Relationship between respiratory problems and vitamin D levels in very low birth weight infants

Abstract

AimThe impact of vitamin D on the developing lungs and respiratory diseases in early life is increasingly attracting the attention of neonatologists. This study aimed to investigate the association between vitamin D[25 (OHD)] levels and respiratory problems in blood in infants with very low birth weight (VLBW).MethodsSixty-six infants with VLBW were divided into two groups: those with a vitamin D level less than 20 ng/mL (Group 1) and infants with a vitamin D level equal to or greater than 20 ng/mL (Group 2). Infants’ demographic data such as birth weight, gender, maternal age, gestational week, mode of delivery, and durations of mechanical ventilation, and length of stay in the hospital, mortality status, and BPD status were recorded.ResultsThe median birth weight was 995.00 (min-max: 565–1500) g. The median gestational age was 28 (23–32) weeks and the median maternal age was 32 (21–46) years. All infants (n = 66;100%) developed respiratory distress syndrome. A significant relationship was found between the severity of respiratory distress syndrome (RDS) and vitamin D deficiency in infants with VLBW (r = 0.898, p=0.001). There was a significant correlation between the duration of hospitalization and 25 (OH) D levels within the first 24 hours (p=0.001).ConclusionLow 25 (OH) D levels in infants with VLBW were correlated with early-onset sepsis, severity of RDS, and duration of hospitalization. There was no significant correlation between vitamin D levels and PDA and BPD.

Keywords

Introduction

Vitamin D (25[OH] D) is a steroid hormone, which functions primarily in the development of a healthy skeleton and in the regulation and maintenance of body levels of calcium levels.¹ The importance of 25 (OH) D in newborns has been increasingly better understood in the last few years.² Furthermore, vitamin D seems to play a crucial role in the regulation of lung development in the fetus, lung maturation and cellular growth.³ Therefore, the impact of 25 (OH) D on developing neonatal lungs and respiratory diseases in early life is increasingly attracting the attention of neonatologists.
Maternal 25 (OH) D deficiency increases the risk of developing gestational diabetes mellitus, preeclampsia, intrauterine growth restriction and premature delivery.⁴ These, in turn, trigger preterm delivery and preterm infants are at a greater risk of developing vitamin D deficiency. Vitamin D levels of the infant reflect the maternal levels. Since placental transfer is the primary source of vitamin D for the developing fetus, this means that maternal 25 (OH) D deficiency reflects vitamin D deficiency in a newborn.⁵ Vitamin D deficiency has been correlated with various respiratory problems, including neonatal sepsis and respiratory system infections.⁶ Studies have associated low 25OHD levels at birth with subsequent respiratory infections, such as respiratory syncytial virus.⁷ There are also studies reporting that the prevalence of asthma is higher among preterm infants with low levels of 25OHD.⁸
Very low birth weight (VLBW) infants are defined as infants born with a birth weight < 1500 g. These infants tend to develop several diseases, including respiratory problems. The majority of VLBW infants have respiratory distress syndrome. Bronchopulmonary dysplasia (BPD) was defined for the first time in 1967 by Northway in premature infants with respiratory distress syndrome (RDS) after prolonged ventilator support.⁹ Some studies have reported that BPD remains the most common long-term complication of VLBW despite the use of minimally invasive strategies of respiratory support, prenatal steroids, and exogenous surfactants.¹⁰ However, whether vitamin D deficiency is associated with BPD in VLBW infants is controversial and its potential contribution to BPD is not clear.¹¹ This study aimed to investigate the association between vitamin D[25 (OHD)] levels in the blood and respiratory problems in infants with VLBW.

Materials and Methods

This study was designed as a prospective cross-sectional study. In total, the study included 66 infants with VLBW in a range of 565 and 1500 g who were followed-up in our neonatal intensive care unit (NICU) between 2016 and 2017. Infants receiving vitamin D before enrollment, those with congenital anomalies and infants with a history of maternal immunosuppressant therapy in the antenatal period were excluded from the study. Serum 25 (OH) D levels were measured on the postnatal 1st day, 28th day and 36th gestational week. The infants were divided into two groups: those with a vitamin D level less than 20 ng/mL (Group 1) and those with a vitamin D level equal to or greater than 20 ng/mL (Group 2).
Infants’ demographic data such as birth weight, gender, maternal age, gestational week, mode of delivery, durations of mechanical ventilation, and length of stay in the hospital, mortality status, BPD status, surfactant use, number of times of receiving surfactant, antenatal steroids use, sepsis, pneumonia, oligohydramnios, 1st and 5th minutes Apgar scores, and CPAP status were recorded. In addition, the presence of oligohydramnios and preeclampsia was also recorded.
All infants included in the study received surfactant therapy. In infants in whom extubation could not be achieved immediately, synchronized intermittent mandatory ventilation (SIMV) was the primary mode of ventilation, providing a tidal volume with inspiratory time of 0.35 to 0.38 seconds, respiratory rates of 40 to 60 breaths/minute, and a positive end-expiratory pressure (PEEP) of 5-6 cm H2O. When a PIP of 15 cmH2O, PEEP of 4 -5 cmH2O, respiratory rate (RR) of 15 per minute and a FiO2 value ≤30% were obtained, patients were extubated to receive nasal CPAP.
The presence of patent ductus arteriosus (PDA) was evaluated through echocardiography in all infants included in the study on the 3rd day of life. If hemodynamically significant PDA was diagnosed, ibuprofen was given as pharmacologic treatment.
The associations between the levels of 25 (OH) D and respiratory disorders, including BPD, surfactant requirement, cPAP status, PDA status, length of hospital stay and mortality were investigated.
Blood samples of all patients were collected at the time of admission, on the 28th day and in the 36th gestational week during routine blood sampling. Plasmas of the blood samples were separated and kept at −80 °C until analysis. A High-Performance Liquid Chromatography (HPLC) System (Shimadzu LC-20AT model) was used to determine the levels of 25 (OH)D.Ethical ConsiderationsWritten informed consent was taken from the parents before the participation of their neonates in the study. The study was performed in accordance with the Declaration of Helsinki revised in 2013.Ethical ApprovalEthics Committee approval for the study was obtained. Ethics Committee approval for the study was obtained from the local ethics committe of the Zeynep Kamil Maternity and Children Training and Research Hospital (Date: 25.11.2016, Decision No: 158).Statistical AnalysisData obtained in this study were statistically analyzed using the SPSS version 21.0 (SPSS, Statistical Package for Social Sciences, IBM Inc., Armonk, USA). The normality of the variables was tested using the Kolmogorov-Smirnov method and expressed as a mean ± standard deviation or median (IQR) as appropriate. Qualitative variables are expressed as percentages and frequencies, normally distributed continuous variables as means (standard deviations, SD) and non-normally distributed variables as medians (interquartile range[IQR] p25-p75). Pearson’s correlation was used to evaluate the correlations between 25 OH vitamin D and other variables. The Chi-square test was performed for categorical variables. P- values <0.05 were considered statistically significant.

Results

This study included a total of 66 infants followed-up and treated in our NICU. The median birth weight was 995.00 (min-max: 565-1500) g. The median gestational age was 28 (23-32) weeks and the median maternal age was 32 (21-46) years. Of all infants, 30 (45.45%) were male and 36 (54.55%) were female. Table 1 shows antenatal and demographic data of the infants. The median 25 (OH) D level on the 1st day was 4.95 (3.90-10.53) ng/ml, and the median 25 (OH) D on the 26th day or at discharge was 15.5 (7.5-37.8) ng/ml. The distribution of patients according to 25 (OH) D is shown in Figure 1. There was no significant difference between infants with 25 (OH) D <20 and ≥20 ng/mL between the two measurement times (p=0.083). All infants (n = 66;100%) developed respiratory distress syndrome. Sixteen (24.24%) developed BPD, while 24 (36.36%) infants developed PDA and 20 (30.30%) developed pneumonia. Preeclampsia was observed in 19 (28.79%) and oligohydramnios in 6 (9.09%) mothers. Early sepsis was observed in 23 (34.85%) infants and late sepsis in 28 (42.42%) infants. Surfactants were required in 54 (81.82%) patients and steroids in 32 (48.48%) patients. The median duration of mechanical ventilation was 2 (0-8.50) days. The median duration of transit to enteral feeding was 14.50 (8.0-22.25) days. The median duration of hospitalization was 41.50 (26.5-68.0) days. Mortality occurred in 11 (16.67%) infants (Figure 2). In the correlation analysis, a significant correlation was found between vitamin D deficiency and the severity of RDS in infants with VLBW (r = 0.898, p=0.001). There was a significant correlation between low 25 (OH) D levels (<20 ng/mL) measured on the first day and sepsis (r = -0.557, p=0.003). However, there was no statistically significant correlation between low 25 (OH) D levels (<20 ng/mL) measured on the 28th day or at discharge and late sepsis (r = 0.97, p=.094). No significant relationship was observed between BPD and 25(OH) D levels (p>0.05). No statistically significant correlation was observed between low levels of 25 (OH) D (<20 ng/mL) measured on the first day and PDA (p=0.887). Similarly, no statistically significant correlation was observed between low 25 (OH) D levels (<20 ng/mL) measured on the 28th day and PDA (p=0.615). A significant correlation was found between the duration of hospitalization and the levels of 25 (OH) D in the first 24 hours (p=0.001). No correlation was observed between 25 (OH) D levels in the first 24 hours and mortality (r = 0.492, p=0.931).

Discussion

There is increasing global interest regarding the role of vitamin D in health and disease. Vitamin D is known to play a role in human pulmonary function.¹² Studies have shown that patients with lung diseases often have low Vitamin D serum levels. Epidemiological data indicate that low levels of serum Vitamin D are associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases.¹³ Vitamin D deficiency in blood has also been associated with increased incidence of respiratory tract infections during infancy.¹⁴ Wide biological effects of Vitamin D, suggest that the deficiency of vitamin D during the fetal and neonatal periods may have long-lasting health consequences.¹⁵ It has also been shown that low blood levels of Vitamin D are associated with an increased risk of respiratory problems.¹⁶ In the present study, we evaluated the effects of Vitamin D deficiency on respiratory problems in low-birth-weight infants. Neonatal RDS is a common cause of respiratory distress in newborns that present within hours after birth. RDS primarily affects preterm infants.¹⁷ Critical factors playing a role in the pathogenesis of neonatal RDS include surfactant deficiency and pulmonary immaturity. In the present study, 54/66 infants required surfactant therapy. In our study, all VLBW infants had respiratory distress syndrome. In addition, a significant relationship was found between the severity of RDS and deficiency of vitamin D in infants with VLBW (r = 0.898, p=0.001). Dogan et al. showed that vitamin D deficiency was an independent factor for the development of RDS in premature infants.¹⁸ Neonatal sepsis is defined as a systemic condition originating from bacterial, viral or fungal causes and is associated with hemodynamic changes and clinical findings causing severe morbidity and mortality.¹⁹ While early-onset sepsis describes cases presenting manifestations within the first 72 hours of life, late-onset sepsis describes cases diagnosed after the first seven days.²⁰ Low vitamin D levels that are generally common in the neonatal population have been found to be significantly higher in neonates with sepsis.²¹ In the present study, there was a significant correlation between low 25 (OH) D levels (<20 ng/mL) measured on the first day and sepsis (r = -0.557, p=0.003). However, there was no statistically significant correlation between low 25 (OH) D levels (<20 ng/mL) measured on the 28th day or at discharge and late sepsis (r = 0.97, p=.094). We think that the difference in late sepsis may be due to the effect of surfactant supplementation, which was initiated from the first day of life in our study. BPD is a chronic pulmonary disorder that primarily affects preterm infants. The new BPD definition differs from the first and is characterized by pulmonary vascular dysplasia or hypoplasia and alveolar simplification rather than scarring and fibrosis of the lungs.²² Potential contribution of Vitamin D deficiency to BPD is unknown. Joung et al found no correlation between 25(OH) D levels and the development of BPD.¹¹ In our study also no significant relationship was observed between BPD and the levels of 25(OH) D (p>0.05). Furthermore, in a meta-analysis and systematic review, including eight studies, the authors concluded that the vitamin D levels at the time of birth, reflecting maternal and fetal vitamin D status during pregnancy, was significantly correlated with the incidence of BPD. However, no information was given about the later measurements of vitamin D levels.²³ A patent ductus arteriosus occurs commonly in preterm infants, especially in those with respiratory distress syndrome. In our study, PDA occurred in 36.36% (24/66) of VLBW infants. Studies have proposed that severe RDS justifies a controlled trial of very early closure of the PDA in the very low-birth-weight infant with severe RDS.²⁴ In a study by Kim et al., PDA occurred in 48.4% of VLBW infants.²⁵ In our study, PDA was observed in 24 (36.4%) of VLBW infants. We could not find a significant difference between Vitamin D deficiency and PDA. In the present study, a significant correlation was observed between hospitalization duration and the levels of 25 (OH) D in the first 24 hours (p=0.001). No correlation was observed between 25 (OH) D levels in the first 24 hours and mortality (r = 0.492, p=0.931).

Limitations

The main limitations of this study include its single-center design and relatively small number of patients. In addition, a control group with term infants could be created. Finally, we could not compare maternal and neonatal vitamin D levels. However, given the limited number of existing data in the literature and the need for further studies, we believe that our results will guide for future more comprehensive studies.

Conclusion

The results of this study revealed that low 25 (OH) D levels in infants with VLBW were correlated with early-onset sepsis, severity of RDS, and duration of hospitalization. There was no statistically significant correlation between the levels of vitamin D and BPD and PDA. However, there is a need for further comprehensive studies with larger series to better enlighten these correlations.

Declarations

References

1. Jäpelt RB, Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Front Plant Sci. 2013;4:136. doi:10.3389/fpls.2013.00136
   Article · PubMed · Google Scholar
2. Christesen HT, Elvander C, Lamont RF, Jørgensen JS. The impact of vitamin D in pregnancy on extraskeletal health in children: a systematic review. Acta Obstet Gynecol Scand. 2012;91(12):1368-1380. doi:10.1111/aogs.12006
   Article · PubMed · Google Scholar
3. Yang Y, Feng Y, Chen X, et al. Is there a potential link between vitamin D and pulmonary morbidities in preterm infants? J Chin Med Assoc. 2018;81(5):482-486. doi:10.1016/j.jcma.2017.07.011
   Article · PubMed · Google Scholar
4. Wei SQ. Vitamin D and pregnancy outcomes. Curr Opin Obstet Gynecol. 2014;26(3):438-447. doi:10.1097/gco.0000000000000117
   Article · PubMed · Google Scholar
5. Al-Beltagi M, Rowiesha M, Elmashad A, et al. Vitamin D status in preterm neonates and the effects of its supplementation on respiratory distress syndrome. Pediatr Pulmonol. 2020;55(1):108-115.
   PubMed · Google Scholar
6. Terek D, Ozcan G, Ergin F, et al. Vitamin D deficiency in premature infants and its effects on neonatal prognosis. J Pediatr Res. 2018;5(1):37-40. doi:10.4274/jpr.82788
   Article · PubMed · Google Scholar
7. Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics. 2011;127(6):e1513-e1520. doi:10.1542/peds.2010-3054
   Article · PubMed · Google Scholar
8. Brehm JM, Acosta-Pérez E, Klei L, et al. Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med. 2012;186(2):140-146. doi:10.1164/rccm.201203-0431oc
   Article · PubMed · Google Scholar
9. McEvoy CT, Aschner JL. The natural history of bronchopulmonary dysplasia: the case for primary prevention. Clin Perinatol. 2015;42(4):911-931. doi:10.1016/j.clp.2015.08.014
   Article · PubMed · Google Scholar
10. Mahmoud RA, Roehr CC, Schmalisch G. Current methods of non-invasive ventilatory support for neonates. Paediatr Respir Rev. 2011;12(3):196-205. doi:10.1016/j.prrv.2010.12.001
    Article · PubMed · Google Scholar
11. Joung KE, Burris HH, Van Marter LJ, et al. Vitamin D and bronchopulmonary dysplasia in preterm infants. J Perinatol. 2016;36(10):878-882. doi:10.1038/jp.2016.115
    Article · PubMed · Google Scholar
12. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin D and pulmonary function in the third national health and nutrition examination survey. Chest. 2005;128(6):3792-3798. doi:10.1378/chest.128.6.3792
    Article · PubMed · Google Scholar
13. Herr C, Greulich T, Koczulla RA, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12(1):31. doi:10.1186/1465-9921-12-31
    Article · PubMed · Google Scholar
14. Panda M, McIntosh J, Chaudhari T, Kent AL. Do maternal vitamin D levels influence vitamin D levels in preterm neonates? Int J Pediatr. 2019;2019:8613414. doi:10.1155/2019/8613414
    Article · PubMed · Google Scholar
15. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353-373. doi:10.4065/81.3.353
    Article · PubMed · Google Scholar
16. Camargo CA Jr, Ingham T, Wickens K, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics. 2011;127(1):e180-e187. doi:10.1542/peds.2010-0442
    Article · PubMed · Google Scholar
17. Yadav S, Lee B, Kamity R. Neonatal respiratory distress syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
    PubMed · Google Scholar
18. Dogan P, Ozkan H, Koksal N, et al. Vitamin D deficiency and its effect on respiratory distress syndrome in premature infants: results from a prospective study in a tertiary care centre. Afr Health Sci. 2020;20(1):437-443. doi:10.4314/ahs.v20i1.50
    Article · PubMed · Google Scholar
19. Ozmeral Odabasi I, Bulbul A. Neonatal sepsis. Med Bull Sisli Etfal Hosp. 2020;54(2):142-158.
    PubMed · Google Scholar
20. Dong Y, Speer CP. Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F257-F263. doi:10.1136/archdischild-2014-306213
    Article · PubMed · Google Scholar
21. Workneh Bitew Z, Worku T, Alemu A. Effects of vitamin D on neonatal sepsis: a systematic review and meta-analysis. Food Sci Nutr. 2020;9(1):375-388.
    PubMed · Google Scholar
22. Xu YP. Bronchopulmonary dysplasia in preterm infants born at less than 32 weeks gestation. Glob Pediatr Health. 2016. doi:10.1177/2333794X16668773
    Article · PubMed · Google Scholar
23. Park HW, Lim G, Park YM, et al. Association between vitamin D level and bronchopulmonary dysplasia: a systematic review and meta-analysis. PLoS One. 2020;15(7):e0235332. doi:10.1371/journal.pone.0235332
    Article · PubMed · Google Scholar
24. Nemri AM. Patent ductus arteriosus in preterm infant: basic pathology and when to treat. Sudan J Paediatr. 2014;14(1):25-30.
    PubMed · Google Scholar
25. Kim I, Kim SS, Song JI, et al. Association between vitamin D level at birth and respiratory morbidities in very-low-birth-weight infants. Korean J Pediatr. 2019;62(5):166-172. doi:10.3345/kjp.2018.06632
    Article · PubMed · Google Scholar

Tables

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions