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ORIGINAL ARTICLE
Year : 2022  |  Volume : 11  |  Issue : 4  |  Page : 206-211

Association between serum 25-hydroxy Vitamin D and bilirubin levels in term neonates with hyperbilirubinemia: A cross-sectional, observational study


Department of Neonatology, ABVIMS and Dr. RML Hospital, New Delhi, India

Date of Submission01-Jun-2022
Date of Decision10-Jul-2022
Date of Acceptance14-Jul-2022
Date of Web Publication04-Oct-2022

Correspondence Address:
Arti Maria
Department of Neonatology, ABVIMS and Dr. RML Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_61_22

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  Abstract 


Introduction: Neonatal jaundice is a common cause of hospital admission among neonates in the 1st week of life. The condition results from an imbalance between oxidative stress and antioxidant mechanisms. Considering the fact that the metabolism of both bilirubin and 25-hydroxy Vitamin D occurs in the liver and 25-hydroxy Vitamin D being a potent antioxidant, we hypothesized that there exists an association between 25-hydroxy Vitamin D and serum bilirubin levels. Methods: A total of 174 neonates were enrolled in the study and were further subclassified into 4 groups: Group A (no clinical jaundice), Group B (clinical jaundice with the value of serum bilirubin <10 mg/dl), Group C (clinical jaundice with the value of serum bilirubin >10 mg/dl but not in phototherapy range), and Group D (clinical jaundice with serum bilirubin value requiring initiation of phototherapy). 25-hydroxy Vitamin D and serum bilirubin levels along with parathyroid hormone, calcium, phosphorus, and alkaline phosphatase levels were estimated. Results: The mean 25-hydroxy Vitamin D levels were highest in Group A and lowest in Group D (21.92 ± 20.85 vs. 14.38 ± 8.52, P = 0.020) and vice versa for serum bilirubin levels (15.08 ± 0.93 vs. 4.28 ± 0.97, P < 0.001). There was a nonsignificant negative correlation between serum 25-hydroxy Vitamin D and bilirubin levels (correlation coefficient: −0.113 [−0.257–0.0364], P = 0.138). Conclusion: The present study suggests a lack of association between serum 25-hydroxy Vitamin D and bilirubin levels. However, the results need to be confirmed by further prospective studies to conclude that 25-hydroxy Vitamin D has no role in the pathogenesis of neonatal hyperbilirubinemia.

Keywords: 25-hydroxy Vitamin D, bilirubin, neonatal jaundice


How to cite this article:
Kumar H, Bandyopadhyay T, Kumari P, Maria A, Upadhyay S. Association between serum 25-hydroxy Vitamin D and bilirubin levels in term neonates with hyperbilirubinemia: A cross-sectional, observational study. J Clin Neonatol 2022;11:206-11

How to cite this URL:
Kumar H, Bandyopadhyay T, Kumari P, Maria A, Upadhyay S. Association between serum 25-hydroxy Vitamin D and bilirubin levels in term neonates with hyperbilirubinemia: A cross-sectional, observational study. J Clin Neonatol [serial online] 2022 [cited 2022 Dec 4];11:206-11. Available from: https://www.jcnonweb.com/text.asp?2022/11/4/206/357818




  Introduction Top


Neonatal hyperbilirubinemia is a common problem that affects approximately 60%–80% of neonates.[1] This entity is largely physiological during the 1st week of life, but in approximately 5%–10% of neonates, it may become pathological requiring intervention.[1] Although, the outcome of neonatal hyperbilirubinemia in the majority of cases is benign, but left untreated particularly in cases with severe hyperbilirubinemia (defined as values exceeding 20 mg/dl) can lead to chronic neurological disability (kernicterus).[2]

Approximately three-fourth of bilirubin present in the blood is derived from the hemolysis of senescent RBCs in the reticuloendothelial system.[3],[4] However, this contribution may particularly increase if the RBCs are subjected to oxidative stress as neonatal RBCs are very sensitive to oxidative damage compared to adults.[5] This is largely due to the fact that the major components of the antioxidant defense system in neonatal red blood cells (RBCs) include reduced glutathione, and NADH-dependent methemoglobin reductase, the levels of both of which are reduced in neonatal as compared to the adult RBCs.[5],[6],[7],[8]

25-hydroxy Vitamin D is a pleiotropic hormone with potent antioxidant potential.[9] The extraosseous role of 25-hydroxy Vitamin D has been well elucidated in medical research, where derangement can lead to cardiovascular, pulmonary, obesity, diabetes, and neoplastic diseases such as breast and colorectal carcinoma.[10] This is largely attributed to its antioxidant potential due to the inhibition of zinc- and iron-induced lipid peroxidation.[9]

The final activation in the 25-hydroxy Vitamin D pathway occurs in the kidneys, but the liver is mainly involved in the 25-hydroxy Vitamin D synthesis as well as it also plays a major role in converting indirect bilirubin to direct bilirubin.[11] At present, the mechanism of the relationship between Vitamin D and neonatal hyperbilirubinemia is unclear. The reported biological plausibilities are: (a) the indirect bilirubin present in the blood is mostly derived from the degradation of RBCs. Since, erythropoietin is mainly responsible for red blood cell production. Several studies have shown that Vitamin D can reduce the level of erythropoietin, so Vitamin D deficiency may increase the risk of neonatal jaundice.[12],[13],[14] (b) It has also been shown that neonatal RBCs are susceptible to oxidative damage, and since Vitamin D has an antioxidant effect, hence, it reduces the oxidative damage to the RBCs as well.[13],[15] Hence, based on the above two facts, it can be assumed that the metabolism of bilirubin is associated closely with that of 25-hydroxy Vitamin D metabolism.

Evidence from a limited number of observational studies with smaller sample size has shown a significant negative correlation between serum bilirubin and 25-hydroxy Vitamin D levels.[16] However, the previous observational studies and the recent systematic review and meta-analysis of six clinical trials (four case–control studies and two prospective case–control studies) have only evaluated the association between serum bilirubin and 25-hydroxy Vitamin D levels in those babies requiring vis-a-vis not requiring phototherapy.[16],[17],[18] Hence, this study with a larger sample size than the previous studies was undertaken to investigate any association between 25-hydroxy Vitamin D and bilirubin levels in otherwise healthy full-term, appropriate-for-gestational-age (AGA) exclusively breastfed inborn babies with or without clinical jaundice between day 2 and day 5 of life. Further, in babies with clinical jaundice, we tried to assess the association between 25-hydroxy Vitamin D and bilirubin levels in babies with either pathological or physiological hyperbilirubinemia.


  Methods Top


This cross-sectional study was conducted in the department of neonatology at a tertiary care hospital between November 2014 and March 2017. The study was approved by the institute ethics committee and informed consent was taken from parents before inclusion in the study.

Study population

Inclusion criteria

Inborn, full-term, appropriately grown babies on exclusive breastfeeding between 2nd and 5th days of life with or without clinical jaundice were included.

Exclusion criteria

Babies requiring phototherapy within the first 48 h of life, ABO or Rh incompatibility, cephalohematoma/ significant bruising, glucose-6-phosphate dehydrogenase deficiency, hypothyroidism, receiving frequent formula feeds (>3 formula feeds in a day) or calcium or 25-hydroxy Vitamin D supplementation after birth.

Jaundice associated with significant feeding problem, mothers receiving 25-hydroxy Vitamin D and any other drug which could interferes with the metabolism of 25-hydroxy Vitamin D, calcium and phosphorus in babies were also excluded.

Clinical data

Detailed baseline information of maternal and neonatal variables was recorded in a predesigned pro forma including the age of the mother, religion, geographical region of residence, history of use of 25-hydroxy Vitamin D/calcium supplementation during pregnancy, history of any drug intake, or disease that might affect 25-hydroxy Vitamin D level in the newborn. Among the newborns, sex, birth weight, gestational and postnatal age type of delivery, APGAR score at 1 and 5 min. after birth, and blood groups of both mother and baby were recorded. The weight of the newborn was recorded immediately after delivery on electronic weighing scale with an accuracy within 5 g.

Clinical monitoring of jaundice

In all the included babies, at least twice daily visual screening and transcutaneous bilirubin (TcB) monitoring for jaundice was done. It was done more frequently if warranted. Serial screenings were continued till the TcB values start decreasing, and at the first instance of the fall in TcB value from the previous higher value, blood was sampled for the estimation of serum 25-hydroxy Vitamin D and bilirubin levels. This was to ensure that the samples for 25-hydroxy Vitamin D and serum bilirubin levels were taken at around the peak levels of bilirubin. Based on the severity of jaundice, the study subjects were further subclassified into four groups: Group A (no clinical jaundice), Group B (clinical jaundice with the value of serum bilirubin <10 mg/dl), Group C (clinical jaundice with the value of serum bilirubin >10 mg/dl but not in phototherapy range), and Group D or significant hyperbilirubinemia (clinical jaundice with serum bilirubin value requiring initiation of phototherapy). This classification was done to assess the association between 25-hydroxy Vitamin D and bilirubin levels in babies with pathological hyperbilirubinemia, as well as at two different levels of physiological hyperbilirubinemia (i.e., clinical jaundice with serum bilirubin values <10 mg/dl and clinical jaundice with serum bilirubin >10 mg/dl but not in phototherapy range).

The management of neonatal jaundice was done as per the recommendations by the American Academy of Pediatrics.[19]

Laboratory analysis

1.5–2.0 ml of free-flowing venous blood sample was collected for the estimation of serum bilirubin, 25-hydroxy Vitamin D, total alkaline phosphatase (ALP), parathyroid hormone (PTH), calcium, and phosphorous levels from all the babies included in the study. 25-hydroxy Vitamin D and PTH were analyzed within 24 h using chemiluminescence on the vitros Eci immunoassay analyzer. Calcium, phosphorus, and ALP were analyzed within 24 h of collection by chemiluminescence on the vitros Eci immunoassay analyzer.

Outcome variables

  • Primary: To document an association between serum bilirubin and 25-hydroxy Vitamin D levels in otherwise healthy full-term, AGA babies on exclusive breastfeeding with postnatal age between the 2nd and 5th days of life with or without clinical jaundice
  • Secondary: To document biochemical levels of PTH, calcium, phosphorus, and total ALP and their association with serum 25-hydroxy Vitamin D levels among the enrolled neonates.


Statistical analysis

Statistical analysis was done using the Statistical analysis was done using the SPSS statistical package (SPSS Inc. Released 2012. SPSS for Windows, Version 21.0. Chicago, SPSS Inc.). Data were expressed as mean ± standard deviation for continuous variables and as percentages for categorical variables. Quantitative variables were compared using ANOVA or Kruskal–Wallis test as applicable between the groups. Qualitative variables were compared using Chi-square or Fisher's exact test as applicable. Spearman's correlation coefficient was used to assess the association between various quantitative variables. P < 0.05 was considered statistically significant.


  Results Top


Maternal characteristics

The flow of participants into the study is presented in [Figure 1]. A total of 174 infants were enrolled in the study. They were further subclassified into four groups (Group A: n = 31, Group B: n = 38, Group C: n = 69, and Group D: n = 36).
Figure 1: Flow diagram of study participants. AGA: Appropriate for gestational age; G6PD: Glucose-6-phosphate dehydrogenase

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There was no significant difference in the baseline characteristics of study participants as depicted in [Table 1].
Table 1: Baseline characteristics of the study participants

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The data in [Table 2] show the comparison of serum 25-hydroxy Vitamin D and bilirubin levels across the study groups as well as based on risk stratification for predischarge bilirubin. The mean 25-hydroxy Vitamin D levels were highest in Group A and lowest in Group D (21.92 ± 20.85 vs. 14.38 ± 8.52, P = 0.020) and vice versa for serum bilirubin levels (15.08 ± 0.93 vs. 4.28 ± 0.97, P < 0.001). Further, when stratified based on risk categories for predischarge bilirubin, it was found that the mean 25-hydroxy Vitamin D levels were highest in the high intermediate group and lowest for the high-risk group (29.22 ± 8.91 vs. 14.38 ± 8.52, P = 0.008).
Table 2: Comparison of serum Vitamin D and bilirubin levels across the study groups as well as based on risk stratification for predischarge bilirubin

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[Figure 2] depicts the correlation between serum bilirubin and serum 25-hydroxy Vitamin D levels. The 25-hydroxy Vitamin D level showed nonsignificant negative correlation with serum bilirubin level (correlation coefficient: −0.113 [−0.257–0.0364], P = 0.138).
Figure 2: Correlation between serum bilirubin and serum 25-hydroxy Vitamin D levels

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The data in [Table 3] showed the comparison of serum PTH, ALP, calcium, and phosphorus levels across the study groups. The mean PTH and total ALP values are significantly higher in Group D as compared to Group A.
Table 3: Comparison of parathyroid hormone, alkaline phosphatase, calcium, and phosphorus values across the study groups

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On further analysis, it was found that serum PTH had a significant negative correlation with 25-hydroxy Vitamin D levels (correlation coefficient: −0.0269, P < 0.001) whereas serum calcium had a significant positive correlation with 25-hydroxy Vitamin D levels (correlation coefficient: 0.324, P < 0.001).


  Discussion Top


The present study has shown that although the mean 25-hydroxy Vitamin D levels were significantly lower in babies with significant hyperbilirubinemia, it was not significantly related to serum bilirubin levels. In a prospective study by Mutlu et al. evaluating 25-hydroxy Vitamin D levels in infants with pathologic and physiological hyperbilirubinemia, it was found that significant differences exist in the 25-hydroxy Vitamin D levels between the case and control groups. A significantly negative correlation was also observed between 25-hydroxy Vitamin D, serum bilirubin, and the PTH levels in the enrolled infants.[16] The lack of correlation between serum bilirubin and 25-hydroxy Vitamin D levels in the present study as compared to the just described study can be explained by the two facts: first, we have tried to assess the relationship between these two variables across the whole spectrum of hyperbilirubinemia rather than just two extremes of hyperbilirubinemia (i.e., with or without pathological hyperbilirubinemia), and second, the mean serum bilirubin values in the present study in babies requiring phototherapy were much lower as compared to the study by Mutlu et al. representing prompt initiation of phototherapy in babies at our center before any manifestation of bilirubin-induced brain injury.[16] The results of the present study are in agreement with the study done by Mehrpisheh et al. and Aletayeb et al. who have also found no significant correlation between serum 25-hydroxy Vitamin D and bilirubin values as the mean bilirubin values in those two previous studies are similar to our study.[11],[20]

In 25-hydroxy Vitamin D deficiency, serum calcium levels may be low or normal, phosphorus levels normal or low, ALP normal or high, and PTH level normal or high.[21] In the present study, there was a significant negative correlation between PTH and 25-hydroxy Vitamin D levels despite the lack of differences in calcium, phosphorus, and total ALP values in neonates as well as maternal 25-hydroxy Vitamin D levels across the groups; this can be attributed to the short duration of 25-hydroxy Vitamin D deficiency among the enrolled neonates.[22]

The present study has some limitations as well. First, the sample size of the present study is small, and hence, the findings of the present study need to be confirmed by future well-conducted study with adequate sample size. Second, although the Vitamin D levels were highest in the high-intermediate group, the number of babies enrolled in this subgroup was small (n = 6); hence, the mean value of Vitamin D levels estimated in this subgroup may not indicate the true estimate in this situation. Third, we could not delineate the mechanism causing Vitamin D deficiency in the study group. Hence, further study is needed to explain this.


  Conclusion Top


The result of the present study showed that mean 25-hydroxy Vitamin D levels were significantly lower in babies with significant hyperbilirubinemia, but it was not significantly related to serum bilirubin levels. Even though a wider spectrum of hyperbilirubinemia was examined in this study compared to the previous studies, future well-conducted research is still needed to generalize the results of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kim HA, Perrelli A, Ragni A, Retta F, De Silva TM, Sobey CG, et al. Vitamin D deficiency and the risk of cerebrovascular disease. Antioxidants (Basel) 2020;9:E327.  Back to cited text no. 9
    
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Mehrpisheh S, Memarian A, Mahyar A, Valiahdi NS. Correlation between serum 25-hydroxy vitamin D level and neonatal indirect hyperbilirubinemia. BMC Pediatr 2018;18:178.  Back to cited text no. 11
    
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Pincikova T, Paquin-Proulx D, Sandberg JK, Flodström-Tullberg M, Hjelte L. Vitamin D treatment modulates immune activation in cystic fibrosis. Clin Exp Immunol 2017;189:359-71.  Back to cited text no. 14
    
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Aletayeb SM, Dehdashtiyan M, Aminzadeh M, Malekyan A, Jafrasteh S. Comparison between maternal and neonatal serum 25-hydroxy vitamin D levels in term jaundiced and nonjaundiced cases. J Chin Med Assoc 2016;79:614-7.  Back to cited text no. 20
    
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Chanchlani R, Nemer P, Sinha R, Nemer L, Krishnappa V, Sochett E, et al. An overview of rickets in children. Kidney Int Rep 2020;5:980-90.  Back to cited text no. 21
    
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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