Prebiotics for the prevention of hyperbilirubinaemia in neonates

Review question: Do prebiotics prevent hyperbilirubinaemia, an elevated level of bilirubin that leads to jaundice, in newborn infants?

Background: Jaundice occurs in approximately two-thirds of all newborns during the first days of life. Phototherapy is commonly used for management of neonatal jaundice. Phototherapy does not seem to cause serious side effects, but recently some clinical trials have raised concerns based on animal or cell culture studies regarding its potential to damage DNA. Therefore, other types of treatment for neonatal jaundice are being considered. Some evidence suggests that enteral feeding supplementation with prebiotics reduces jaundice among neonates.

Study characteristics: We included three small studies (with a total of 154 infants) that compared the effects of feeding supplementation with prebiotics on neonatal jaundice to a placebo (such as distilled water). The evidence is up to date as of 14 June 2018.

Key results: There is inadequate evidence to assess the effectiveness of prebiotics on neonatal jaundice. According to the available data, the incidence of neonatal hyperbilirubinaemia (low-quality evidence) and treatment with phototherapy (low-quality evidence) were decreased by feeding supplementation with prebiotics, but only one small study reported on these outcomes.

The meta-analyses of these small studies demonstrated a significant reduction in the length of hospital stay (low-quality evidence) and a significant increase in stool frequency (high-quality evidence) in infants with prebiotic supplementation versus placebo. Furthermore, meta-analyses showed no significant difference in maximum plasma bilirubin levels (low-quality evidence), duration of phototherapy (low-quality evidence) and neonatal mortality (low-quality evidence) between groups. The review found only three randomised clinical trials that compared prebiotic supplementation with a placebo. More research is needed.

Authors' conclusions: 

Current studies are unable to provide reliable evidence about the effectiveness of prebiotics on hyperbilirubinaemia. Additional large, well-designed RCTs should be undertaken in neonates that compare effects of enteral supplementation with prebiotics on neonatal hyperbilirubinaemia with supplementation of milk with any other placebo (particularly distilled water) or no supplementation.

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Background: 

Hyperbilirubinaemia occurs in approximately two-thirds of all newborns during the first days of life and is frequently treated with phototherapy. Although generally seen as safe, there is rising concern regarding phototherapy and its potentially damaging effects on DNA and increased side effects particularly for preterm infants. Other methods, such as enteral feeding supplementation with prebiotics, may have an effective use in the management of hyperbilirubinaemia in neonates.

Objectives: 

To determine whether administration of prebiotics reduces the incidence of hyperbilirubinaemia among term and preterm infants compared with enteral supplementation of milk with distilled water/placebo or no supplementation.

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 14 June 2018), Embase (1980 to 14 June 2018), and CINAHL (1982 to 14 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials.

Selection criteria: 

We considered all RCTs that studied neonates comparing enteral feeding supplementation with prebiotics versus distilled water/placebo or no supplementation.

Data collection and analysis: 

Two reviewers screened papers and extracted data from selected papers. We used a fixed-effect method in combining the effects of studies that were sufficiently similar. We then used the GRADE approach to assess the quality of the evidence.

Main results: 

Three small studies evaluating 154 infants were included in this review. One study reported a significant reduction in the risk of hyperbilirubinaemia and rate of treatment with phototherapy associated with enteral supplementation with prebiotics (risk ratio (RR) 0.75, 95% confidence interval (95% CI) 0.58 to 0.97; one study, 50 infants; low-quality evidence). Meta-analyses of two studies showed no significant difference in maximum plasma unconjugated bilirubin levels in infants with prebiotic supplementation (mean difference (MD) 0.14 mg/dL, 95% CI -0.91 to 1.20, I² = 81%, P = 0.79; two studies, 78 infants; low-quality evidence). There was no evidence of a significant difference in duration of phototherapy between the prebiotic and control groups, which was only reported by one study (MD 0.10 days, 95% CI -2.00 to 2.20; one study, 50 infants; low-quality evidence). The meta-analyses of two studies demonstrated a significant reduction in the length of hospital stay (MD -10.57 days, 95% CI -17.81 to -3.33; 2 studies, 78 infants; I² = 0%, P = 0.004; low-quality evidence). Meta-analysis of the three studies showed a significant increase in stool frequency in the prebiotic groups (MD 1.18, 95% CI 0.90 to 1.46, I² = 90%; 3 studies, 154 infants; high-quality evidence). No significant difference in mortality during hospital stay after enteral supplementation with prebiotics was reported (typical RR 0.94, 95% CI 0.14 to 6.19; I² = 6%, P = 0.95; 2 studies; 78 infants; low-quality evidence). There were no reports of the need for exchange transfusion and incidence of acute bilirubin encephalopathy, chronic bilirubin encephalopathy, and major neurodevelopmental disability in the included studies. None of the included studies reported any side effects.

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