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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 152-159

25-hydroxy Vitamin D deficiency – A potential risk factor neonatal sepsis correlation with biochemical markers and neonatal sequential organ failure assessment score


1 Department of Pediatric, Faculty of Medicine, Minia University, Minya, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Minia University, Minya, Egypt

Date of Submission21-Feb-2021
Date of Decision18-May-2021
Date of Acceptance16-Jun-2021
Date of Web Publication28-Jul-2021

Correspondence Address:
Nagwa Mohamed Sabry Mahmoud
Department of Pediatric, Faculty of Medicine, Minia University, Minya
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_30_21

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  Abstract 


Background: Sepsis could be a life-threatening organ dysfunction generated due to the dysregulation of the immunological response to infection. An operational definition of organ dysfunction applicable to neonates that predicts mortality within the infection setting is lacking. The neonatal sequential organ failure assessment (nSOFA) score was developed to predict mortality from late-onset neonatal sepsis in term babies (late-onset sepsis [LOS]). Objectives: This study aimed to focus on Vitamin D role in late-onset neonatal sepsis in term babies and to search out the correlation of Vitamin D levels with inflammatory markers, the severity of the disease, and association with nSOFA score and mortality risk. Patients and Methods: We screened all term newborns admitted to the neonatal intensive care unit (NICU) due to suspected or confirmed LOS during the study period. Our final cohort consisted of 148 patients with valid test results and data. Neonates with suspected LOS (Group 1 n = 52) confirmed LOS (Group 2 [n = 74]) or septic shock (group 3 [n = 24]). Baseline clinical data, nSOFA score within the first 24 h, cardiovascular support, the duration of mechanical ventilation, length of the NICU stay, 7th and 28th-day mortality recorded, plasma levels of 25-hydroxyvitamin D (25[OH] D), C-reactive protein, and pre- and procalcitonin were investigated. Newborns were followed until they discharge from the NICU or death. Results: Term newborns with late-onset neonatal sepsis had lower levels of 25(OH) D. We revealed a negative correlation between the levels of 25(OH) D and biochemical markers/nSOFA score in all patients with late-onset neonatal sepsis. Thirty-seven (25%) patients with LOS died within 28 days of NICU admission (with a median 25(OH) D level of 18.3 nmol (interquartile range: 8.7–23.8). There were 35 patients (23.64%) who received vasopressors (N-SOFA ≥3) during their NICU stay. These patients had significantly lower 25(OH) D levels.(P < 0.0001). Lower 25(OH) D levels among study groups were independently associated with a higher n-SOFA score. Conclusion: Our results showed that Vitamin D deficiency predisposed to the development of late-onset neonatal sepsis negatively correlated with biochemical markers and nSOFA score.

Keywords: 25-hydroxyvitamin D, neonatal sepsis, neonatal sequential organ failure assessment score, procalcitonin, systemic inflammatory response syndrome, Vitamin D


How to cite this article:
Mahmoud NM, Elela MA. 25-hydroxy Vitamin D deficiency – A potential risk factor neonatal sepsis correlation with biochemical markers and neonatal sequential organ failure assessment score. J Clin Neonatol 2021;10:152-9

How to cite this URL:
Mahmoud NM, Elela MA. 25-hydroxy Vitamin D deficiency – A potential risk factor neonatal sepsis correlation with biochemical markers and neonatal sequential organ failure assessment score. J Clin Neonatol [serial online] 2021 [cited 2021 Oct 26];10:152-9. Available from: https://www.jcnonweb.com/text.asp?2021/10/3/152/322534




  Introduction Top


Vitamin D, or calciferol, is a generic term and refers to a group of lipid-soluble compounds with a four-ringed cholesterol backbone. 25-hydroxyvitamin D (25[OH] D) is the major circulating form of Vitamin D.[1] Vitamin D3 (cholecalciferol) is synthesized nonenzymatically in the skin from 7-dehydrocholesterol during exposure to ultraviolet rays from sunlight. Vitamin D3 from the skin or diet must be 25-hydroxylated within the liver and then 1-hydroxylated within the kidneys to its active form, calcitriol.[2],[3] In addition to its role in calcium and bone homeostasis, Vitamin D potentially regulates many other cellular functions. The Vitamin D receptor (VDR) is almost universally expressed in nucleated cells. Approximately 3% of the human genome is under the control of 1,25-dihydroxy Vitamin D, the active form of Vitamin D. Furthermore, a minimum of 10 extrarenal tissues express 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for converting the inactive Vitamin D form to its active form; thus, the active hormone is generated in an auto or paracrine way. The spectrum of activity of Vitamin D in the endocrine system is far more extensive than calcium/bone homeostasis, and in this regard, the Vitamin D-VDR system resembles that of other ligands of nuclear receptors, such as those associated with hormones.[4]

A large number of epidemiological studies indicate that the risks of infectious, autoimmune disorders, and cardiovascular diseases increase when serum levels of Vitamin D (25[OH] D) levels are <20 ng/mL (50 nmol/L) and that these risks decrease with higher serum levels of 25(OH) D. However, no randomized trial data have reported that Vitamin D supplements might decrease the risk of infectious, autoimmune, cardiovascular, or metabolic diseases.[5],[6]

Although the incidence of sepsis in full-term newborns is low (approximately 1–6 cases per 1000 births), the potential for serious adverse outcomes, including mortality, is of such a great consequence that caregivers should have a low index threshold for evaluation and management of possible sepsis. The estimated incidence rates vary; globally, neonatal sepsis and other severe infections were responsible for an estimated 430,000 neonatal deaths in 2013, accounting for about 15% of all neonatal deaths.[7] The distinction between infection and sepsis is not defined in the neonatal intensive care unit (NICU). In contrast to sepsis definitions for adults and children, the definition of sepsis commonly employed in neonatology is variable and heavily predicated on the isolation of pathogens from the blood.[1],[5] Sepsis is defined as a systemic inflammatory response syndrome (SIRS) in the presence of suspected or proven infection. Several definitions further describe sepsis in terms of severity and response to therapy. Sepsis is considered severe when it is associated with cardiovascular dysfunction, acute respiratory distress syndrome, or dysfunction in two or more noncardiac or respiratory organ systems. Septic shock refers to sepsis with cardiovascular dysfunction that persists despite the administration of ≥40 mL/kg of isotonic fluid in 1 h.[8] In multiple organ failure, reliably identifying and quantifying organ dysfunction is useful for tracking clinical changes and therapy responses in children with septic shock. The International Consensus on Pediatric Sepsis[8] developed criteria for organ dysfunction based upon several scoring systems.[9],[10] SIRS is a widespread inflammatory response that may be associated with infection. The presence of two or more of the following criteria (one of which must be abnormal temperature or leukocyte count) defines SIRS: (1) core temperature of >38.5°C or <36°C, (2) tachycardia, defined as a heart rate of more than two standard deviations (SD) above normal for age or bradycardia defined as a mean heart rate <10th percentile for age, (3) respiratory rate of more than two SD above normal for age or mechanical ventilation (MV) for an acute pulmonary disorder, and (4) leukocyte count increased or depressed for age or more than 10% immature neutrophils.[9],[10],[11]

Clinical manifestations are progressed along a continuum of severity ranging from sepsis to severe sepsis, septic shock, and multiple organ failure.[11] Organ dysfunction indicates a pathology more complex than simply infection plus an accompanying inflammatory response. The presence of life-threatening organ dysfunction can be demonstrated using a sequential organ failure assessment (SOFA) to work out NICU admission or mortality risk.[12]


  Patients and Methods Top


This study was a prospective observational cohort study conducted in the NICU, Minia University Hospital for Obstetrics and Gynecology, and Pediatrics. Our study was approved by the Research and Ethics Committee, Faculty of Medicine, Mania University, Egypt. The participant's anonymity and confidentiality was protected, and the use of deceptive practices was avoided. We did not receive financial support for the study. We declare no conflicts of interest concerning this study.

Inclusion and exclusion criteria

We screened all term babies admitted to the NICU with late-onset neonatal sepsis from September 2018 to January 2020. Mania University Hospital for Obstetrics and Gynecology and Pediatrics is a 32-bed tertiary level academic NICU that performs an average of 12,000 deliveries per year and has 1300 annual admissions. Patients who had an estimated NICU stay of more than 48 h and whose ages ranged from 4 to 28 days of life were considered eligible to participate and were enrolled within the first 24 h of the NICU admission. Exclusion criteria consisted of patients admitted to the NICU for early-onset sepsis (EOS) within the first 72 h of life, postoperative monitoring, multiple pregnancies, small gestational age or large for gestational age, preeclampsia, gestational diabetes mellitus, smoking tobacco during pregnancy, significant congenital anomalies, newborns with asphyxia at birth, suspicion of primary immunodeficiency disease or use of immunosuppressive therapy, congenital cyanotic heart disease, and maternal anti-epileptic drug use. Patients in terminal stages with presumed death within 24 h from the time of NICU admission were also excluded from the study. Mothers of recruited babies were then interviewed via a detailed questionnaire concerning their Vitamin D supplementation during pregnancy, including their Vitamin D intake or any other Vitamin D supplements. If the total number of maternal Vitamin D supplements per day was ≥400 IU, it was considered sufficient.

Neonatologists thoroughly examined all babies. Baseline clinical data consisted of age, sex, weight, mode of delivery, oxygen requirements, SOFA score in the first 24 h, cardiovascular support, the duration of MV, length of NICU stay, and 28th-day mortality. Newborns were followed closely until their discharge from the NICU or death.

Blood samples (3 ml per sample) were obtained from all babies as early as possible upon NICU admission and before both treatment and enteral and parenteral nutrition. Each blood specimen was collected in heparin tubes and centrifuged for 10 min to obtain 2 mL serum, frozen at −80°C, and sent to the laboratory for the quantitative analysis of 25(OH) D. Routine laboratory investigations in the form of complete and differential blood count, C-reactive protein (CRP), procalcitonin (PCT), and blood and site-specific cultures as indicated were performed. CRP levels were measured using an immunoturbidimetric method, and PCT levels were measured by the electrochemiluminescence immunoassay “ECLIA” method. The competitive enzyme-linked immunosorbent assay technique evaluated plasma levels of 25(OH) D. All the parameters and results described in this study were obtained from samples taken the day after admission to the intensive care unit (ICU) (within 24 h). MV in NICU was defined as any form of MV for a total of more than 24 h. The severity of the illness in the first 12 h was measured using the neonatal sequential organ failure assessment (nSOFA) score [Table 1].
Table 1: Neonatal sequential organ failure assessment components and scoring (0-15-point range)

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Late-onset sepsis (LOS) is defined as an event that met several criteria: (1) sepsis occurred after the third day of life, (2) a single bacterial/fungal pathogen isolated from blood, cerebrospinal, pleural, peritoneal fluid or sputum, (3) a white blood cell (WBC) count of < 1000 or > 50,000/μL, (4) increased absolute neutrophil count (ANC) of >17,670/microL, (5) increase in immature-to-total (I/T) ratio of ≥ 0.2), (6) and a decrease in platelet count (<50,000/microL).[26] Sequential assessment of CRP values and Elevated serum levels of Procalcitonin (PCT) supported the diagnosis of sepsis.[13]

Suspected sepsis included all babies who met the criteria for SIRS but were negative for microorganisms and had received a course of antibiotics. The neonate has a clinical course that is concerning for sepsis (such as ongoing temperature fluctuations, ongoing respiratory, cardiocirculatory, or neurological symptoms unexplained by other conditions, and ongoing laboratory abnormalities suggestive of sepsis (such as cerebrospinal fluid pleocytosis, elevated ratio of I/T neutrophil counts, or elevated CRP).

SIRS is recognized when the temperature is abnormal (fever or hypothermia) or age-specific abnormal WBC count and one or more of several issues: (1) tachycardia, (2) bradycardia, (3) respiratory distress, and (4) pulmonary condition requiring MV [Table 2]. SIRS in the presence of suspected or proven infection constitutes sepsis. Clinical presentation typically progresses along a continuum of severity from sepsis to severe sepsis, septic shock, and multiple organ failure.[8]
Table 2: Pediatric systemic inflammatory response syndrome vital signs and laboratory values by age

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Septic shock refers to sepsis with cardiovascular dysfunction and multiple organ failure that persists despite the administration of ≥40 mL/kg of isotonic fluid over 1 h[11] in a patient with a confirmed or suspected sepsis and who is on inotropic support (nSOFA score ≥3) at NICU admission.

Range of reference values

As defined by the Global Consensus, the serum levels of 25(OH) D were divided into three groups: (1) >20 ng/mL as is normal, (2) 15–20 ng/mL, which is considered a relative deficiency, and < 15 ng/mL, defined as an absolute deficiency. This study defined 25(OH) D deficiency as a level <20 ng/mL.[14]

Statistical methods

Data were analyzed using SPSS version 20 (IBM, Corp., Atlanta, GA, USA). The abnormally distributed variables were expressed as median (interquartile range [IQR] or 95% confidence interval [CI]) as appropriate. Categorical variables were presented as counts and percentages. Spearman's correlation coefficient was used to assess the association of 25(OH) D with other variables, the Mann–Whitney test for dichotomous variables, and the Kruskal–Wallis test for multicategorical variables as most variables were not distributed normally. We used multivariate logistic regressions to evaluate the influence of risk factors on Vitamin D deficiency, nSOFA score, complete blood count parameters, CRP, and PCT. Patient characteristics associated with 25(OH) D in univariate analysis (P ≤ 0.10) or potential predictors were included in the multivariable models. Results from the regression were reported as adjusted odds ratios (OR) and corresponding 95% CIs. P < 0.05 in a two-tailed test was taken as a criterion for being considered statistically significant.


  Results Top


We screened all term babies admitted to NICU during the study period because of suspected or confirmed LOS. Our final cohort consisted of 148 patients with valid test results and data. Neonates with suspected LOS (Group 1), confirmed LOS (Group 2), or septic shock (Group 3) and with supposed hospitalization length of more than 24 h were included in the study, in addition to eighty normal healthy newborns with postnatal ages of 3–10 days and gestational ages of 37–40 weeks, both genders, of any mode of delivery who were enrolled in our study as a control group. There were no clear differences in the demographic data between the three groups included for analysis [Table 3] and [Table 4].
Table 3: Baseline demographic and clinical characteristics of all patients

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Table 4: Baseline demographic and clinical characteristics of all studied group regarding 25-hydroxyvitamin D

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We identified 52 (100%) survivors with suspected sepsis, 52 (72.2%) survivors with confirmed sepsis, and 17 (70.83%) survivors with septic shock who met our definition of LOS [Table 5]. The groups were similar concerning birth weight, gestational age, delivery mode, sex, and race.
Table 5: Correlation of 25-hydroxyvitamin D with plasma levels of modern biochemical markers in different groups of patients and values of clinical neonatal sequential organ failure assessment score

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Thirty-seven (25%) patients died within 28 days of NICU admission ( with a median 25(OH) D level of 18.3 nmol (IQR: 8.7–23.8). There were 35 patients (23.64%) who received vasopressors (N-SOFA ≥3) during their NICU stay. These patients had significantly lower 25(OH) D levels (P < 0.0001). Lower 25(OH) D levels among groups under study were independently associated with a higher n-SOFA score.

Patients with confirmed or suspected infection had lower 25(OH) D levels, with a mean (±SD) of 25(OH) D level of 19.07 ± 8.44 and 14.13 ± 3.59 respectively, however, 25(OH) D levels were markedly lower in the 24 patients with septic shock with mean ± SD (11.08 ± 4.96) than other confirmed or suspected infectious (P < 0.0001) [Table 6].
Table 6: Comparison of laboratory markers and plasma 25-hydroxyvitamin D levels between groups of patients

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  Discussion Top


Vitamin D deficiency is considered a worldwide public health problem with a high prevalence in all pediatric age groups.[15] Vitamin D status is evaluated by the level of circulating 25-hydroxy D (25(OH) D) as the best-accepted marker.[16]

This deficiency explicitly prevents the establishment of a consensus definition for neonatal sepsis, a prerequisite for improved sepsis outcomes. While defining infection was not the objective of this work, the identification of patients with infections who have an increase in risk of mortality based on objective organ dysfunction was the goal of the study and forms the prerequisite to redefining sepsis in this population.

To the best of our knowledge, only one study was conducted in neonates by Wynn and Polin[17] who studied the value of nSOFA score in predicting mortality due to LOS in preterm and low birth weight infants.

This study identified term babies at a high risk of mortality among those with LOS. nSOFA scores and 25(OH) D deficiency apply specifically to this patient population and predict mortality in LOS settings.

The nSOFA score includes measures of organ dysfunction related to sepsis mortality in evidence-based studies. The nSOFA score has excellent potential to help clinicians and nurses improve patient safety outcomes. Notification of clinical providers when a threshold score is reached or a rate of change that is concerning occurs may be additionally useful, especially for large NICUs.

We intentionally excluded EOS examination because the degree of organ dysfunction immediately after birth may be high in the absence of infection. Furthermore, microbiologically confirmed EOS is rare, especially in term infants, so to test the utility of the nSOFA for EOS mortality would require a multicenter or large database approach to address other confounding conditions that lead to organ dysfunction and early death (pulmonary hypoplasia, severe intraventricular hemorrhage, and hypoxia–ischemic encephalopathy).

In this study, we also found an increased incidence of 25(OH) D deficiency in critically ill neonates; 25 (OH) D serum levels were inversely correlated with the nSOFA score.

We found that the median levels of 25(OH) D in critically ill neonates with septic shock were significantly lower than those found for sick neonates with suspected or confirmed LOS (P < 0.0001). The 40% incidence of Vitamin D deficiency in our critically ill neonates was lower than that reported in a previous study (69%) by Asilioglu et al.,[18] who studied serum Vitamin D status and outcomes in critically ill children, but more similar to another study (40%) by Madden et al. who studied Vitamin D deficiency in critically ill children.[19]

A previous study found that metabolomics profiles are significantly different in critically ill patients with a 25(OH) D level ≤ of 15 ng/mL relative to those with levels more than 15 ng/mL.[20] A highly significant difference in 25(OH) D levels between the three study patient groups (suspected or confirmed sepsis and septic shock) in the current study was found (P < 0.0001).

Previous studies have concluded that neonates with LOS may have lower 25(OH) D levels and that 25(OH) D deficiency is associated with higher mortality and incidence of positive blood cultures in critically ill infants and children.[21],[22] In this study, babies with septic shock presented lower 25(OH) D levels than babies with confirmed or suspected LOS infection. In addition, babies with septic shock had significantly lower levels of 25(OH) D, which were near related to higher n-SOFA scores (r = −0.206; P < 0.001). Our studies of the association between Vitamin D and septic shock have not previously examined neonates with LOS. A previous study concluded that septic shock children with extremely low Vitamin D levels needed vasopressor support for more extended periods.[23] Another study also reported that Vitamin D deficiency affects the catecholamine system and annoys cardiovascular system instability.[24]

The association between septic shock and 25(OH) D is yet to be explained; however, the low 25(OH) D levels in LOS may be attributed to protein catabolism, which decreases the level of 25(OH) D binding protein, a critical protein that is a predictor of mortality in the NICU and is associated with the early stage of neonatal sepsis and a poor prognosis when its absolute levels decline. Alternatively, the known effects of serum 25(OH) D include inhibition of T-cell proliferation, regulation of pro-and anti-inflammatory cytokines,[25],[26] and 25(OH) D deficiency, which may also be contributing to the progression of septic shock. Furthermore, many neonates with septic shock were given large boluses of fluid as fluid resuscitation in the early stages, which diluted the blood and could partly explain the low levels of 25(OH) D levels observed in babies in septic shock.

We reported that a higher nSOFA score is associated with lower 25(OH) D levels in this study. Using regression analysis, a statistically significant negative correlation between 25(OH) D levels and nSOFA was reported. These results suggest that lower serum 25(OH) D levels are more likely to be associated with LOS severity and affect promoting progression to septic shock and multi-organ failure. Therefore, 25(OH) D levels may help evaluate critical illness in LOS, and monitoring serum 25(OH) D concentrations in neonates in NICU may help determine the progression and prognosis of LOS and septic shock.

Previous studies have reported that a deficiency of 25(OH) D was associated with poor outcomes and increased mortality, while others did not.[27] In this study, we reported that neonates who died within 7 and 28 days of admission to NICU had significantly lower 25(OH) D levels compared to survivors. This finding was in contrast to the results of Dang et al., who confirmed that 25(OH) D deficiency was not correlated with mortality in critically ill children admitted to pediatric ICU.

In this study, we reported a high prevalence of Vitamin D deficiency in critically ill neonates admitted to the NICU and a negative correlation between 25(OH) D levels and nSOFA score, which provides additional prognostic value in term neonates with LOS.

Limitations

Lack of serial measurements of Vitamin D for the study group, and we do not routinely assess and follow up the trend in 25(OH) D levels throughout NICU patients.

Vitamin D levels in the mothers of these babies could not be measured not because of financial aspect and limited resources in our hospital.

nSOFA is a good score, but it has not been validated globally.

Recommendations

Extensive studies with larger sample size and more extended period are necessary to clarify further the mechanism of different forms of deficiency of Vitamin D in the severity of neonatal sepsis in NICU and to evaluate the value of nSOFA score in predicting mortality in term babies with LOS that is a critical step towards improvement in the outcome of neonatal sepsis. The nSOFA may address a critical unmet need for a useful, objective operational definition of organ dysfunction applicable to neonates that can align neonatal sepsis investigators, allow longitudinal disease stratification including prediction, and facilitate predictive enrichment for future prospective interventional clinical trials.


  Conclusion Top


25-Hydroxy Vitamin D deficiency predispose to the development of late onset neonatal sepsis, and negatively correlated with biochemical markers and nSOFA score.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



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



 

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