: 24)c
p
1,061 277
1,139 286
1,198 187
0.257
Mean SD
27,9 2,4
28,3 2,3
29,2 1,8
0.229
median, IQR
28/25–30
28/27–31
29/28–31
Female
13 (68.4)
20 (52.6)
12 (50)
Male
6 (31.6)
18 (47.4)
12 (50)
Mode of delivery, n %
Vaginal
8 (42.1)
14 (36.8)
7 (29.2)
CS
11(57.9)
24 (63.2)
17 (70.8)
Antenatal steroid, n %
Yes
15 (78.9)
26 (68.4)
22 (91.7)
No
4 (21.1)
12 (31.6)
2 (8.3)
0.426 0.668 0.102
Abbreviations: CS, cesarean section; IQR, interquartile range; SD, standard deviation. a 25(OH)D 5 ng/mL. b 25(OH)D 5–15 mg/mL. c 25(OH)D > 15 ng/mL.
4 days [IQR, 2–10], p ¼ 0.9). Twenty-one patients (36.8%) were diagnosed with bronchopulmonary dysplasia (BPD) in Group 1, and 2 patients (8.3%) were diagnosed with BPD in Group 2 (p ¼ 0.014). Four deaths occurred, three in Group 1a due to septicemia and one in Group 1b. There were no differences between groups in inclusion rate between summer and winter according to their vitamin D levels. When the gestational week, BW, gender, antenatal steroid use, mode of delivery, and 25(OH)D level of umbilical cord blood were accepted as possible independent risk variables in the multiple regression analysis, it was observed that low 25(OH)D levels of umbilical cord blood (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2–1.7; p ¼ 0.001) and GA (OR, 2.6; 95% CI, 1.3–5.5; p ¼ 0.001) increased the risk of RDS development. ROC analysis identified vitamin D cutoff value of 12.5 mg/dL (area under the curve 0.91) with a sensitivity of 88.5% and specificity of 83.6%.
Fig. 1 Distribution of 25-hydroxyvitamin D levels and gestational age of infants with and without respiratory distress syndrome.
Discussion 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.7–9 The normal range of 25(OH)D is not precise in defining vitamin D insufficiency and deficiency. The borderline of the sufficient and insufficient levels of vitamin D has yet to be clearly defined. In the current study, according to the American Academy of Pediatrics, a vitamin D level 15 ng/mL is determined as deficiency, and a vitamin D level 5 ng/mL as severe deficiency.6 Surfactant synthesis is regulated by many hormones, growth factors, and cytokines. Corticosteroids and thyroid hormones play a role in both surfactant synthesis and lung maturation. In animal studies, it has been found that a steroidal hormone 1,25(OH)D affects fetal lung development.10,11 In a study performed by Nguyen et al,12 the activation of receptors on Type 2 pneumocyte surfaces in rat lungs for 1,25(OH)D binding at the same time
Fig. 2 25-hydroxyvitamin D levels in patients with and without respiratory distress syndrome (RDS). American Journal of Perinatology
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No. 3/2015
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Group 1a (n: 19)a
Vitamin D Level in Respiratory Distress Syndrome
Fettah et al.
with the beginning of differentiation of Type 2 pneumocytes and surfactant secretion has been shown with the monoclonal antibody method. In the same study, it was demonstrated that in Type 2 pneumocytes, 1,25(OH)D increased surfactant synthesis by increasing intracellular phosphatidylcholine and phosphatidylglycerol and increased surfactant secretion by providing migration of newly formed osmophilic lamellar bodies to the apex of the cell. Vitamin D not only plays a role in the regulation of the proliferation, differentiation, and apoptosis of different cells but also regulates the homeostasis of the extracellular matrix in specific extraosseous tissues, such as lung and skin tissue, by direct and indirect control of transforming growth factor-β, matrix metalloproteinase, and plasminogen activator systems.13 Sakurai et al7 stated that 1,25(OH)D and its metabolite C-3 epimer play key role in alveolar epithelial–mesenchymal interaction, lipofibroblast proliferation, and apoptosis of lung fibroblasts, which have critical roles in perinatal lung maturation. In the current study, it was seen that RDS developed in 52 patients (91.2%) out of 57 patients with vitamin D deficiency and in 18 patients (94.7%) out of 19 patients with severe vitamin D deficiency. When GA, BW, gender, antenatal steroid use, mode of delivery, and level of 25(OH)D in umbilical cord blood were considered as possible independent risk variables, it was seen that low levels of 25(OH)D in umbilical cord blood increased the risk of RDS development. Interestingly, a significance difference in having RDS was not shown between severe (Group 1a) and mild Group 1b) 25(OH)D deficient groups in this study. Considering the fact that the borderline of the sufficient and insufficient levels of vitamin D has yet to be clearly defined, we also speculated that a vitamin D level 15 ng/mL might be acceptable as deficiency for low-birth-weight preterm infants as well. In their study, Burris et al revealed that infants born before 32 weeks of GA had lower 25(OH)D levels compared with infants born during 32 to 37 weeks of GA and full-term infants.14 The vitamin D levels of umbilical cord blood are closely related to maternal serum levels of 25(OH)D. It has been detected that the concentration of 25(OH)D in umbilical cord blood was 50 to 60% of the concentration of 25(OH)D in maternal circulation. It was detected that this relation was linear and was also valid for the intake of pharmacological doses of vitamin D.15–17 It has been reported that the umbilical cord blood levels of 25(OH)D are correlated with maternal vitamin D levels in preterm infants, as well as full-term infants.16,17 In the current study, the maternal 25(OH)D levels could not examined unfortunately. Limitation of our study is that sample size in each group is small and not stratified properly. Although there were no differences between groups according to their GA, it is seen that lowest vitamin D levels were seen in the lower GA infants. On the contrary, there is still insufficient data about normal levels of vitamin D level during each gestational week and also about levels seemed normal or low. To the best of our knowledge, this is the first report of an association between vitamin D and RDS. In conclusion, it is to be further determined whether higher cord vitamin D may be a reflection of higher gestation infants with less RDS risk, or that the higher levels were protective of RDS. Further studies are necessary on this subject. American Journal of Perinatology
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No. 3/2015
Note The clinical trials registration number of this study is NCT01812681.
Conflict of Interest The authors declare that they have no conflict of interest.
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