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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 1  |  Page : 1-6

Vitamin D supplementation in the prevention of neonatal bronchopulmonary dysplasia: Is it beneficial?


1 Department of Pediatrics, College of Medicine, Jouf and Tanta University, KSA and Egypt
2 Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
3 Department of Surgery, College of Medicine, Jouf and Alazhar University, KSA and Egypt

Date of Submission16-Sep-2021
Date of Decision18-Sep-2021
Date of Acceptance18-Oct-2021
Date of Web Publication03-Jan-2022

Correspondence Address:
Mohamed Shawky Elfarargy
Department of Pediatrics, College of Medicine, Jouf and Tanta University, KSA and Egypt

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_114_21

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  Abstract 


Background: Neonatal bronchopulmonary dysplasia (BPD) is a chronic neonatal respiratory disease that is precipitated by prolonged oxygenation and mechanical ventilation (MV), leading to respiratory distress (RD). Aim of Study: The aim of the study is to assess the role of Vitamin D as adjuvant treatment in the prevention and management of BPD in neonates. Patients and Methods: Prospective randomized controlled trial with identification number TCTR20210622001 on 100 premature neonates who had RD and were put on MV. The examined neonates were classified into 2 groups: Group 1, which received Vitamin D (Vit D), and Group 2, which had placebo. Urinary β2-microglobulin (B2M) in addition to plasma Krebs von den Lungen-6 (KL-6) levels were measured on the 1st and the 14th day of hospitalization. Results: There was a decrease in urinary B2M and plasma KL-6 levels in Group 1, if compared with Group 2 neonates (P < 0.05). There was a decrease in hospitalization in Group 1 neonates (P < 0.05). Group 1 neonates showed a decrease of the developed BPD cases (P < 0.05). Conclusion: Vit D supplementation may help in the prevention of BPD in neonates, but further studies with larger number of neonates should be done. Recommendation: Routine Vit D supplementation in a dose of 800 IU to preterm who are susceptible to develop BPD.

Keywords: Bronchopulmonary dysplasia, Neonate, respiratory distress, therapy, Vitamin D


How to cite this article:
Elfarargy MS, Al-Ashmawy G, El Hady HA. Vitamin D supplementation in the prevention of neonatal bronchopulmonary dysplasia: Is it beneficial?. J Clin Neonatol 2022;11:1-6

How to cite this URL:
Elfarargy MS, Al-Ashmawy G, El Hady HA. Vitamin D supplementation in the prevention of neonatal bronchopulmonary dysplasia: Is it beneficial?. J Clin Neonatol [serial online] 2022 [cited 2022 Dec 4];11:1-6. Available from: https://www.jcnonweb.com/text.asp?2022/11/1/1/334730




  Introduction Top


Bronchopulmonary dysplasia (BPD) is a chronic neonatal lung disease which occurs mainly in preterm who needed mechanical ventilation (MV) and exposed to high O2 therapy. BPD is characterized by fibrous tissue replacement of the normal lung tissue leading to neonatal respiratory distress (RD).[1],[2]

BPD causes prolonged O2 requirement as a result of high O2 exposure for 28 days or more with abnormal chest X-rays.[3]

BPD might be mild, moderate, or severe differs according to the degree of RD and the O2 requirement of neonates.[3]

Mild BPD could be maintained without RD in room air at discharge.[3] Moderate BPD could be maintained without RD in ≤30% O2 at discharge.[3] Finally, severe BPD could be maintained without RD in >30% O2 at discharge.[3]

The incidence of BPD is increasing in the world by the development of ventilation strategies to the preterm.[4]

KL-6 is a glycoprotein which is formed by pneumocytes (type II), it is raised in BPD and could be considered as a marvelous marker for the prediction of neonatal BPD.[5],[6],[7]

β2-microglobulin (B2M) is present in some body cells, especially the lung. Urinary B2M could be a noninvasive predictor for neonatal BPD.[8],[9],[10]

Vitamin D (Vit D) is a hormone that has antifibrotic, antioxidative, and anti-inflammatory actions and helps in lung development and maturation. Therefore, the decrease in Vitamin D might increase the risk of BPD.[11],[12]

Vit D is important in surfactant production, essential in alveolar structure and functions, it also prevents the inflammation and fibrosis with decrease incidence of BPD.[13]

Vit D has low cost and minimal adverse effects. Vit D is available and could be used in neonates from 400 IU/day to 1000 IU/day, especially in preterm.[14],[15]

The aim of this study is to assess the role of Vit D as adjuvant treatment in the prevention and management of BPD in neonates.


  Patients and Methods Top


A prospective double-blinded randomized controlled trial that was performed at TUH and Thai Clinical Trials Registry (TCTR) identification number is TCTR20210622001, it was done from August 2016 to February 2018 on 100 neonates with RD and needed MV and exposed to FIO2 >21%, Approval from Ethical Committee of the college of Medicine, TUH was taken, and informed consent from the family of the studied neonates was done before the study. The examined neonates (n = 100), Group 1: 50 preterm who had given Vit D and Group 2: 50 preterm who had given placebo in the form of 2 ml distilled water where lottery method was done by foreign neonatologists for simple random sample.

Plasma KL-6 and urinary B2M were monitored at the 1st and 14th days of hospitalization and used as markers of neonatal BPD.

Established cases of BPD were diagnosed as prolonged O2 requirement as a result of high O2 exposure for 28 days or more with abnormal chest X-rays revealing multiple opacifications with high density.[3]

Inclusion criteria

Premature neonates suffering from severe RD needing MV and exposed to FIO2 >21%.

Exclusion criteria

Full-term neonates, neonatal infections, congenital anomalies, HIE, death, and transfer to another incubator.

Primary outcome

Development of BPD in the studied neonates.

Secondary outcomes

Development of pneumothorax or pulmonary hemorrhage in the studied neonates.

Group 1 (n = 50): They had received single daily enteral 8 drops of Vit D (800 IU) for 2 weeks.[16],[17]

The sample size and power analysis were done by Epi-Info software statistical package created by World Health organization and center for Disease Control and Prevention, Atlanta, Georgia, USA version 2002.[18] The criteria used for sample size calculation were as follows: 95% confidence limit, 80% power of the study, the sample size was found at n = 50 neonates in each group.

Determination of plasma KL-6

The plasma KL-6 levels were measured using ELISA.

Estimation of urinary β2-microglobulin

The urinary B2M level was measured by ELISA.

Statistical analysis

Using SPSS version 21, IBM, Armonk, NY, USA, mean ± standard deviation were used. P < 0.05 was considered as a statistically significant.


  Results Top


The studied neonates (n = 100), Group 1 (n = 50) who had given Vit D, and Group 2 (n = 50) who received placebo. No side effects were detected in cases of Group 1 from Vit D supplementation.

There were 141 cases who assessed for eligibility where 41 cases were exclude by exclusion criteria and the studied 100 cases were randomized divided into 50 neonates who have vit D supplementation, in which there were 2 cases who developed established BPD and 50 cases who have placebo, in which 9 cases who developed established BPD [Figure 1].
Figure 1: Consort or study flow chart of participating neonates during the research

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There were 1 case in Group 1 and 2 cases in Group 2 which developed pneumothorax and there were 1 case in Group 1 and 2 cases in Group 2 which developed pulmonary hemorrhage and this may be attributed to an adverse effect of MV to the studied premature neonates.

[Table 1] shows no significance as regard all its items (weight, GA, Down score, duration of MV and exposure to FIO2 >21%, mode of delivery and sex) and the P value was >0.05.
Table 1: Comparative characteristics between studied groups

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[Table 2] shows that in Group 1, plasma KL-6 on the 1st day of hospitalization was 103.1 ± 31 U/ml, while plasma KL-6 on the 14th day of presence in the incubators was 75.6 ± 20 U/ml, with statistically significant difference (SSD) (P < 0.05), while in Group 2, plasma KL-6 on the 1st day of hospitalization was 102.9 ± 32 U/ml, and the plasma KL-6 level on the 14th day of admission was 99.3 ± 30.2 U/ml with no SSD (P > 0.05). There was no SSD in plasma KL-6 between both groups (P > 0.05) on the 1st day, but there was SSD in plasma KL-6 between Groups 1 and 2 (P < 0.05) on the 14th day in the incubator.
Table 2: Plasma Krebs von den Lungen-6 and urinary β2-microglobulin at the 1st and 14th day of admission

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[Table 3] illustrates that in Group 1, urinary B2M on the 1st day of admission was 3.2 ± 0.9 mg/L, while urinary B2M on the 14th day of presence in the hospital was 1.8 ± 0.5 mg/L, with SSD between 1st and 14th days (P < 0.05). In Group 2, urinary B2M on the 1st day of hospitalization was 3.3 ± 0.85 mg/L, and urinary B2M on the 14th day of hospitalization was 3.1 ± 0.6 mg/L, with no SSD (P > 0.05). There was no SSD in urinary B2M between Groups 1 and 2 (P > 0.05) on the 1st day, but there was SSD in the urinary B2M between the 2 groups (P < 0.05) on the 14th day in the hospital.
Table 3: Serum 25 (OH) Vitamin D levels before and after therapy in both groups

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[Table 3] shows that the serum 25 (OH) Vit D levels before the treatment were 20 ± 3.6 ng/ml in Group 1 and 21 ± 3.7 ng/ml in Group 2 with no SSD (P > 0.05) while after treatment, the serum 25 (OH) Vit D levels were 39 ± 4.3 ng/ml in Group 1 and 21.5 ± 3.8 ng/ml in Group 2 with SSD between both groups (P < 0.05).

[Table 4] shows that there was decreased the need for MV in cases of Group 1 who had taken Vit D if compared with those who did not take it.
Table 4: Methods of treatment among both groups

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[Table 5] shows that the duration of hospitalization of the examined neonates in Group 1 was 24.9 ± 7.1 days, while the duration of incubator stays of neonates in Group 2 was 32.5 ± 8.9 days, with SSD between the two groups (P < 0.05).
Table 5: Duration of hospitalization of the examined neonates

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[Table 6] shows that there were 2 cases of established BPD in Group 1, where there were 9 cases of established BPD in Group 2, with SSD between Groups 1 and 2 (P < 0.05).
Table 6: The number of established bronchopulmonary dysplasia cases among the studied neonates

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  Discussion Top


BPD is a serious disease in neonates that occur mainly in premature neonates due to exposure to MV and prolonged high oxygen therapy which had various adjuvant therapies for seeking of proper management.[1],[19],[20],[21],[22],[23],[24],[25]

KL-6 could be used as an early predictor for the occurrence of BPD.[5] Urinary B2M is an important predictor for the neonatal BPD.[26],[27]

High O2 exposure of the preterm will cause oxidative stress with release of O2 free radicals, this contributes to the process of chronic pathological process which occurs in the neonatal lung which, therefore, leads to the occurrence of neonatal BPD that could be counteracted by safe and cheap antioxidant, antifibrotic and anti-inflammatory hormone-like Vit D.[11],[12]

This study showed that the levels of plasma KL-6 and urinary B2M in neonates of Group 1 who received Vit D were markedly decreased after giving Vit D indicating that adjuvant therapy of Vit D to those neonates lead to decrease in plasma KL-6 and urinary B2M which are good markers for neonatal BPD.

In agreement with the results of this research, there were some researches that showed that Vit D deficiency may have a role in BPD severity, suggesting that Vit D might have an important clinical value in the prognosis and management of neonatal BPD.[28]

Some researches revealed that the majority of preterm are susceptible to Vit D deficiency and there were a relation between Vit D deficiency and occurrence of neonatal BPD, so the early administration of 800 IU/day of Vit D may decrease the chance of Vit D deficiency in these preterm and this agreed with the results of this research.[29]

There was a study concluded that low Vit D levels in neonates were accompanied by neonatal BPD and these results were agreed with the results of this research which showed an importance of Vit D administration in preventing of BPD in neonates.[30]

As regard of the importance and safety of administration of 800 IU/day of Vit D to the preterm, there were studies that supported and agreed with the results of this current research.[31]

In disagreement with this current research, there were some studies that revealed that there was no association between Vit D levels in the preterm and presence of BPD and this was be interpreted as all preterm in these studies had 25(OH) D levels >30 ng/ml, which is thought to be sufficient in neonates and infancy.[32]

Vit D supply as well as the proper dose of Vit D for the possibility of prevention of BPD in the preterm neonates is still not yet well known, but there were some researches which agreed with the results of this research and concluded that in preterm, good supplementation of Vit D in doses of 800–1000 IU was better than 400 IU as regard the incidence of BPD in the studied neonates.[33],[34]

Many researches have reported the suspected effect of Vit D as a safe and cheap therapy on the BPD, however, there was no final evidence of the addition of Vit D in the treatment protocols of BPD as a main regimen of treatment and what is the best dose of Vit D for proper prevention of BPD.[12],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44]


  Conclusion Top


Vit D supplementation may help in the prevention of BPD in neonates, but further studies with larger number of neonates should be done.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tracy MK, Berkelhamer SK. Bronchopulmonary dysplasia and pulmonary outcomes of prematurity. Pediatr Ann 2019;48:e148-53.  Back to cited text no. 1
    
2.
Bancalari E, Jain D. Bronchopulmonary dysplasia: 50 years after the original description. Neonatology 2019;115:384-91.  Back to cited text no. 2
    
3.
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-9.  Back to cited text no. 3
    
4.
Escobar V, Soares DS, Kreling J, Ferrari LS, Felcar JM, Camillo CAM, et al. Influence of time under mechanical ventilation on bronchopulmonary dysplasia severity in extremely preterm infants: A pilot study. BMC Pediatr 2020;20:241.  Back to cited text no. 4
    
5.
Ogihara T, Hirano K, Morinobu T, Kim HS, Ogawa S, Hiroi M, et al. Plasma KL-6 predicts the development and outcome of bronchopulmonary dysplasia. Pediatr Res 2006;60:613-8.  Back to cited text no. 5
    
6.
Dilli D, Özyazici A, Dursun A, Beken S. Predictive values of plasma KL-6 in bronchopulmonary dysplasia in preterm infants. Turk J Med Sci 2017;47:621-6.  Back to cited text no. 6
    
7.
Wang K, Huang X, Lu H, Zhang Z. A comparison of KL-6 and Clara cell protein as markers for predicting bronchopulmonary dysplasia in preterm infants. Dis Markers 2014;2014:736536.  Back to cited text no. 7
    
8.
Shima Y, Kumasaka S, Nishimaki S. Urinary β2-microglobulin and bronchopulmonary dysplasia: Trends in preterm infants. Pediatr Int 2017;59:1169-73.  Back to cited text no. 8
    
9.
Capoluongo E, Vento G, Ameglio F, Lulli P, Matassa PG, Carrozza C, et al. Increased levels of IGF-1 and beta2-microglobulin in epithelial lining fluid of preterm newborns developing chronic lung disease. Effects of rhG-CSF. Int J Immunopathol Pharmacol 2006;19:57-66.  Back to cited text no. 9
    
10.
Otsubo Y, Hashimoto K, Kanbe T, Sumi M, Moriuchi H. Association of cord blood chemokines and other biomarkers with neonatal complications following intrauterine inflammation. PLoS One 2017;12:e0175082.  Back to cited text no. 10
    
11.
Chen L, Wilson R, Bennett E, Zosky GR. Identification of Vitamin D sensitive pathways during lung development. Respir Res 2016;17:47.  Back to cited text no. 11
    
12.
Cetinkaya M, Cekmez F, Erener-Ercan T, Buyukkale G, Demirhan A, Aydemir G, et al. Maternal/neonatal Vitamin D deficiency: A risk factor for bronchopulmonary dysplasia in preterms? J Perinatol 2015;35:813-7.  Back to cited text no. 12
    
13.
Mohamed Hegazy A, Mohamed Shinkar D, Refaat Mohamed N, Abdalla Gaber H. Association between serum 25 (OH) Vitamin D level at birth and respiratory morbidities among preterm neonates. J Matern Fetal Neonatal Med 2018;31:2649-55.  Back to cited text no. 13
    
14.
Khalessi N, Kalani M, Araghi M, Farahani Z. The relationship between maternal Vitamin D deficiency and low birth weight neonates. J Family Reprod Health 2015;9:113-7.  Back to cited text no. 14
    
15.
Stessman LE, Peeples ES. Vitamin D and its role in neonatal hypoxic-ischemic brain injury. Neonatology 2018;113:305-12.  Back to cited text no. 15
    
16.
Anderson-Berry A, Thoene M, Wagner J, Lyden E, Jones G, Kaufmann M, et al. Randomized trial of two doses of Vitamin D3 in preterm infants <32 weeks: Dose impact on achieving desired serum 25(OH) D3 in a NICU population. PLoS One 2017;12:e0185950.  Back to cited text no. 16
    
17.
Dutta S, Singh B, Chessell L, Wilson J, Janes M, McDonald K, et al. Guidelines for feeding very low birth weight infants. Nutrients 2015;7:423-42.  Back to cited text no. 17
    
18.
Su Y, Yoon SS. Epi info – Present and future. AMIA Annu Symp Proc 2003;2003:1023.  Back to cited text no. 18
    
19.
Ghanta S, Leeman KT, Christou H. An update on pharmacologic approaches to bronchopulmonary dysplasia. Semin Perinatol 2013;37:115-23.  Back to cited text no. 19
    
20.
Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: Clinical aspects and preventive and therapeutic strategies. J Transl Med 2018;16:36.  Back to cited text no. 20
    
21.
Hwang JS, Rehan VK. Recent advances in bronchopulmonary dysplasia: Pathophysiology, prevention, and treatment. Lung 2018;196:129-38.  Back to cited text no. 21
    
22.
Voynow JA. “New” bronchopulmonary dysplasia and chronic lung disease. Paediatr Respir Rev 2017;24:17-8.  Back to cited text no. 22
    
23.
Poindexter BB, Martin CR. Impact of nutrition on bronchopulmonary dysplasia. Clin Perinatol 2015;42:797-806.  Back to cited text no. 23
    
24.
Williams E, Greenough A. Advances in treating bronchopulmonary dysplasia. Expert Rev Respir Med 2019;13:727-35.  Back to cited text no. 24
    
25.
Miyake F, Ito M, Minami H, Tamura M, Namba F. Management of bronchopulmonary dysplasia in Japan: A 10-year nationwide survey. Pediatr Neonatol 2020;61:272-8.  Back to cited text no. 25
    
26.
Nishimaki S, Shima Y, Sato M, An H, Hashimoto M, Nishiyama Y, et al. Urinary beta 2-microglobulin in premature infants with chorioamnionitis and chronic lung disease. J Pediatr 2003;143:120-2.  Back to cited text no. 26
    
27.
Nishimaki S, Sato M, An H, Shima Y, Akaike T, Yokoyama U, et al. Comparison of markers for fetal inflammatory response syndrome: Fetal blood interleukin-6 and neonatal urinary beta(2)-microglobulin. J Obstet Gynaecol Res 2009;35:472-6.  Back to cited text no. 27
    
28.
Ge H, Liu W, Li H, Zhang M, Zhang M, Liu C, et al. The association of Vitamin D and Vitamin E levels at birth with bronchopulmonary dysplasia in preterm infants. Pediatr Pulmonol 2021;56:2108-13.  Back to cited text no. 28
    
29.
Kim I, Kim SS, Song JI, Yoon SH, Park GY, Lee YW. Association between Vitamin D level at birth and respiratory morbidities in very-low-birth-weight infants. Korean J Pediatr 2019;62:166-72.  Back to cited text no. 29
    
30.
Park HW, Lim G, Park YM, Chang M, Son JS, Lee R. Association between Vitamin D level and bronchopulmonary dysplasia: A systematic review and meta-analysis. PLoS One 2020;15:e0235332.  Back to cited text no. 30
    
31.
Cho SY, Park HK, Lee HJ. Efficacy and safety of early supplementation with 800 IU of Vitamin D in very preterm infants followed by underlying levels of Vitamin D at birth. Ital J Pediatr 2017;43:45.  Back to cited text no. 31
    
32.
Joung KE, Burris HH, Van Marter LJ, McElrath TF, Michael Z, Tabatabai P, et al. Vitamin D and bronchopulmonary dysplasia in preterm infants. J Perinatol 2016;36:878-82.  Back to cited text no. 32
    
33.
Yang Y, Li Z, Yan G, Jie Q, Rui C. Effect of different doses of Vitamin D supplementation on preterm infants – An updated meta-analysis. J Matern Fetal Neonatal Med 2018;31:3065-74.  Back to cited text no. 33
    
34.
Naeem A, Ahmed I, Silveyra P. Bronchopulmonary dysplasia: An update on experimental therapeutics. Eur Med J (Chelmsf) 2019;4:20-9.  Back to cited text no. 34
    
35.
Fort P, Salas AA, Nicola T, Craig CM, Carlo WA, Ambalavanan N. A comparison of 3 Vitamin D dosing regimens in extremely preterm infants: A randomized controlled trial. J Pediatr 2016;174:132-8.e1.  Back to cited text no. 35
    
36.
Chen C, Weng H, Zhang X, Wang S, Lu C, Jin H, et al. Low-dose Vitamin D protects hyperoxia-induced bronchopulmonary dysplasia by inhibiting neutrophil extracellular traps. Front Pediatr 2020;8:335.  Back to cited text no. 36
    
37.
Wang Y, Jiang L. Role of Vitamin D-Vitamin D receptor signaling on hyperoxia-induced bronchopulmonary dysplasia in neonatal rats. Pediatr Pulmonol 2021;56:2335-44.  Back to cited text no. 37
    
38.
Yao L, Shi Y, Zhao X, Hou A, Xing Y, Fu J, et al. Vitamin D attenuates hyperoxia-induced lung injury through downregulation of toll-like receptor 4. Int J Mol Med 2017;39:1403-8.  Back to cited text no. 38
    
39.
Lykkedegn S, Sorensen GL, Beck-Nielsen SS, Christesen HT. The impact of Vitamin D on fetal and neonatal lung maturation. A systematic review. Am J Physiol Lung Cell Mol Physiol 2015;308:L587-602.  Back to cited text no. 39
    
40.
Yang Y, Feng Y, Chen X, Mao XN, Zhang JH, Zhao L, et al. Is there a potential link between Vitamin D and pulmonary morbidities in preterm infants? J Chin Med Assoc 2018;81:482-6.  Back to cited text no. 40
    
41.
Koroglu OA, Onay H, Cakmak B, Bilgin B, Yalaz M, Tunc S, et al. Association of Vitamin D receptor gene polymorphisms and bronchopulmonary dysplasia. Pediatr Res 2014;76:171-6.  Back to cited text no. 41
    
42.
Kazzi SN, Karnati S, Puthuraya S, Thomas R. Vitamin D deficiency and respiratory morbidity among African American very low birth weight infants. Early Hum Dev 2018;119:19-24.  Back to cited text no. 42
    
43.
Taylor SK, Sakurai R, Sakurai T, Rehan VK. Inhaled Vitamin D: A novel strategy to enhance neonatal lung maturation. Lung 2016;194:931-43.  Back to cited text no. 43
    
44.
Popatia R, Pai V, Zandieh SO. Cord-blood Vitamin D levels and risk of recurrent wheezing, effect of sleep-disordered breathing on blood pressure in children, and long-term impact of bronchopulmonary dysplasia. Am J Respir Crit Care Med 2012;185:1125-6.  Back to cited text no. 44
    


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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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