http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1023710

ORIGINAL ARTICLE

Association of vitamin D deficiency with acute lower respiratory tract infections in newborns Nurdan Dinlen, Aysegul Zenciroglu, Serdar Beken, Arzu Dursun, Dilek Dilli, and Nurullah Okumus J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by Kainan University on 04/09/15 For personal use only.

Division of Neonatology, Sami Ulus Maternity and Children’s Education and Research Hospital, Ankara, Turkey

Abstract

Keywords

Objective: To determine the association between serum 25-hydroxy vitamin D [25(OH)D] levels and acute respiratory tract infections (ALRTI) in newborns. Study design: The study group consisted of 30 term newborns with ALRTI who were admitted to our neonatal intensive care unit. Controls were 30 healthy newborns with the same age as the study group. Newborns and their mothers were tested for serum 25(OH)D levels, with a low level defined as 15 ng/mL. Results: The groups were similar in gestational week, birthweight, postnatal age and gender. Forty-three of the 60 infants (including study and control) had low 25(OH)D levels. The median 25(OH)D levels were lower [9.5 ng/mL (IQR ¼ 7.9–12.2)] in the study group than those of the control group [15.5 ng/mL (IQR: 12–18)] (p ¼ 0.0001). The median serum 25(OH)D levels in the mothers of the study group were also lower than those in the mothers of the control group [11.6 ng/mL (IQR ¼ 9.4–15.8) and 17.3 ng/mL (IQR ¼ 13.7–20.6), respectively] (p ¼ 0.0001). Conclusion: Lower blood 25(OH)D levels might be associated with increased risk of ALRTI in term newborn babies. Appropriate vitamin D supplementation during pregnancy and early childhood may enhance newborns’ respiratory health.

25-Hydroxyvitamin D, acute lower respiratory infection, newborn, vitamin D deficiency

Introduction Vitamin D is a steroidal hormone that has important roles in bone metabolism and neuromuscular functions. Recent knowledge of the extra-osseous effects such as the antiproliferative, pro-differentiative, pro-apoptotic, and immune modulator functions of vitamin D has led this hormone to be examined for different aspects [1]. Pregnancy has been emphasized as a critical period, especially in terms of the extra-osseous effects of vitamin D and the effects of vitamin D deficiency during pregnancy on the fetus. The effects may continue throughout infancy [2]. Recent evidence suggests that vitamin D enhances the innate immune response by induction of cathelicidin, which is highly expressed at barrier sites including respiratory epithelium, and endogenous anti-microbial peptide produced by macrophages and neutrophils [3,4]. Vitamin D is necessary for interferon-g dependent T-cell responses to infection and, in low vitamin D states, dysfunctional macrophage activity becomes evident. Vitamin D is also an important link between Toll-like receptor (TLR) activation and anti-bacterial response [5]. Genetic polymorphisms in vitamin D receptors are associated with hospitalization for acute respiratory tract infections (ALRTI) Address for correspondence: Dr Nurdan Dinlen, Division of Neonatology, Sami Ulus Maternity and Children’s Education and Research Hospital, Ankara, Turkey. E-mail: [email protected]

History Received 21 January 2015 Revised 18 February 2015 Accepted 24 February 2015 Published online 19 March 2015

in infancy [6]. ALRTI is also a serious infection during the newborn period because it is usually part of the sepsis [7,8]. However, few studies have investigated vitamin D deficiency in newborns with ALRTI. In this study, we aimed to determine the association between serum 25(OH)D plasma levels and ALRTI in newborns and their mothers.

Materials and methods This prospective study was conducted in Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey, from October 2013 to March 2014. The study was approved by the Local Ethics Committee. All parents were fully informed about the investigational nature of this study as well as its aim. Written consent was obtained from all parents. Inclusion and exclusion criteria The newborns who attended to outpatient clinics with respiratory symptoms were evaluated by a pediatrician or neonatologist and hospitalized in our neonatal intensive care unit (NICU) if required. A total of 60 term newborn babies were hospitalized in the NICU with signs and symptoms of pneumonia during the study period. Exclusion criteria were intrauterine developmental deficiency, gestational weeks less than 37 weeks, major congenital abnormality

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(including congenital cardiac disease), vitamin D supplementation initiated within 15 d after birth, requirement of formula feeding, and cases for which parents did not provide consent. Thirty of the infants (18, preterm babies; 2, congenital heart disease; 1, trisomy 18; 9, received vitamin D supplementation before admission) were therefore excluded from the study. The remaining 30 term newborns with ALRTI and their mothers enrolled to study. Control group consisted of 30 healthy newborns with a similar gestational week, gender, and postnatal age and their mothers.

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Demographic and clinical characteristics In order to collect the demographic characteristics, the neonates’ gestational week, birthweight (BW) and birthlength (BL), head circumference, and gender were recorded. A questionnaire was used to collect demographic data from the mothers, including their age, number of pregnancies, level of education, and use of vitamin supplements during pregnancy. Diagnostic tests The ALRTI diagnosis was made following the WHO criteria for pneumonia. These criteria included a history of cough and/or difficult breathing of less than 3 weeks duration, with (a) increased respiratory rate (rate  60/min); (b) lower chest wall in drawing or (c) cyanosis and/or inability to feed; and radiographic findings (unilateral/bilateral streaky densities, opacified areas, consolidation, and bilateral alveolar densities with air bronchograms) [9]. Complete blood count, serum C-reactive protein (CRP), blood culture and PCR multiplex for viral agents (RSV A and B, influenza A and B, coronavirus, H1N1, human metapneumovirus, parainfluenza, and adenovirus) were tested in the study group. A chest X-ray was also administered to study group participants. When necessary, patients were administered extra oxygen or a blood gas analysis. Tracheal aspirate cultures were obtained from the intubated patients. All study patients were evaluated by echocardiography to rule out congenital heart disease. Appropriate antibiotics and supportive treatment including oxygen, fluid, resuscitation, and inotropic agents were administered. We used clinical deterioration, blood culture and/or tracheal aspirate positivity in combination with chest radiograph, temperature abnormality, high blood leukocyte count and serum CRP values to make decisions for treatment with antibiotics. Clinical courses, oxygen and/or ventilatory requirements, bacteriological culture and PCR results were all recorded.

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25OH-Vit.D3-Ria-CT kits (BioSource Europe S.A. Rue de I’Industrie, 8, B–1400 Nivelles, Belgium). The investigators were blinded for vitamin D results. Vitamin D levels 15 ng/mL were considered deficient and levels 5 ng/mL were considered severely deficient, based on the recommendations of the Lawson Wilkins Pediatric Endocrine Society [10]. Statistical analyses Study data were evaluated by a computer using SPSS 18.0 statistics package program (SPSS Inc., Chicago, IL). Descriptive statistics were represented as the number of observations and their percentage. The Kolmogorov–Smirnov test was used to assess whether the data fit a normal distribution. Parametric data were represented as mean ± standard deviation and non-parametric data were represented as the median and interquartile range (IQR). The Student’s t-test or Mann–Whitney U-test was used to compare the continuous variables between independent groups; the chi-square test was used to compare the categorical values. The Wilcoxon test was used to compare the dependent groups. The Friedman analysis was used to compare the repetitive continuous variables. Pearson test was used to correlate the continuous variables. For the multivariate analysis, the possible factors identified with univariate analyses were further entered into the logistic regression analysis to determine independent risk factors of ALRTI development; results with a p value of 50.05 were considered statistically significant.

Results Mothers’ demographic data and use of vitamin D supplements during pregnancy The mothers’ ages, level of education, number of pregnancies and prenatal vitamin supplementation are presented in Table 1. Level of education, number of pregnancies, and use of prenatal vitamin supplementation did not significantly differ between the two groups. Newborns’ demographic and clinical data The newborns in the study group included 16 male and 14 female neonates, while the control group included 15 male and 15 female neonates. Mean postnatal age was not significantly different between the study and the control Table 1. Mothers’ demographic data and use of vitamin D supplements during pregnancy. Study group Control group p n: 30 n: 30 value

Laboratory evaluation for serum 25(OH)D levels Venous blood samples for measurement of 25(OH)D were obtained from infants in both study and control groups, as well as from their mothers on admission. For measurement of 25(OH)D vitamin levels, 2 mL of total blood were obtained in a non-anti-coagulant tube and stored at s20  C until the time of analysis. The 25(OH)D levels were measured using the APPLIED 3200 Biosystem (DPC Cirrus Inc., Diagnostic Products Corporation Los Angeles, CA) device following 2 h of incubation at room temperature with the BioSource

Mother age (year)* Number of pregnancy** Education years (year)** Education status** 0–5 years 5–8 years  9 years Supplementation of D vitamin _ (400 IU/d) (43 months), n (%) *mean; **median.

26.5 ± 6,1 2 (1–3) 8 (5–11) 10 9 11 25

(33.3) (30) (36.7) (83.3)

25.2 ± 5,3 2 (1–3) 9,5 (8–11) 5 10 15 26

(16.7) (33.3) (50) (86.7)

0.37 1 0.18 0.53 0.71

Effect of vitamin D on newborn pneumonia

DOI: 10.3109/14767058.2015.1023710

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Table 2. Anthropometric characteristics and levels of 25(OH)D in the study and control groups. Study group n: 30 Birth weight(g)* Length (cm)* Head circumference (cm)* Gestational age (week)* 25(OH)D levels of neonates (ng/mL) 25(OH)D levels of mothers (ng/mL)

Control group n: 30

3315 ± 299 3305 ± 303 49.5 ± 1.35 49.2 ± 1.36 34.6 ± 1.1 34.9 ± 1.2 38.9 ± 0.84 38.76 ± 0.72 9.5 (7.9–12.2) 15.5 (12–18)

p value 0.51 0.39 0.21 0.89 0.0001

11.6 (9.4–15.8) 17.3 (13.7–20.6) 0.0001

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*Mean.

groups (12.2 ± 4.6 d and 10.3 ± 5.2 d, respectively; p ¼ 0.72). Anthropometric characteristics of the study and control groups, including the gestational week, BW, BL, and head circumference were not significantly different (Table 2). There were no differences between groups regarding their mode of delivery. Control and study group, newborns were breastfeed. In radiographic evaluation, 10 unilateral/bilateral streaky densities, 5 opacified areas, 12 consolidations, and 3 bilateral alveolar densities with air bronchograms were defined. Three patients in the study group were followed-up on a mechanical ventilator, while two were followed-up on nasal CPAP treatment. The median duration of oxygen support during hospitalization was 4.5 d (IQR: 2.7–6.0) and the median duration of hospitalization was 11 d (IQR: 8.7–14.5).

Figure 1. Correlation between vitamin D levels of neonates and their mothers.

Serum 25(OH)D vitamin levels In the newborns, the median 25(OH)D vitamin level was lower in the study group [9.5 ng/mL (IQR 7.9–12.2)] than in the control group [15.5 ng/mL (IQR ¼ 12–18)] (p ¼ 0.0001). In the mothers, the median 25(OH)D vitamin level was also lower in the study group [11.6 ng/mL (IQR ¼ 9.4–15.8)] than in the control group [17.3 ng/mL (IQR ¼ 13.7–20.6)] (p ¼ 0.0001) (Table 2). A total of 43 newborns (26 in the study group and 17 in the control group) had vitamin D levels less than 15 ng/mL. Three patients exhibited severe vitamin D deficiency (below 5 ng/ mL). All three belonged to the study group. An evaluation of the mothers’ vitamin D levels showed that 22 mothers in the study group and 12 mothers in the control group had vitamin D levels below 15 ng/mL while seven mothers in the control group and only one mother in the study group had vitamin D levels above 20 ng/mL. A strong correlation was found between the vitamin D levels of the neonates and their mothers (r ¼ 0.71, p ¼ 0.001) (Figure 1) and a negative correlation was noted between the duration of oxygen therapy and vitamin D levels (r ¼ 0.73, p ¼ 0.001) (Figure 2). Among the blood culture samples obtained from each patient during hospitalization, only one showed microbial growth. Tracheal aspirate cultures obtained from the three intubated patients did not show any growth. PCR-multiplex results obtained for all patients showed that 13 patients were RSV (+), one patient had parainfluenza virus and one patient had human metapneumovirus.

Figure 2. Correlation between duration of oxygen therapy and vitamin D levels.

When the variables including mothers’ level of education, number of pregnancies, pregnancy age, and vitamin D deficiency in the neonates (15 ng/mL) were added into a model of multiple regression analysis, only vitamin D deficiency in the neonates were found to increase the risk of ALRTI development [OR: 5.3, 95% CI (1.3–21.1), p ¼ 0.01].

Discussion In the present study, serum 25(OH)D levels in the newborns who were monitored with ALRTI were found to be lower than in the healthy neonates. 25(OH)D levels in the mothers in the

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study group were also lower than the levels measured in mothers in the control group. Furthermore, a strong correlation was detected between the vitamin D levels of the mothers and the neonates in both the study and control groups. These findings are important because they show that newborns with vitamin D deficiency may have an increased risk of suffering from ALRTI, and the ALRTI is common cause of morbidity and mortality in the newborn period, especially in developing countries [7]. Vitamin D appears to be necessary for interferon-g dependent T-cell responses to infection. Vitamin D is also an important link between TLR activation and anti-bacterial response [11]. Animal studies have revealed that another steroid hormone, 1.25(OH)2D, affects fetal lung development [12,13]. In their study performed on rats, Sakurai et al. [14] reported that 1.25(OH)2D and one of its metabolites, the C-3 epimer, play key roles in the alveolar epithelial–mesenchymal interaction, which is a critical component of perinatal lung maturation, as well as in the proliferation and apoptosis of the lung lipofibroblasts. In our previous study, we also showed that lower cord blood 25(OH)D levels might be associated with increased risk of neonatal respiratory distress syndrome (RDS) in preterm infants with very low BW [15]. Another study performed by Mansbach et al. [16] demonstrated that the infants of women with vitamin D deficiency during pregnancy had an increased rate of wheezing. Infants with low levels of vitamin D in the blood taken from the umbilical cord were exposed to increased risk of respiratory diseases during the first 3 months of their life. In another study performed by Karatekin et al. [17], the serum concentrations of 25(OH)D in the neonates with ALRTI diagnosis and no clinical rickets were evaluated; their mothers were evaluated as well. According to these findings, infants with subclinical vitamin D deficiency were exposed to an increased risk of impairment by ALRTI. Given the early susceptibility of these infants with vitamin D deficiency in the newborn period, it is possible that vitamin D may play a role in in utero lung development. To further explore this question, Zosky et al. used a mouse model to study the relationship between vitamin D deficiency and somatic growth, lung function, and lung structure at 2 weeks of age. The offspring of vitamin D deficient mice were found to have significantly reduced lung volume [18]. Given this potential in utero influence that vitamin D has on lung development, it is possible that, in addition to the previously described effect on infection risk, vitamin D deficiency may augment susceptibility to infection by decreasing the respiratory reserve of infants. In order to define vitamin D insufficiency and deficiency, various studies have determined the normal range for 25(OH)D, which is the major form of vitamin D and the best indicator for tissue levels. There is still no consensus on the most convenient serum vitamin D levels. For children, it is advised to evaluate the status based on a table recently introduced by the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee; it shows the vitamin D status according to the level of 25(OH)D define as severe deficiency 5 ng/mL and low level 15 ng/mL that we also used in our study [10].

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The study also shows that the newborns with ALRTI were hospitalized for about 11 d on average in NICU. This indicates the economic burden on family and community due to vitamin D deficiency in newborns. The strengths of the current study involve the assessment of vitamin D levels in newborns and their mothers, the similarity between the cases with respect to the gestational week, and performance of the assessments within the same season. The limitations of the present study include the small sample size, which did not allow the researchers to evaluate the association between the severity of ALRTI and vitamin D levels. On the other hand, other biochemical parameters such as calcium, phosphorus, alkaline phosphatase and parathormone levels were not recorded in the subjects. However, we can say that none of the study subjects and the mothers had any clinical signs of vitamin D deficiency. This study was conducted during the winter months. Since it is known that vitamin D concentrations show seasonal variation, conducting similar studies in different seasons, especially in autumn, could further generalize the results of the study [19]. In addition, we excluded babies who received vitamin D supplementation from the study group becauseif we have enrolled these babies, correlation of the vitamin D levels between babies and mothers would not reflect the true relation. In conclusion, 25(OH)D vitamin deficiency in the neonates may increase the risk of ALRTI. The most appropriate dose and timing of maternal vitamin D intake during pregnancy to maintain adequate levels in mother and fetus are not known. Monitoring mothers’ compliance with vitamin D supplement therapy and personalization of the vitamin D supplement levels based on the measured levels of vitamin D would improve the vitamin D levels in the neonates. Messages on the importance of proper nutrition, vitamin D supplementation and sunlight exposure during pregnancy should be given to mothers. Longitudinal studies are required to confirm our findings and establish the mechanisms between serum 25(OH)D levels and ALRTI in newborns that underlie these observations.

Declaration of interest The authors declare no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Association of vitamin D deficiency with acute lower respiratory tract infections in newborns.

To determine the association between serum 25-hydroxy vitamin D [25(OH)D] levels and acute respiratory tract infections (ALRTI) in newborns...
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