Serum Periostin Levels at Birth as a Predictor for Bronchopulmonary Dysplasia in Premature Infants.

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Hayato Go, Junya Ono, Hitoshi Ohto, Kenneth E. Nollet, Kenichi Sato, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-100219/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. Periostin plays an important role in the development of various disease such as allergic and pulmonary diseases. The objectives of this study were to evaluate the perinatal factors affecting serum periostin levels at birth and to establish whether serum periostin at birth, day of life (DOL) 28 and corrected 36 week’s gestational age could be potential biomarkers for BPD. Methods: A total of 139 preterm (n=98) and healthy (n=41) infants were included in this study. Among of them, 98 infants born < 32 weeks were divided into BPD (n=44) and non-BPD infants (n=54). Serum periostin levels were measured using an enzyme-linked immunosorbent assay. Results: The median serum periostin levels at birth in preterm infants born < 32 weeks were significantly higher than those in healthy infants. Furthermore, there were significant inverse correlations between gestational age, birth weight, and serum periostin levels at birth among all 139 preterm and healthy infants. Among preterm infants born < 32 weeks, with BPD and without BPD infants, the median serum periostin levels at birth were higher with BPD than without (345.0 ng/mL vs 278.0 ng/mL, P=0.002 ). Multivariate analysis revealed that serum periostin levels at birth was significantly associated with BPD ( P=0.032 ). Receiver operating characteristic analysis for serum periostin levels at birth in infants with and without BPD revealed that the area under the curve were 0.725 (95% CI 0.627- 0.822, P=0.0001 ). Serum periostin levels at birth with moderate/severe BPD were significantly higher than those with non-BPD/mild BPD (338.5 ng/mL vs 283.5 ng/mL, P=0.0032 ). Conclusions: Serum periostin levels at birth were significantly correlated with BW and GA. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD. Pediatrics Health Economics & Outcomes Research biomarker periostin bronchopulmonary dysplasia gestational age birth weight Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects neurodevelopmental impairment and long-term respiratory outcomes such as childhood wheezing and asthma ( 1 , 2 ). BPD results from various perinatal factors including maternal inflammation, surfactant deficiency, ventilation and oxygen toxicity ( 3 , 4 ). Premature infants are often exposed to positive pressure ventilation, and supplemental oxygen, contributing to the development of BPD. An important pathophysiological feature of infants affected with BPD is developmental arrest of alveolarization ( 4 ). Such structural alterations are accompanied by characteristic inflammatory changes and extensive remodeling of the extracellular matrix (ECM), together with increased smooth muscle mass in small pulmonary arteries and airways ( 5 ). Periostin is characterized as both a matricellular protein as well as ECM protein belonging to the fasciclin family ( 6 , 7 ). Periostin plays an important role in the development of allergic, pulmonary, and the other diseases ( 7 , 8 ). Lung periostin is expressed in human lung fibroblasts and human bronchial epithelial cells ( 9 ). Since periostin is regulated by interleukin (IL)-4 and IL-13 and is involved in pathogenesis of fibrosis and allergy in various diseases, many studies reported that serum and plasma periostin levels were a potential biomarker for various disease such as idiopathic lung fibrosis in adults and asthma ( 7 , 10 , 11 , 12 ). Furthermore, various factors such as transforming growth factor-beta (TGF-β), IL-4, IL-13, mechanical stress, and connective tissue growth factor upregulate periostin ( 13 ). In the pathogenesis of BPD, TGF-β is involved in lung vascular development. Periostin are associated with TGF-β mediated fibrosis and lung development exposed to hyperoxia ( 8 , 14 ). TGF-β, in turn, is associated with the pathogenesis of BPD during lung vascular development. Although periostin expression is increased in autopsy lungs of preterm neonates with BPD ( 14 ), few reports have been suggesting the relationship between serum periostin levels at birth and BPD. Although Ahlfeld et al reported that elevated plasma periostin levels in BPD patients on day 28 of life (DOL28) compared with that’s’ of non-BPD patients, their study had several limitations, such as a low sample number and their choice of sampling times (DOL7 and DOL28) ( 15 ). While some studies propose reference intervals for serum periostin in children ( 16 , 17 ), reports correlating serum periostin levels in term and preterm births with other perinatal factors are lacking. In this study, we hypothesized that serum periostin at birth might increase in BPD patients, and could serve as biomarkers of BPD. The objectives of the present study were to evaluate the perinatal factors affecting serum periostin levels at birth in preterm and healthy infants and to validate whether serum periostin at birth, DOL28 and corrected 36 week’s gestational age could be potential biomarkers for BPD. Materials And Methods Ethics approval and compliance This research was approved by the Institutional Review Board of Fukushima Medical University, which is guided by local policy, national law, and the World Medical Association Declaration of Helsinki. As our human subjects were neonates, informed consent was solicited from parents or other legal guardians, and documented in writing. NICU Patients Blood samples were obtained from mechanically ventilated or oxygenated patients with parental consent in the neonatal intensive care unit (NICU) of Fukushima Medical University from November 2014 to July 2020. We examined cord blood at birth and venous blood at 36 weeks postmenstrual age and DOL28. Newborns with congenital anomalies or those who died prior to postnatal day 28 were excluded. Data for analysis included gestational age, phenotypic sex, body weight at birth, invasive mechanical ventilation at DOL28, supplemental oxygen at DOL14, respiratory distress syndrome (RDS), being small for gestational age (SGA), patent ductus arteriosus (PDA), Apgar scores and maternal complications: chorioamnionitis (CAM), premature rupture of membrane (PROM), hypertensive disorders of pregnancy (HDP) were recorded. BPD was defined in accordance with the National Institutes of Health consensus definition for infants ( 18 ). At a postmenstrual age of 36 weeks, the infants were classified into the following groups: mild BPD was defined as the need for supplemental oxygen at ≥ 28 days but not at 36 weeks postmenstrual age; moderate BPD was defined as the need for supplemental oxygen at 28 d, in addition to supplemental oxygen at FiO 2 (fraction of inspired oxygen) ≤ 0.30 at 36 weeks postmenstrual age; and criteria for severe BPD included the need for supplemental oxygen at 28 days and, at 36 weeks postmenstrual age, the need for mechanical ventilation and/or FiO 2 (fraction of inspired oxygen) > 0.30 ( 18 ). SGA was defined as a birth weight of <-1.5 standard deviations that was corrected for the gestational age and sex in accordance with the criteria from previous study ( 19 ). Healthy neonatal subjects Healthy neonates who were born from 36.6 weeks to term in our hospital were included if informed consent was obtained from parents and/or legal guardians and documented in writing. Serum periostin measurements Serum samples were obtained from neonates at birth, DOL 28, and corrected 36 weeks. Using serum samples stored at -80℃ until assay, serum periostin levels were measured using an enzyme-linked immunosorbent assays (ELISA) at Shino-Test (Kanagawa, Japan), as previously described ( 20 , 21 , 22 ). Statistical analysis All data are presented as the medians. The Mann–Whitney U -test was used to compare continuous variables, and χ2 test was used for nominal variables. To evaluate the correlation between two parameters, Pearson’s correlation coefficient was calculated. We performed multivariate analyses to determine factors significantly associated with serum periostin levels at birth as BW, GA, RDS, BPD, oxygen supplementation at DOL 14, invasive mechanical ventilation at DOL 28, and Apgar score at 1 min < 3 in premature infants born at less than 32 weeks. Next, we also performed multivariate analyses to determine factors significantly associated with BPD as potential confounding factors such as BW, GA, invasive mechanical ventilation at DOL 28, Apgar Score at 1 min < 3, oxygen supplementation at DOL 14 and serum periostin levels at birth in premature infants born at less than 32 weeks. The accuracy of diagnosing of classifying BPD was evaluated by receiver operating characteristics (ROC) curves with area under the curve (AUC) use to quantify the sensitivity of independent risks for BPD. The levels of significance were set 0.05 (P < 0.05). Data analysis was performed with SPSS (version 21.0) and GraphPad Prism version 8 software. Results Clinical characteristics and Serum periostin levels at birth in preterm and term infants. A total of 139 preterm (n = 98) and healthy (n = 41) infants were included in this study. The clinical characteristics of preterm infants born at less than 32 weeks and healthy control are summarized in Table 1 . Figure 1 shows the serum periostin levels at birth in preterm and term infants. The median serum periostin levels at birth among preterm infants born at less than 32 weeks was significantly higher than those among healthy infants (292.0 ng/mL vs 142.0 ng/mL, P < 0.0001 ) (Fig. 1 A). Furthermore, there were significant inverse correlations between BW (r=-0.672, P < 0.0001 ), GA (r=-0.640, P < 0.0001 ), and serum periostin levels at birth in 139 preterm and term infants (Fig. 1 B and C). Table 1 Characteristics of subjects Healthy control (N = 41) Preterm Infants < 32 weeks (N = 98) Gestational age, median (IQR), weeks 38.7 (37.7–39.9) 26.0 (24.2–28.2) Birth weight, median (IQR), g 2948 (2588–3122) 743 (621–1068) Male gender, n (%) 18 (43.9) 48 (49.0) CAM, n (%) NA 43 (43.9) Antenatal steroid, n (%) 0 (0) 90 (91.8) PROM, n (%) 0 (0) 26 (26.5) HDP, n (%) 0 (0) 8 (8.2) RDS, n (%) NA 71 (72.4) SGA, n (%) 0 (0) 15 (15.3) PDA, n (%) NA 55 (56.1) BPD, n (%) NA 44 (44.9) Oxygen supplementation at DOL14, n (%) NA 51 (52.0) Invasive Mechanical ventilation at DOL28, n (%) NA 61 (62.2) Apgar score at 1 min < 3, n (%) 0 (0) 26 (26.5) Apgar score at 5 min < 3, n (%) 0 (0) 10 (10.2) IQR: interquartile range, NA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, ROP: retinopathy of prematurity, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus. Perinatal factors and serum periostin levels at birth in preterm infants born at less than 32 weeks. Next, among preterm infants born less than 32 weeks, we correlated serum periostin levels at birth with perinatal factors (Table 2 ). GA and BW were negatively correlated with serum periostin levels at birth. Additionally, serum periostin levels at birth were significantly higher in RDS, BPD, invasive mechanical ventilation at DOL 28, and Apgar score at 1 min < 3. In particular, the median serum periostin levels at birth were higher with BPD than without (345.0 ng/mL vs 278.0 ng/mL, P = 0.002 ). Multivariate analysis revealed that serum periostin levels at birth was significantly associated with BPD ( P = 0.032 ). Table 2 Associations between serum periostin levels at birth and perinatal factors in preterm infants born < 32 weeks Serum periostin levels at birth (ng/mL) coefficient Univariate analysis (P-value) Multivariate analysis (P-value) Gestational age - -0.265 0.008 0.588 Birth weight - -0.326 0.001 0.396 Male vs Female 306.5 vs 287.5 - 0.234 - CAM vs non-CAM 289.0 vs 296.5 - 0.994 - Antenatal steroid vs no antenatal steroid 300.0 vs 266.6 - 0.078 - PROM vs non-PROM 295.5 vs 291.5 - 0.554 - HDP vs non-HDP 300.0 vs 266.6 - 0.315 - RDS vs non-RDS 303.0 vs 256.0 - 0.008 0.081 SGA vs non-SGA 290.0 vs 321.0 - 0.598 - PDA vs non-PDA 299.0 vs 291.0 - 0.155 - BPD vs non-BPD 345.0 vs 278.0 - 0.002 0.032 Oxygen supplementation at DOL14 vs no oxygen supplementation at DOL14 303.0 vs 284.0 - 0.188 - Invasive mechanical ventilation at DOL28 vs no invasive mechanical ventilation at DOL28 305.0 vs 252.0 - 0.002 0.845 Apgar score at 1 min < 3 vs no Apgar score at 1 min < 3 326.5 vs 283.0 - 0.022 0.364 Apgar Sscore at 5 min < 3 vs no Apgar score at 5 min < 3 300.0 vs 291.5 - 0.469 - NA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus. Serum periostin levels in BPD infants To investigate whether serum periostin levels were associated with BPD, preterm infants born at less than 32 weeks were divided into BPD neonates (n = 44) and non-BPD neonates (n = 54) (Table 3 ). The median GA in BPD infants was significantly lower than those in non-BPD neonates (24.4 weeks vs 27.2 weeks, P < 0.001 ). The median BW in BPD neonates was also significantly lower than those in non-BPD infants (638 g vs 952 g, P < 0.001 ). The occurrence of Apgar score at 1 min < 3 (40.9% vs 14.8%, P < 0.005 ) was significantly higher in BPD infants compared with those in non-BPD infants. Furthermore, the incidence of the invasive mechanical ventilation at DOL 28 and oxygen supplementation at DOL14 in BPD infants were significantly higher than those in non-BPD infants. There were no significant differences between BPD and non-BPD infants in terms of phenotypic sex, antenatal steroid usage, SGA, PDA, CAM, HDP and PROM (Table 3 ). In multivariate analysis of the correlation between serum periostin at birth and clinical parameters, serum periostin levels at birth significantly correlated with BPD ( P = 0.013 ) and BW ( P = 0.021 ) (Table 3 ). Receiver operating characteristic analysis for serum periostin levels at birth in infants with and without BPD revealed that the area under the curve were 0.725 (95% CI 0.627–0.822, P = 0.0001 ) (Fig. 2 ). Using a threshold of serum perisostin > 305 ng/mL at birth identified BPD with 71.7% sensitivity and 63.4% specificity. Table 3 Characteristics of BPD and non-BPD infants Non-BPD (N = 54) BPD (N = 44) Univariate analysis Multivariate analysis P-value P-value Gestational age, median (IQR), week 27.2 (25.6–29.6) 24.4 (23.7–26.3) <0.001 0.242 Birth weight, median (IQR), gram 952 (622–1210) 638 (438–734) <0.001 0.027 Male gender, n (%) 26 (51.8) 22 (46.5) 0.508 - CAM, n (%) 23 (39.3) 20 (48.8) 0.311 - Antenatal steroid, n (%) 50 (94.6) 40 (90.7) 0.522 - PROM, n (%) 13 (24.1) 13 (29.5) 0.647 - HDP, n (%) 7 (13.0) 1 (2.3) 0.070 - RDS, n (%) 35 (64.3) 36 (81.4) 0.072 - SGA, n (%) 6 (12.5) 9 (20.9) 0.262 - PDA, n (%) 34 (76.7) 21 (53.5) 0.155 - Oxygen supplementation at DOL14, n (%) 20 (37.0) 31 (70.5) 0.001 0.041 Invasive mechanical ventilation at DOL28, n (%) 21 (66.1) 40 (90.9) < 0.001 0.391 Apgar score at 1 min < 3, n (%) 8 (14.8) 18 (40.9) 0.005 0.571 Apgar score at 5 min < 3, n (%) 3 (5.6) 7 (15.9) 0.107 - Serum periostin levels at birth (ng/mL) 345.0 278.0 0.002 0.013 IQR: interquartile range, NA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus. P-value was compared between BPD and non-BPD neonates Figure 3 shows the serum periostin levels at birth, DOL 28 and corrected 36-week’s postmenstrual age in BPD and non-BPD infants. The median periostin levels on DOL 28 in BPD infants were significantly lower compared with those at birth (345.0 ng.mL vs 281.5 ng/mL, P = 0.003 ). However, the median serum periostin levels on DOL 28 and corrected age of 36-week’s gestational were not significantly differed in BPD infants compared with non-BPD infants (DOL 28: 281.0 ng/mL vs 238.5 ng/mL, corrected 36-week’s postmenstrual age: 327.5 ng/mL vs 332.0 ng/mL). Next, we evaluated the relationships between serum periostin at birth and severity of BPD (Fig. 4 ). Serum periostin levels at birth with moderate/severe BPD were significantly higher than those with non-BPD/mild BPD (338.5 ng/mL vs 283.5 ng/mL, P = 0.0032 ). Discussion To our knowledge, this is the first study to describe an association between serum periostin levels at birth and perinatal factors in preterm and term infants and the correlation between serum periostin levels at birth and BPD. The present study revealed that higher serum periostin levels at birth in preterm infants born at less than 32 week’s gestational age are independent risk factors for BPD and reflects the severity for BPD. Although there are many studies trying to demonstrate an association between serum biomarkers and the risk of BPD, few suggest a correlation between blood periostin levels and BPD. In this study, we also demonstrated that serum periostin levels on DOL28 and corrected 36 week’s postmenstrual age could not serve as potential biomarkers for BPD. Ahlfeld et al previously suggested that early elevation of plasma periostin on DOL28 is significantly associated with chronic ventilator-dependent bronchopulmonary dysplasia ( 15 ). This may be due to the differences in the type of sample, sample size, and method of analysis. Ahlfeld’s study used plasma samples and did not include multivariate or measure periostin levels at birth. In terms of the relationship between periostin and lung disease, previous studies demonstrated that elevated serum periostin levels were associated with various lung disease such as asthma, idiopathic pulmonary fibrosis, and COPD in children and adults ( 5 , 8 , 23 , 24 ). Furthermore, the expression of lung periostin was upregulated in patients with idiopathic lung fibrosis ( 8 , 11 ). Bozyk et al. also reported that periostin expression increased in autopsy lungs of preterm neonates with BPD ( 14 ). In a murine model of BPD exposed to hyperoxia, hyperoxia upregulated periostin expression in neonatal mice lung ( 14 ). Furthermore, lung periostin levels were also increased during the saccular stage, as previously shown ( 25 ). Although the mechanism by which periostin is associated with the pathogenesis of BPD remains poorly understood, we speculate that the linkage of periostin and TGF- β might be associated with the pathogenesis of BPD. Periostin and TGF-β are known to play a critical role in the proliferation of lung fibroblasts ( 9 ). Furthermore, many studies in different animal models of BPD confirm elevated TGF-β expression levels and activation of its associated pathways as an important part of lung disease pathophysiology ( 22 , 26 , 27 ). Also, we previously reported that serum TGF-β levels were upregulated in BPD patients ( 28 ). Another new finding in this study was significant correlation of serum periostin levels at birth with BW and GA. Fujitani et al. reported that periostin levels in non-allergic children from 0 years to 15 years were almost 91.9-124.8 ng/mL ( 29 ). They also suggested that serum periostin levels gradually increased after age 10 years. Anderson et al also reported that serum periostin levels at ages 2–6 years ranged from 120–150 ng/mL ( 16 ). In this study, serum periostin levels of healthy neonates were around 140 ng/mL. Furthermore, serum periostin levels at birth in neonates born at less than 32 week’s gestational age was almost 340 ng/mL. On the other hand, a previous study proposed a periostin threshold of 95 ng/mL based on values from healthy adult controls ( 30 ). Thus, serum periostin levels in infants were the highest when comparing infants, children, and adult. These developmental changes of serum periostin levels may be related to metabolic turnover and growth as periostin is a component of the extracellular matrix and regulates serum type I collagen formation, which is essential component of skin, tendon, and bone development ( 16 , 31 ). Compared with term infants, the cord blood serum procollagen type I C-terminal propeptide (PICP) as bone information in preterm infants was significantly higher and influenced by fetal age ( 32 ). Our study has several limitations. First, it was performed at a single center and the sample size of BPD patients was small. To validate our observations, a larger sample size with multiple centers and different ethnic cohorts would be invaluable. Second, we could not evaluate lung periostin. A previous study demonstrated that lung periostin in BPD infants was higher than in healthy lungs at term ( 9 ). Third, we could not detect the cellular sources of periostin. Thus, our next goal is to determine the cell types secreting periostin as well as the mechanism(s) of upregulation of periostin in BPD neonates; this will advance understanding of the pathogenesis of BPD. Lastly, in this study, we did not investigate the correlation between periostin levels and Th2 cytokines such as IL-4 and IL-13. It is noteworthy that upon stimulation by IL-4 and IL-13, periostin could be detected in lung fibroblasts ( 2 ). One of the main consequences of BPD is lung fibrosis. Although a previous study suggested that IL-4 and IL-13 levels of tracheal aspirates from premature infants were very low and did not correlate with BPD ( 29 ), premature infants born at less than 32 week’s gestational age have increased nasal airway IL-4 and IL-13 secretion during rhinovirus infections ( 30 ). In summary, we conclude that serum periostin levels were significantly correlated with birth weight and gestational age. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD and severity of BPD. The mechanism by which serum periostin is upregulated in BPD infants and inversely correlated with gestational age and birth weight remains to be further elucidated. Abbreviations BPD: bronchopulmonary dysplasia BW: birth wight GA: gestational age RDS: respiratory distress syndrome CAM: chorioamnionitis PROM: premature rupture of membrane HDP: hypertensive disorders of pregnancy SGA: small for gestational age RDS: respiratory distress syndrome PDA: patent ductus arteriosus Declarations GRANTS This work was supported by Grants-in-Aid Scientific Research from the Japan society for the promotion of science (JSPS), KAKENHI (Grant number: 20K08233(HG)). DISCLOSUREs Junya Ono is a salaried employee of Shino-Test Co., Ltd., which provided ELISA for periostin without stipulations or influence over the interpretation of test results. The authors have no other potential or actual conflicts of interest pertaining to the contents of this article. Author Contribution Hayato Go designed the study, carried out the analyses and drafted the manuscript, and reviewed and revised the manuscript. Hitoshi Ohto, Kenneth Nollet, Satoshi Nunomura, Kenji Izuhara, and Mitsuaki Hosoya reviewed the manuscript. Junya Ono carried out the analyses and reviewed the manuscript. Hajime Maeda, Kei Ogasawara, Maki Sato, Yohei Kume, Hirotaka Ichikawa, Yuji Kanai, Nozomi Kashiwabara, and Kentaro Haneda collected the samples and reviewed the manuscript. All author approved the final manuscript as submitted and agree to accountable for all aspects of the work. Disclosure statement The authors have no other potential or actual conflicts of interest pertaining to the contents of this article. References Gough A, Spence D, Linden M, Halliday HL, McGarvey LPA. General and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia: a systematic review. Chest . 2012;141(6):1554-1567. Gough A, Linden M, Spence D, Patterson CC, Halliday HL, McGarvey LP. Impaired lung function and health status in adult survivors of bronchopulmonary dysplasia. Eur Respir J. 2014 Mar;43(3):808-16. 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Mokres LM, Parai K, Hilgendorff A, et al. Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice. Am J Physiol Lung Cell Mol Physiol . 2010;298(1):L23-L35. Hilgendorff A, Parai K, Ertsey R, et al. Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth. Am J Physiol Lung Cell Mol Physiol . 2012;303(3): L215-L227. Go H, Maeda H, Miyazaki K, et al. Extracellular vesicle miRNA-21 is a potential biomarker for predicting chronic lung disease in premature infants. Am J Physiol Lung Cell Mol Physiol . 2020;318(5): L845-L851. Fujitani H, Kasuga S, Ishihara T, et al. Age-related changes in serum periostin level in allergic and non-allergic children. Allergol Int . 2019;68(2):285-286. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132:305e12. Kudo A. Periostin in fibrillogenesis for tissue regeneration: periostin actions inside and outside the cell. Cell Mol Life Sci . 2011;68(19):3201-3207. Aly H, Moustafa MF, Amer HA, Hassanein S, Keeves C, Patel K. Gestational age, sex and maternal parity correlate with bone turnover in premature infants. Pediatr Res . 2005;57(5 Pt 1):708-711. Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol . 2006;118(1):98-104. Baier RJ, Loggins J, Kruger TE. Interleukin-4 and 13 concentrations in infants at risk to develop Bronchopulmonary Dysplasia. BMC Pediatr . 2003;3:8. Perez GF, Pancham K, Huseni S, et al. Rhinovirus-induced airway cytokines and respiratory morbidity in severely premature children. Pediatr Allergy Immunol . 2015;26(2):145-152. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-100219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":4156747,"identity":"651c7a8c-e714-4c67-8ee6-7e6152b5ca44","order_by":0,"name":"Hayato Go","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIiWNgGAWjYHACNoYPNlCmBLFaGGekkaqFmSeNsCoEkHdvYHtsk7AtsYH98AMGyx1EaDE8c4DdOCfhdmIDT5oBg+QZYrTMyP8mnfsDqIUhh4FBso0oLQls0hYgW/jfEKlFXgKohQGkRYJYWwx4DrBJ9iTcNm6TeGZwgCi/yLc3sEn8SLgt28+f/PCxJDEhZnAAymAD4sOSDcTYgqyI8SMxWkbBKBgFo2DEAQDaqTElN2ekAAAAAABJRU5ErkJggg==","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hayato","middleName":"","lastName":"Go","suffix":""},{"id":4156748,"identity":"4f829c60-7e7e-4807-8e78-d6fdb309cd1a","order_by":1,"name":"Junya Ono","email":"","orcid":"","institution":"Shino Test. Co. Ltd","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Junya","middleName":"","lastName":"Ono","suffix":""},{"id":4156749,"identity":"31cdb14d-fd2f-4e3f-8a42-96dc12a64233","order_by":2,"name":"Hitoshi Ohto","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hitoshi","middleName":"","lastName":"Ohto","suffix":""},{"id":4156750,"identity":"60e1340d-1983-4310-ae67-115c51282aa3","order_by":3,"name":"Kenneth E. Nollet","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenneth","middleName":"E.","lastName":"Nollet","suffix":""},{"id":4156751,"identity":"9fb7bb2c-26e9-478a-b82e-cdf3fceaf068","order_by":4,"name":"Kenichi Sato","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenichi","middleName":"","lastName":"Sato","suffix":""},{"id":4156752,"identity":"c82efa3f-5795-4ebb-89aa-8dcdeadcc140","order_by":5,"name":"Yohei Kume","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Kume","suffix":""},{"id":4156753,"identity":"e7a7e04a-343a-41da-a69d-6a0e7c6ac173","order_by":6,"name":"Hajime Maeda","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hajime","middleName":"","lastName":"Maeda","suffix":""},{"id":4156754,"identity":"423dd7b7-009f-4848-a49a-96e9caa8e715","order_by":7,"name":"Mina Chishiki","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mina","middleName":"","lastName":"Chishiki","suffix":""},{"id":4156755,"identity":"6b3ce3c6-3ba5-4911-99d1-1e1abd2a0768","order_by":8,"name":"Kentaro Haneda","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Haneda","suffix":""},{"id":4156756,"identity":"48fb0c99-8826-46eb-86ad-53631e18f868","order_by":9,"name":"Hirotaka Ichikawa","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirotaka","middleName":"","lastName":"Ichikawa","suffix":""},{"id":4156757,"identity":"5de90093-c699-444e-9674-92aa3d052dac","order_by":10,"name":"Nozomi Kashiwabara","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nozomi","middleName":"","lastName":"Kashiwabara","suffix":""},{"id":4156758,"identity":"0f82dbd4-9752-4b33-a3dd-cdb01ea5cb02","order_by":11,"name":"Yuji Kanai","email":"","orcid":"","institution":"Fukushima Kenritsu Ika Daigaku","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Kanai","suffix":""},{"id":4156759,"identity":"1c657c0a-bdc8-409f-91cc-2adef8986954","order_by":12,"name":"Kei Ogasawara","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Ogasawara","suffix":""},{"id":4156760,"identity":"5a08dab3-47dc-4ceb-9ee6-320fa2fc1c69","order_by":13,"name":"Maki Sato","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Maki","middleName":"","lastName":"Sato","suffix":""},{"id":4156761,"identity":"224422f0-553f-4d3f-8a63-b9821f44ae75","order_by":14,"name":"Koichi Hashimoto","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Hashimoto","suffix":""},{"id":4156762,"identity":"7620b4e1-fbea-4d94-a6dc-65cf1c7c3970","order_by":15,"name":"Satoshi Nunomura","email":"","orcid":"","institution":"Saga medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Nunomura","suffix":""},{"id":4156763,"identity":"37ca19f6-4b5f-46c0-a2d8-de04e6a17fa4","order_by":16,"name":"Kenji Izuhara","email":"","orcid":"","institution":"Saga medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Izuhara","suffix":""},{"id":4156764,"identity":"4183068d-3d0b-4cdd-bd2f-dafabd31d4b2","order_by":17,"name":"Mitsuaki Hosoya","email":"","orcid":"","institution":"Fukushima Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mitsuaki","middleName":"","lastName":"Hosoya","suffix":""}],"badges":[],"createdAt":"2020-10-29 18:43:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-100219/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-100219/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":3337454,"identity":"b15b679c-955b-4069-8ef0-023b780c7b80","added_by":"auto","created_at":"2020-11-02 18:54:41","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":230393,"visible":true,"origin":"","legend":"A: Comparing healthy neonates and preterm neonates born at less than 32 week’s gestational age, serum periostin levels at birth were higher in the preterm neonates born at less than 32 week’s gestational age. B-C: Serum periostin levels at birth were significantly correlated with GA (gestational age) and BW (birth weight). Horizontal bars denote the median values in each group of infants.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-100219/v1/dd6953b83413919c2c840e07.jpg"},{"id":3337455,"identity":"a2861b77-4b88-4610-aab4-9316fc995857","added_by":"auto","created_at":"2020-11-02 18:54:41","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":145652,"visible":true,"origin":"","legend":"Comparison of receiver operating characteristics curve analyses of serum periostin levels at birth that distinguish infants with and without BPD. ROC: receiver operating characteristics.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-100219/v1/bf2b94cc6c757ca2368bcd00.jpg"},{"id":3337456,"identity":"7d64fbdb-c1a0-48cb-b138-c2246dbeff7a","added_by":"auto","created_at":"2020-11-02 18:54:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":127550,"visible":true,"origin":"","legend":"Serum periostin levels at birth were significantly higher in BPD neonates compared with non-BPD neonates. Serum periostin levels on DOL28 and corrected 36 week’s postmenstrual age did not differ in infants with or without BPD. Horizontal bars denote the median values in each group of infants. NS: not significant.","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-100219/v1/40d07796df36cc315c1d1e24.jpg"},{"id":3337457,"identity":"ff9068d9-b226-42e3-a3a0-a4a9178d116c","added_by":"auto","created_at":"2020-11-02 18:54:42","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":122527,"visible":true,"origin":"","legend":"Serum periostin levels at birth were higher in moderate/severe BPD compared with no BPD/mild BPD. Values are the median (no BPD/mild BPD: n=71, moderate/severe BPD: n=27). Horizontal bars denote the median in each group of infants. The other P values were calculated using the Mann-Whitney U test. ","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-100219/v1/4e6aa2a67a25de6d4517e923.jpg"},{"id":13610209,"identity":"12fc5d9b-02db-4d47-8833-85fa38942a1c","added_by":"auto","created_at":"2021-09-17 06:23:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":584433,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-100219/v1/e809531d-1703-47c3-83a5-36bee742f9c8.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eSerum Periostin Levels at Birth as a Predictor for Bronchopulmonary Dysplasia in Premature Infants.\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eBronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects neurodevelopmental impairment and long-term respiratory outcomes such as childhood wheezing and asthma (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). BPD results from various perinatal factors including maternal inflammation, surfactant deficiency, ventilation and oxygen toxicity (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Premature infants are often exposed to positive pressure ventilation, and supplemental oxygen, contributing to the development of BPD. An important pathophysiological feature of infants affected with BPD is developmental arrest of alveolarization (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Such structural alterations are accompanied by characteristic inflammatory changes and extensive remodeling of the extracellular matrix (ECM), together with increased smooth muscle mass in small pulmonary arteries and airways (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Periostin is characterized as both a matricellular protein as well as ECM protein belonging to the fasciclin family (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePeriostin plays an important role in the development of allergic, pulmonary, and the other diseases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Lung periostin is expressed in human lung fibroblasts and human bronchial epithelial cells (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Since periostin is regulated by interleukin (IL)-4 and IL-13 and is involved in pathogenesis of fibrosis and allergy in various diseases, many studies reported that serum and plasma periostin levels were a potential biomarker for various disease such as idiopathic lung fibrosis in adults and asthma (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Furthermore, various factors such as transforming growth factor-beta (TGF-β), IL-4, IL-13, mechanical stress, and connective tissue growth factor upregulate periostin (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In the pathogenesis of BPD, TGF-β is involved in lung vascular development. Periostin are associated with TGF-β mediated fibrosis and lung development exposed to hyperoxia (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). TGF-β, in turn, is associated with the pathogenesis of BPD during lung vascular development. Although periostin expression is increased in autopsy lungs of preterm neonates with BPD (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), few reports have been suggesting the relationship between serum periostin levels at birth and BPD. Although Ahlfeld et al reported that elevated plasma periostin levels in BPD patients on day 28 of life (DOL28) compared with that\u0026rsquo;s\u0026rsquo; of non-BPD patients, their study had several limitations, such as a low sample number and their choice of sampling times (DOL7 and DOL28) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhile some studies propose reference intervals for serum periostin in children (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), reports correlating serum periostin levels in term and preterm births with other perinatal factors are lacking.\u003c/p\u003e \u003cp\u003eIn this study, we hypothesized that serum periostin at birth might increase in BPD patients, and could serve as biomarkers of BPD. The objectives of the present study were to evaluate the perinatal factors affecting serum periostin levels at birth in preterm and healthy infants and to validate whether serum periostin at birth, DOL28 and corrected 36 week\u0026rsquo;s gestational age could be potential biomarkers for BPD.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval and compliance\u003c/h2\u003e \u003cp\u003eThis research was approved by the Institutional Review Board of Fukushima Medical University, which is guided by local policy, national law, and the World Medical Association Declaration of Helsinki. As our human subjects were neonates, informed consent was solicited from parents or other legal guardians, and documented in writing.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eNICU Patients\u003c/h2\u003e \u003cp\u003eBlood samples were obtained from mechanically ventilated or oxygenated patients with parental consent in the neonatal intensive care unit (NICU) of Fukushima Medical University from November 2014 to July 2020. We examined cord blood at birth and venous blood at 36 weeks postmenstrual age and DOL28. Newborns with congenital anomalies or those who died prior to postnatal day 28 were excluded. Data for analysis included gestational age, phenotypic sex, body weight at birth, invasive mechanical ventilation at DOL28, supplemental oxygen at DOL14, respiratory distress syndrome (RDS), being small for gestational age (SGA), patent ductus arteriosus (PDA), Apgar scores and maternal complications: chorioamnionitis (CAM), premature rupture of membrane (PROM), hypertensive disorders of pregnancy (HDP) were recorded. BPD was defined in accordance with the National Institutes of Health consensus definition for infants (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). At a postmenstrual age of 36 weeks, the infants were classified into the following groups: mild BPD was defined as the need for supplemental oxygen at \u0026ge;\u0026thinsp;28 days but not at 36 weeks postmenstrual age; moderate BPD was defined as the need for supplemental oxygen at 28 d, in addition to supplemental oxygen at FiO\u003csub\u003e2\u003c/sub\u003e (fraction of inspired oxygen)\u0026thinsp;\u0026le;\u0026thinsp;0.30\u0026nbsp;at 36 weeks postmenstrual age; and criteria for severe BPD included the need for supplemental oxygen at 28 days and, at 36 weeks postmenstrual age, the need for mechanical ventilation and/or FiO\u003csub\u003e2\u003c/sub\u003e (fraction of inspired oxygen)\u0026thinsp;\u0026gt;\u0026thinsp;0.30 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). SGA was defined as a birth weight of \u0026lt;-1.5 standard deviations that was corrected for the gestational age and sex in accordance with the criteria from previous study (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eHealthy neonatal subjects\u003c/h2\u003e \u003cp\u003eHealthy neonates who were born from 36.6 weeks to term in our hospital were included if informed consent was obtained from parents and/or legal guardians and documented in writing.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSerum periostin measurements\u003c/h2\u003e \u003cp\u003eSerum samples were obtained from neonates at birth, DOL 28, and corrected 36 weeks. Using serum samples stored at -80℃ until assay, serum periostin levels were measured using an enzyme-linked immunosorbent assays (ELISA) at Shino-Test (Kanagawa, Japan), as previously described (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll data are presented as the medians. The Mann\u0026ndash;Whitney \u003cem\u003eU\u003c/em\u003e-test was used to compare continuous variables, and χ2 test was used for nominal variables. To evaluate the correlation between two parameters, Pearson\u0026rsquo;s correlation coefficient was calculated. We performed multivariate analyses to determine factors significantly associated with serum periostin levels at birth as BW, GA, RDS, BPD, oxygen supplementation at DOL 14, invasive mechanical ventilation at DOL 28, and Apgar score at 1 min\u0026thinsp;\u0026lt;\u0026thinsp;3 in premature infants born at less than 32 weeks. Next, we also performed multivariate analyses to determine factors significantly associated with BPD as potential confounding factors such as BW, GA, invasive mechanical ventilation at DOL 28, Apgar Score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3, oxygen supplementation at DOL 14 and serum periostin levels at birth in premature infants born at less than 32 weeks. The accuracy of diagnosing of classifying BPD was evaluated by receiver operating characteristics (ROC) curves with area under the curve (AUC) use to quantify the sensitivity of independent risks for BPD. The levels of significance were set 0.05 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Data analysis was performed with SPSS (version 21.0) and GraphPad Prism version 8 software.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003eClinical characteristics and Serum periostin levels at birth in preterm and term infants.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eA total of 139 preterm (n\u0026thinsp;=\u0026thinsp;98) and healthy (n\u0026thinsp;=\u0026thinsp;41) infants were included in this study. The clinical characteristics of preterm infants born at less than 32 weeks and healthy control are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Figure\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e shows the serum periostin levels at birth in preterm and term infants. The median serum periostin levels at birth among preterm infants born at less than 32 weeks was significantly higher than those among healthy infants (292.0\u0026nbsp;ng/mL vs 142.0\u0026nbsp;ng/mL, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). Furthermore, there were significant inverse correlations between BW (r=-0.672, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e), GA (r=-0.640, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e), and serum periostin levels at birth in 139 preterm and term infants (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB and C).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of subjects\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eHealthy control (N\u0026thinsp;=\u0026thinsp;41)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePreterm Infants\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks (N\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age, median (IQR), weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(37.7\u0026ndash;39.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(24.2\u0026ndash;28.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight, median (IQR), g\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2948\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(2588\u0026ndash;3122)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e743\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(621\u0026ndash;1068)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale gender, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(43.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(49.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(43.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal steroid, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(91.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePROM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(8.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDS, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(72.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(15.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePDA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(56.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPD, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(44.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation at DOL14, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(52.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInvasive Mechanical ventilation at DOL28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(62.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(26.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 5\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e(10.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003eIQR: interquartile range, NA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, ROP: retinopathy of prematurity, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cspan class=\"BoldItalic\"\u003ePerinatal factors and serum periostin levels at birth in preterm infants born at less than 32 weeks.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eNext, among preterm infants born less than 32 weeks, we correlated serum periostin levels at birth with perinatal factors (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). GA and BW were negatively correlated with serum periostin levels at birth. Additionally, serum periostin levels at birth were significantly higher in RDS, BPD, invasive mechanical ventilation at DOL 28, and Apgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3. In particular, the median serum periostin levels at birth were higher with BPD than without (345.0\u0026nbsp;ng/mL vs 278.0\u0026nbsp;ng/mL, \u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.002\u003c/em\u003e). Multivariate analysis revealed that serum periostin levels at birth was significantly associated with BPD (\u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.032\u003c/em\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAssociations between serum periostin levels at birth and perinatal factors in preterm infants born\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSerum periostin levels at birth (ng/mL)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ecoefficient\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003cp\u003e(P-value)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003cp\u003e(P-value)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.265\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.588\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.326\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.396\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale vs Female\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e306.5 vs 287.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.234\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAM vs non-CAM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e289.0 vs 296.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.994\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal steroid vs no antenatal steroid\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e300.0 vs 266.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.078\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePROM vs non-PROM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e295.5 vs 291.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.554\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDP vs non-HDP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e300.0 vs 266.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.315\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDS vs non-RDS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e303.0 vs 256.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.081\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA vs non-SGA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e290.0 vs 321.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.598\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePDA vs non-PDA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e299.0 vs 291.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBPD vs non-BPD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e345.0 vs 278.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.032\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation at DOL14 vs no oxygen supplementation at DOL14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e303.0 vs 284.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.188\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInvasive mechanical ventilation at DOL28 vs no invasive mechanical ventilation at DOL28\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e305.0 vs 252.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.845\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3 vs no Apgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e326.5 vs 283.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.022\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.364\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar Sscore at 5\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3 vs no Apgar score at 5\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e300.0 vs 291.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.469\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eNA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSerum periostin levels in BPD infants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate whether serum periostin levels were associated with BPD, preterm infants born at less than 32 weeks were divided into BPD neonates (n\u0026thinsp;=\u0026thinsp;44) and non-BPD neonates (n\u0026thinsp;=\u0026thinsp;54) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The median GA in BPD infants was significantly lower than those in non-BPD neonates (24.4 weeks vs 27.2 weeks, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e). The median BW in BPD neonates was also significantly lower than those in non-BPD infants (638\u0026nbsp;g vs 952\u0026nbsp;g, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/em\u003e). The occurrence of Apgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3 (40.9% vs 14.8%, \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.005\u003c/em\u003e) was significantly higher in BPD infants compared with those in non-BPD infants. Furthermore, the incidence of the invasive mechanical ventilation at DOL 28 and oxygen supplementation at DOL14 in BPD infants were significantly higher than those in non-BPD infants. There were no significant differences between BPD and non-BPD infants in terms of phenotypic sex, antenatal steroid usage, SGA, PDA, CAM, HDP and PROM (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). In multivariate analysis of the correlation between serum periostin at birth and clinical parameters, serum periostin levels at birth significantly correlated with BPD (\u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.013\u003c/em\u003e) and BW (\u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.021\u003c/em\u003e) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Receiver operating characteristic analysis for serum periostin levels at birth in infants with and without BPD revealed that the area under the curve were 0.725 (95% CI 0.627\u0026ndash;0.822, \u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.0001\u003c/em\u003e) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Using a threshold of serum perisostin\u0026thinsp;\u0026gt;\u0026thinsp;305\u0026nbsp;ng/mL at birth identified BPD with 71.7% sensitivity and 63.4% specificity.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of BPD and non-BPD infants\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eNon-BPD\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBPD\u003c/p\u003e\n\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;44)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUnivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMultivariate analysis\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age, median (IQR), week\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27.2 (25.6\u0026ndash;29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.4 (23.7\u0026ndash;26.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.242\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBirth weight, median (IQR), gram\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e952 (622\u0026ndash;1210)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e638 (438\u0026ndash;734)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.027\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale gender, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (51.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (46.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.508\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (39.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (48.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.311\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAntenatal steroid, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (94.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (90.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.522\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePROM, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (24.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (29.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.647\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHDP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (13.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (2.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.070\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRDS, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (64.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (81.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.072\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSGA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (20.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.262\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePDA, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (76.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (53.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.155\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOxygen supplementation at DOL14, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (37.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (70.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.041\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInvasive mechanical ventilation at DOL28, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (66.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (90.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.391\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 1\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (40.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.005\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.571\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eApgar score at 5\u0026nbsp;min\u0026thinsp;\u0026lt;\u0026thinsp;3, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (5.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (15.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.107\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSerum periostin levels at birth (ng/mL)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e345.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e278.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eIQR: interquartile range, NA: not applicable, CAM: chorioamnionitis, PROM: premature rupture of membrane, HDP: hypertensive disorders of pregnancy, SGA: small for gestational age, RDS: respiratory distress syndrome, PDA: patent ductus arteriosus. P-value was compared between BPD and non-BPD neonates\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e shows the serum periostin levels at birth, DOL 28 and corrected 36-week\u0026rsquo;s postmenstrual age in BPD and non-BPD infants. The median periostin levels on DOL 28 in BPD infants were significantly lower compared with those at birth (345.0\u0026nbsp;ng.mL vs 281.5\u0026nbsp;ng/mL, \u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.003\u003c/em\u003e). However, the median serum periostin levels on DOL 28 and corrected age of 36-week\u0026rsquo;s gestational were not significantly differed in BPD infants compared with non-BPD infants (DOL 28: 281.0\u0026nbsp;ng/mL vs 238.5\u0026nbsp;ng/mL, corrected 36-week\u0026rsquo;s postmenstrual age: 327.5\u0026nbsp;ng/mL vs 332.0\u0026nbsp;ng/mL). Next, we evaluated the relationships between serum periostin at birth and severity of BPD (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Serum periostin levels at birth with moderate/severe BPD were significantly higher than those with non-BPD/mild BPD (338.5\u0026nbsp;ng/mL vs 283.5\u0026nbsp;ng/mL, \u003cem\u003eP\u0026thinsp;=\u0026thinsp;0.0032\u003c/em\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eTo our knowledge, this is the first study to describe an association between serum periostin levels at birth and perinatal factors in preterm and term infants and the correlation between serum periostin levels at birth and BPD. The present study revealed that higher serum periostin levels at birth in preterm infants born at less than 32 week\u0026rsquo;s gestational age are independent risk factors for BPD and reflects the severity for BPD. Although there are many studies trying to demonstrate an association between serum biomarkers and the risk of BPD, few suggest a correlation between blood periostin levels and BPD. In this study, we also demonstrated that serum periostin levels on DOL28 and corrected 36 week\u0026rsquo;s postmenstrual age could not serve as potential biomarkers for BPD. Ahlfeld et al previously suggested that early elevation of plasma periostin on DOL28 is significantly associated with chronic ventilator-dependent bronchopulmonary dysplasia (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This may be due to the differences in the type of sample, sample size, and method of analysis. Ahlfeld\u0026rsquo;s study used plasma samples and did not include multivariate or measure periostin levels at birth. In terms of the relationship between periostin and lung disease, previous studies demonstrated that elevated serum periostin levels were associated with various lung disease such as asthma, idiopathic pulmonary fibrosis, and COPD in children and adults (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Furthermore, the expression of lung periostin was upregulated in patients with idiopathic lung fibrosis (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Bozyk et al. also reported that periostin expression increased in autopsy lungs of preterm neonates with BPD (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In a murine model of BPD exposed to hyperoxia, hyperoxia upregulated periostin expression in neonatal mice lung (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Furthermore, lung periostin levels were also increased during the saccular stage, as previously shown (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Although the mechanism by which periostin is associated with the pathogenesis of BPD remains poorly understood, we speculate that the linkage of periostin and TGF- β might be associated with the pathogenesis of BPD. Periostin and TGF-β are known to play a critical role in the proliferation of lung fibroblasts (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Furthermore, many studies in different animal models of BPD confirm elevated TGF-β expression levels and activation of its associated pathways as an important part of lung disease pathophysiology (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Also, we previously reported that serum TGF-β levels were upregulated in BPD patients (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother new finding in this study was significant correlation of serum periostin levels at birth with BW and GA. Fujitani et al. reported that periostin levels in non-allergic children from 0\u0026nbsp;years to 15\u0026nbsp;years were almost 91.9-124.8\u0026nbsp;ng/mL (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). They also suggested that serum periostin levels gradually increased after age 10\u0026nbsp;years. Anderson et al also reported that serum periostin levels at ages 2\u0026ndash;6\u0026nbsp;years ranged from 120\u0026ndash;150\u0026nbsp;ng/mL (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In this study, serum periostin levels of healthy neonates were around 140\u0026nbsp;ng/mL. Furthermore, serum periostin levels at birth in neonates born at less than 32 week\u0026rsquo;s gestational age was almost 340\u0026nbsp;ng/mL. On the other hand, a previous study proposed a periostin threshold of 95\u0026nbsp;ng/mL based on values from healthy adult controls (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Thus, serum periostin levels in infants were the highest when comparing infants, children, and adult. These developmental changes of serum periostin levels may be related to metabolic turnover and growth as periostin is a component of the extracellular matrix and regulates serum type I collagen formation, which is essential component of skin, tendon, and bone development (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Compared with term infants, the cord blood serum procollagen type I C-terminal propeptide (PICP) as bone information in preterm infants was significantly higher and influenced by fetal age (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, it was performed at a single center and the sample size of BPD patients was small. To validate our observations, a larger sample size with multiple centers and different ethnic cohorts would be invaluable. Second, we could not evaluate lung periostin. A previous study demonstrated that lung periostin in BPD infants was higher than in healthy lungs at term (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Third, we could not detect the cellular sources of periostin. Thus, our next goal is to determine the cell types secreting periostin as well as the mechanism(s) of upregulation of periostin in BPD neonates; this will advance understanding of the pathogenesis of BPD. Lastly, in this study, we did not investigate the correlation between periostin levels and Th2 cytokines such as IL-4 and IL-13. It is noteworthy that upon stimulation by IL-4 and IL-13, periostin could be detected in lung fibroblasts (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). One of the main consequences of BPD is lung fibrosis. Although a previous study suggested that IL-4 and IL-13 levels of tracheal aspirates from premature infants were very low and did not correlate with BPD (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), premature infants born at less than 32 week\u0026rsquo;s gestational age have increased nasal airway IL-4 and IL-13 secretion during rhinovirus infections (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn summary, we conclude that serum periostin levels were significantly correlated with birth weight and gestational age. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD and severity of BPD. The mechanism by which serum periostin is upregulated in BPD infants and inversely correlated with gestational age and birth weight remains to be further elucidated.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eBPD: bronchopulmonary dysplasia\u003c/p\u003e\n\u003cp\u003eBW: birth wight\u003c/p\u003e\n\u003cp\u003eGA: gestational age\u003c/p\u003e\n\u003cp\u003eRDS: respiratory distress syndrome\u003c/p\u003e\n\u003cp\u003eCAM: chorioamnionitis\u003c/p\u003e\n\u003cp\u003ePROM: premature rupture of membrane\u003c/p\u003e\n\u003cp\u003eHDP: hypertensive disorders of pregnancy\u003c/p\u003e\n\u003cp\u003eSGA: small for gestational age\u003c/p\u003e\n\u003cp\u003eRDS: respiratory distress syndrome\u003c/p\u003e\n\u003cp\u003ePDA: patent ductus arteriosus\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eGRANTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Grants-in-Aid Scientific Research from the Japan society for the promotion of science (JSPS), KAKENHI (Grant number: 20K08233(HG)).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDISCLOSUREs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJunya Ono is a salaried employee of Shino-Test Co., Ltd., which provided ELISA for periostin without stipulations or influence over the interpretation of test results. The authors have no other potential or actual conflicts of interest pertaining to the contents of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHayato Go designed the study, carried out the analyses and drafted the manuscript, and reviewed and revised the manuscript. Hitoshi Ohto, Kenneth Nollet, Satoshi Nunomura, Kenji Izuhara, and Mitsuaki Hosoya reviewed the manuscript. Junya Ono carried out the analyses and reviewed the manuscript. Hajime Maeda, Kei Ogasawara, Maki Sato, Yohei Kume, Hirotaka Ichikawa, Yuji Kanai, Nozomi Kashiwabara, and Kentaro Haneda collected the samples and reviewed the manuscript. All author approved the final manuscript as submitted and agree to accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no other potential or actual conflicts of interest pertaining to the contents of this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGough A, Spence D, Linden M, Halliday HL, McGarvey LPA. General and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia: a systematic review.\u0026nbsp;\u003cem\u003eChest\u003c/em\u003e. 2012;141(6):1554-1567.\u003c/li\u003e\n\u003cli\u003eGough A, Linden M, Spence D, Patterson CC, Halliday HL, McGarvey LP. Impaired lung function and health status in adult survivors of bronchopulmonary dysplasia. Eur Respir J. 2014 Mar;43(3):808-16.\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eKinsella JP, Greenough A, Abman SH. 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Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2018;303: L1046\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eNakazawa T, Nakajima A, Seki N, et al. Gene expression of periostin in the early stage of fracture healing detected by cDNA microarray analysis.\u0026nbsp;\u003cem\u003eJ Orthop Res\u003c/em\u003e. 2004;22(3):520-525.\u003c/li\u003e\n\u003cli\u003eBozyk PD, Bentley JK, Popova AP, et al. Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication [published correction appears in PLoS One. 2015;10(6): e0130369].\u0026nbsp;\u003c/li\u003e\n\u003cli\u003eAhlfeld SK, Davis SD, Kelley KJ, Poindexter BB. Early Elevation of Plasma Periostin Is Associated with Chronic Ventilator-Dependent Bronchopulmonary Dysplasia.\u0026nbsp;\u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e. 2016;194(11):1430-1433.\u003c/li\u003e\n\u003cli\u003eAnderson HM, Lemanske RF Jr, Arron JR, et al. Relationships among aeroallergen sensitization, peripheral blood eosinophils, and periostin in pediatric asthma development.\u0026nbsp;\u003cem\u003eJ Allergy Clin Immunol\u003c/em\u003e. 2017;139(3):790-796.\u003c/li\u003e\n\u003cli\u003eFujitani H, Kasuga S, Ishihara T, et al. Age-related changes in serum periostin level in allergic and non-allergic children.\u0026nbsp;\u003cem\u003eAllergol Int\u003c/em\u003e. 2019;68(2):285-286.\u003c/li\u003e\n\u003cli\u003eJobe AH, Bancalari E. Bronchopulmonary dysplasia.\u0026nbsp;\u003cem\u003eAm J Respir Crit Care Med\u003c/em\u003e. 2001;163(7):1723-1729.\u003c/li\u003e\n\u003cli\u003eItabashi K, Miura F, Uehara R, Nakamura. New Japanese neonatal anthropometric charts for gestationalage at birth. \u003cem\u003ePediatric Int.\u003c/em\u003e 2014;56(5):702-8.\u003c/li\u003e\n\u003cli\u003eMatsusaka M, Kabata H, Fukunaga K, Suzuki Y, Masaki K, Mochimaru T, et al. Phenotype of asthma related with high serum periostin levels. \u003cem\u003eAllergol Int\u003c/em\u003e 2015;64: 175e80.\u003c/li\u003e\n\u003cli\u003eKimura H, Konno S, Nakamaru Y, Makita H, Taniguchi N, Shimizu K, et al. Sinus computed tomographic findings in adult smokers and nonsmokers with asthma. Analysis of clinical indices and biomarkers. \u003cem\u003eAnn Am Thorac Soc.\u003c/em\u003e 2017;14: 332e41.\u003c/li\u003e\n\u003cli\u003eOak P, Hilgendorff A. The BPD trio? Interaction of dysregulated PDGF, VEGF, and TGF signaling in neonatal chronic lung disease.\u0026nbsp;\u003cem\u003eMol Cell Pediatr\u003c/em\u003e. 2017;4(1):11.\u003c/li\u003e\n\u003cli\u003eGolpe R, Mart\u0026iacute;n-Robles I, Sanju\u0026aacute;n-L\u0026oacute;pez P, et al. Differences in systemic inflammation between cigarette and biomass smoke-induced COPD.\u0026nbsp;\u003cem\u003eInt J Chron Obstruct Pulmon Dis\u003c/em\u003e. 2017;12: 2639-2646.\u003c/li\u003e\n\u003cli\u003ePavlidis S, Takahashi K, Ng Kee Kwong F, et al. \"T2-high\" in severe asthma related to blood eosinophil, exhaled nitric oxide and\u0026nbsp;serum periostin.\u0026nbsp;\u003cem\u003eEur Respir J\u003c/em\u003e. 2019;53(1):1800938.\u003c/li\u003e\n\u003cli\u003eAhlfeld SK, Gao Y, Wang J, et al. Periostin downregulation is an early marker of inhibited neonatal murine lung alveolar septation.\u0026nbsp;\u003cem\u003eBirth Defects Res A Clin Mol Teratol\u003c/em\u003e. 2013;97(6):373-385.\u003c/li\u003e\n\u003cli\u003eMokres LM, Parai K, Hilgendorff A, et al. Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice.\u0026nbsp;\u003cem\u003eAm J Physiol Lung Cell Mol Physiol\u003c/em\u003e. 2010;298(1):L23-L35.\u003c/li\u003e\n\u003cli\u003eHilgendorff A, Parai K, Ertsey R, et al. Neonatal mice genetically modified to express the elastase inhibitor elafin are protected against the adverse effects of mechanical ventilation on lung growth.\u0026nbsp;\u003cem\u003eAm J Physiol Lung Cell Mol Physiol\u003c/em\u003e. 2012;303(3): L215-L227.\u003c/li\u003e\n\u003cli\u003eGo H, Maeda H, Miyazaki K, et al. Extracellular vesicle miRNA-21 is a potential biomarker for predicting chronic lung disease in premature infants.\u0026nbsp;\u003cem\u003eAm J Physiol Lung Cell Mol Physiol\u003c/em\u003e. 2020;318(5): L845-L851.\u003c/li\u003e\n\u003cli\u003eFujitani H, Kasuga S, Ishihara T, et al. Age-related changes in serum periostin level in allergic and non-allergic children.\u0026nbsp;\u003cem\u003eAllergol Int\u003c/em\u003e. 2019;68(2):285-286.\u003c/li\u003e\n\u003cli\u003eKanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. \u003cem\u003eJ Allergy Clin Immunol.\u003c/em\u003e 2013;132:305e12.\u003c/li\u003e\n\u003cli\u003eKudo A. Periostin in fibrillogenesis for tissue regeneration: periostin actions inside and outside the cell.\u0026nbsp;\u003cem\u003eCell Mol Life Sci\u003c/em\u003e. 2011;68(19):3201-3207.\u003c/li\u003e\n\u003cli\u003eAly H, Moustafa MF, Amer HA, Hassanein S, Keeves C, Patel K. Gestational age, sex and maternal parity correlate with bone turnover in premature infants.\u0026nbsp;\u003cem\u003ePediatr Res\u003c/em\u003e. 2005;57(5 Pt 1):708-711.\u003c/li\u003e\n\u003cli\u003eTakayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals.\u0026nbsp;\u003cem\u003eJ Allergy Clin Immunol\u003c/em\u003e. 2006;118(1):98-104.\u003c/li\u003e\n\u003cli\u003eBaier RJ, Loggins J, Kruger TE. Interleukin-4 and 13 concentrations in infants at risk to develop Bronchopulmonary Dysplasia.\u0026nbsp;\u003cem\u003eBMC Pediatr\u003c/em\u003e. 2003;3:8.\u003c/li\u003e\n\u003cli\u003ePerez GF, Pancham K, Huseni S, et al. Rhinovirus-induced airway cytokines and respiratory morbidity in severely premature children.\u0026nbsp;\u003cem\u003ePediatr Allergy Immunol\u003c/em\u003e. 2015;26(2):145-152.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"biomarker, periostin, bronchopulmonary dysplasia, gestational age, birth weight","lastPublishedDoi":"10.21203/rs.3.rs-100219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-100219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Bronchopulmonary dysplasia (BPD) is the most common morbidity complicating preterm birth and affects long-term respiratory outcomes. Periostin plays an important role in the development of various disease such as allergic and pulmonary diseases. The objectives of this study were to evaluate the perinatal factors affecting serum periostin levels at birth and to establish whether serum periostin at birth, day of life (DOL) 28 and corrected 36 week’s gestational age could be potential biomarkers for BPD.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A total of 139 preterm (n=98) and healthy (n=41) infants were included in this study. Among of them, 98 infants born \u0026lt; 32 weeks were divided into BPD (n=44) and non-BPD infants (n=54). Serum periostin levels were measured using an enzyme-linked immunosorbent assay. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The median serum periostin levels at birth in preterm infants born \u0026lt; 32 weeks were significantly higher than those in healthy infants. Furthermore, there were significant inverse correlations between gestational age, birth weight, and serum periostin levels at birth among all 139 preterm and healthy infants. Among preterm infants born \u0026lt; 32 weeks, with BPD and without BPD infants, the median serum periostin levels at birth were higher with BPD than without (345.0 ng/mL vs 278.0 ng/mL, \u003cem\u003eP=0.002\u003c/em\u003e). Multivariate analysis revealed that serum periostin levels at birth was significantly associated with BPD (\u003cem\u003eP=0.032\u003c/em\u003e). Receiver operating characteristic analysis for serum periostin levels at birth in infants with and without BPD revealed that the area under the curve were 0.725 (95% CI 0.627- 0.822, \u003cem\u003eP=0.0001\u003c/em\u003e). Serum periostin levels at birth with moderate/severe BPD were significantly higher than those with non-BPD/mild BPD (338.5 ng/mL vs 283.5 ng/mL, \u003cem\u003eP=0.0032\u003c/em\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Serum periostin levels at birth were significantly correlated with BW and GA. Furthermore, serum periostin levels at birth could serve as a biomarker for predicting BPD.\u003c/p\u003e","manuscriptTitle":"Serum Periostin Levels at Birth as a Predictor for Bronchopulmonary Dysplasia in Premature Infants.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-11-02 18:54:40","doi":"10.21203/rs.3.rs-100219/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6f7f9b52-9925-4d2e-b25e-1538eb36bf83","owner":[],"postedDate":"November 2nd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":955219,"name":"Pediatrics"},{"id":955220,"name":"Health Economics \u0026 Outcomes Research"}],"tags":[],"updatedAt":"2020-11-02T18:54:42+00:00","versionOfRecord":[],"versionCreatedAt":"2020-11-02 18:54:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-100219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-100219","identity":"rs-100219","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}