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ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 178-181

The role of probiotics in preventing neonatal hyperbilirubinemia


Department of Pediatrics, Hospital Elizabeth Seton; Hospital Elizabeth Seton (Caja Petrolera de Salud), Cochabamba, Bolivia

Date of Submission13-Dec-2020
Date of Decision14-Apr-2021
Date of Acceptance20-Jun-2021
Date of Web Publication28-Jul-2021

Correspondence Address:
Nur Walker-Pizarro
Hospital Elizabeth Seton, Cochabamba
Bolivia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_202_20

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  Abstract 


Introduction: Neonatal jaundice is a common condition and an important cause of hospital admissions. This report reviews the efficacy of Lactobacillus reuteri and Saccharomyces boulardii in preventing high bilirubin levels and associated phototherapy admissions. Materials and Methods: This was a prospective, randomized study involving three groups. Group 1 was designated as a control and received no intervention. During the first 4 days of life, Group 2 received a concentrated dose of L. reuteri whereas Group 3 received a concentrated dose of S. boulardii. Bilirubinemia levels were assessed on day 4. Results: The sample size consisted of 98 subjects, including 36 in control Group 1, 31 in Group 2, and 31 in Group 3. The mean bilirubinemia at day 4 was 14.7 mg/dl in control Group 1, 13.8 mg/dl in Group 2, and 14.9 mg/dl in Group 3 (P > 0.05). Group 2 accounted for the most subjects (45%) in the low-to-intermediate-risk zone, compared to 30% in control Group 1 and 29% in Group 3 (P < 0.05). Eight subjects required light therapy, including two in Group 2 and three in each of control Group 1 and Group 3 (P > 0.05). Conclusions: The use of probiotics to prevent neonatal hyperbilirubinemia or bring down phototherapy admissions does not appear to be cost-effective.

Keywords: Hyperbilirubinemia, jaundice, probiotics


How to cite this article:
Teran CG, Grandy G, Walker-Pizarro N. The role of probiotics in preventing neonatal hyperbilirubinemia. J Clin Neonatol 2021;10:178-81

How to cite this URL:
Teran CG, Grandy G, Walker-Pizarro N. The role of probiotics in preventing neonatal hyperbilirubinemia. J Clin Neonatol [serial online] 2021 [cited 2022 Aug 14];10:178-81. Available from: https://www.jcnonweb.com/text.asp?2021/10/3/178/322530




  Introduction Top


Neonatal jaundice is a common cause of hospital admissions. Management often requires lengthy hospital stays that translate into high costs to the health system, insurance providers, and families. Hyperbilirubinemia, which commonly presents during the neonatal period, usually peaks at the 3rd or 4th day of life and then drops during the 2nd week until it clinically clears.[1] The etiology is often physiological, making it harder to prevent. Neonatal hyperbilirubinemia is caused by a range of factors, notably reduced liver function, a larger number of erythrocytes with a shorter half-life in peripheral blood, and an accelerated enterohepatic circuit.[2] The latter factor could be amenable to interventions that could help prevent or decrease the incidence of clinically significant hyperbilirubinemia.

Conjugated bilirubin reaching the intestinal tract can be deconjugated by enzymes such as beta-glucuronidase. It then enters enterohepatic circulation, thereby accessing peripheral circulation.[3] Adequate bacterial flora plays an important role in the enterohepatic circuit by breaking bilirubin down into metabolites that are easily excreted in feces and urine as well as by blocking beta-glucuronidase. Newborns lack intestinal flora until about day 3, when the first Lactobacillus and Bifidobacterium colonies begin to appear.[4] By the 2nd week of life, the number of colonies has grown to resemble those of adults, although studies have shown delayed colonization in babies born by C-section.[4]

Research into probiotic usage in some medical fields has made significant progress over the past two decades. While most studies have focused on preventing and treating acute infectious diarrhea and antibiotic-associated diarrhea, probiotics have a broader spectrum and have been successfully used to treat allergic diseases, Helicobacter pylori infections, and in cancer prevention.[5],[6] Probiotic use in newborns has been tested and is being used to treat necrotizing enterocolitis and as a supplement in formulas designed to regularize bowel habits and reduce problematic symptoms such as colic, flatulence, diarrhea, and constipation.[7]

The probiotic safety profile is good, with no significant adverse effects observed across age groups, including newborns. As such, it is a matter of interest to see whether probiotic supplementation could play a role in the 1st day of life by potentially decreasing bilirubin levels in newborns. The benefits could be vast, ranging from lower costs to fewer inhospital light therapy admissions. Some clinicians have even suggested a hypothetical impact on reduced bilirubin encephalopathy risk.


  Materials and Methods Top


Research design and objectives

This was a prospective, longitudinal, randomized, descriptive, analytical study intended to determine the efficacy of Lactobacillus reuteri and Saccharomyces boulardii in preventing high levels of neonatal hyperbilirubinemia and associated light therapy admissions. The secondary objectives were to determine bilirubin averages and hyperbilirubinemia risk zones in each group.

Sample size

The sample consisted of all infants born at the Elizabeth Seton Hospital from March 1 to November 1, 2020.

Inclusion criteria

All subjects were healthy term babies (37–41 weeks) born vaginally or by cesarean section. Newborns exhibiting hemoglobinopathies, ABO or Rh factor incompatibility, sepsis, perinatal asphyxia, acidosis, hypoxemia, or hemolytic disease were not included. Newborns fed formula during the first 5 days of life or who did not complete the course of treatment were also omitted.

Procedure

The study was reviewed and approved by the Elizabeth Seton Hospital Research and Ethics Committee, and subjects were recruited with prior informed consent from parents and guardians. Each neonate included in the study was assigned to a group. Control Group 1 received no intervention. Group 2 received a L. reuteri concentrate equivalent to 100 Mn CFU administered as five drops of BioGaia once a day through the first 4 days of life. Group 3 received a S. boulardii concentrate equivalent to one packet of Florestor 200 mg in powder form once a day, also through the first 4 days of life. Probiotic administration was supervised by nursing staff on the first 2 days and by outside consultants on days 3 and 4. On day 4, a peripheral venous blood sample was obtained to assess direct, indirect, and total bilirubin.

Risk zones were evaluated per the American Academy of Pediatrics (AAP) nomogram for hyperbilirubinemia providing the following risk classifications for total bilirubin at day 4: low-risk zone (LRZ): <12.5 mg/dl, low-to-intermediate-risk zone (LIRZ): 12.6–15.2 mg/dl, high-to-intermediate-risk zone: 15.3–17.3 mg/dl, and high-risk zone (HRZ): >17.4 mg/dl. Light therapy is used to treat jaundice in all neonatal subjects exceeding the AAP-suggested levels. Per the hyperbilirubinemia nomogram, light therapy must be considered when total bilirubin exceeds 19.8 mg/dl at 96 h of life.

Statistical analysis

Data collected were entered into JMP v. 6.0 SAS statistical software (SAS Institute, North Carolina, USA). The Shapiro–Wilk w-test was used to obtain median, mean, standard deviation (SD), and P values, and groups were compared using the Kruskal–Wallis test. The calculated sample size was 32 subjects per group in order to achieve 95% confidence and a power level of 90%.


  Results Top


The sample size was 98 subjects, including 36 in control Group 1, 31 in Group 2 (L. reuteri), and 31 in Group 3 (S. boulardii). Four subjects in Groups 1 and 2 who did not complete the course of treatment were omitted. Average bilirubin levels on day 4 ranged from 14.7 mg/dl ± 3.3 SD in control Group 1 to 13.8 mg/dl ± 3.2 SD in Group 2 and 14.9 mg/dl ± 3.0 SD in Group 3. Differences across groups were not statistically significant (P > 0.05) [Figure 1]. Predominant risk zones [Table 1]: Group 2 accounted for the most subjects (45%) in the low to intermediate risk zone, compared to Group 1 (30%) and Group 3 (29%) [Table 1]. No statistically significant difference was found in the other hyperbilirubinemia risk groups. Light therapy was required by eight subjects, including three (8%) in control Group 1, two (6%) in Group 2, and three (10%) in Group 3. No adverse effects were observed in any group.
Figure 1: Mean Bilirubin levels among groups

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Table 1: Percentage of newborns according to the hyperbilirubinemia risk zones and study groups (percentage)

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  Discussion Top


An Internet search turns up little research on the role of probiotics in treating hyperbilirubinemia. Previous studies in various neonatal population types have yielded dissimilar results. In a 2013 study, Demirel et al. showed the value of S. boulardii in neonatal jaundice management in extremely underweight preterm infants.[8] In 2015, Serce et al. reviewed the use of S. boulardii in newborns receiving light therapy, finding no evidence of benefits to be derived from probiotics as an adjunctive treatment measure.[9] In 2016, Suganthi and Das showed that S. boulardii helped decrease bilirubin levels on the 3rd day of life as compared to placebo.[10] This is the second study of its type to show the value of probiotics in preventing hyperbilirubinemia in full-term, healthy newborns. While it perspicuously proves the significance of X, Y, and Z, further research will be required to validate its findings on a larger scale.

In our study, average bilirubin levels were slightly lower in participants who received L. reuteri (13.7 mg/dl) as compared to control Group 1. Conversely, in the group that received S. boulardii, the bilirubin average was higher (14.9 mg/dl) as compared to control Group 1. As expected, only 6% of participants in Group 2 required light therapy, compared to 8% in control Group 1 and 10% in Group 3. Risk zone assessment confirmed this observation, since the group receiving L. reuteri had the lowest share of infants in the HRZ as well as the largest number in the LIRZ, findings that proved to be statistically significant.

Given these differences, a cost–benefit analysis of administering probiotics to all newborns shows this intervention to be nonviable from either financial or clinical standpoints. A 4-day course for each newborn costs on average some USD$15.00 for L. reuteri and USD$8.00 for S. boulardii, whereas a 2-day course of inhospital light therapy averages USD$30.00 to USD$130.00, depending on facility. For every 100 patients, administering probiotic treatment at a cost of some USD$1500 in order to avoid 2% fewer hospital stays is not cost-effective as compared to control Group 1 (USD$65.00–USD$230.00).

This is not a definitive study and further research on a larger scale is required to obtain more definitive conclusions that can help in the design of new guidelines for the management and prevention of neonatal physiological jaundice. Despite the limited sample size, the importance of this study lies in being among the few of its type conducted anywhere. As such, these results may help define the real benefits of using probiotics to treat neonatal jaundice and prevent associated phototherapy admissions.


  Conclusions Top


Probiotics such as L. reuteri provide minimal additional benefits in the prevention of light therapy admissions in full-term, healthy newborns. This intervention does not appear to provide additional benefits or be economically viable. As compared to control Group 1, S. boulardii proved no more effective. These observations were not statistically significant at the time of review, perhaps due to the small sample size. As such, a large-scale study is advised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Avery GB. Jaundice. In: Jeffrey M, Maisels MB, editors. Neonatology: Pathophysiology and Management of the Newborn. 6th ed. J. B. Barrington: Lippincott; 2005. p. 768-836.  Back to cited text no. 1
    
2.
Fanaroff AA, Martin R. Neonatal jaundice and liver disease. In: Kaplan M, Wong RJ, Sibley E, Stevenson DK, editors. Neonatal-Perinatal Medicine. 9th ed. Mosby: Elsevier; 2011. p. 1443-90.  Back to cited text no. 2
    
3.
Erdem G, Oztürk R, Ciliv G, Ozmert E, Tuncer M. Is beta-glucuronidase a contributory factor in early indirect hyperbilirubinaemia? Acta Paediatr 1997;86:120.  Back to cited text no. 3
    
4.
Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the neonatal period in breast-fed and bottle-fed infants. Pediatrics 1983;72:317-21.  Back to cited text no. 4
    
5.
Sanders ME. Probiotics in 2015: Their scope and use. J Clin Gastroenterol 2015;49 Suppl 1:S2-6.  Back to cited text no. 5
    
6.
Butel MJ. Probiotics, gut microbiota and health. Med Mal Infect 2014;44:1-8.  Back to cited text no. 6
    
7.
Waddell L. Management of infantile colic: An update. J Fam Health Care 2013;23:17-22.  Back to cited text no. 7
    
8.
Demirel G, Celik IH, Erdeve O, Dilmen U. Impact of probiotics on the course of indirect hyperbilirubinemia and phototherapy duration in very low birth weight infants. J Matern Fetal Neonatal Med 2013;26:215-8.  Back to cited text no. 8
    
9.
Serce O, Gursoy T, Ovali F, Karatekin G. Effects of Saccharomyces boulardii on neonatal hyperbilirubinemia: A randomized controlled trial. Am J Perinatol 2015;30:137-42.  Back to cited text no. 9
    
10.
Suganthi V, Das AG. Role of Saccharomyces boulardii in reduction of neonatal hyperbilirubinemia. J Clin Diagn Res 2016;10:C12-5.  Back to cited text no. 10
    


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