新生児高ビリルビン血症予防のためのプレバイオティクス
Abstract
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 methods
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.
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.
PICOs
一般語訳
新生児高ビリルビン血症予防のためのプレバイオティクス
レビューの論点プレバイオティクスは、ビリルビン値の上昇により黄疸を発症する新生児の高ビリルビン血症を予防するか？
背景：黄疸は、生後数日の間に新生児のおよそ3分の2に起こる。一般的には新生児黄疸の管理には、光線療法が用いられている。光線療法は重篤な副作用を引き起こさないとされるが、最近の臨床試験では、動物または細胞培養を用いた研究に基づいて、DNAへのダメージの可能性が懸念が提起されてきている。従って、新生児黄疸に対し他の治療が考慮されている。プレバイオティクスの経腸栄養法が、新生児の黄疸を減少することを示唆するエビデンスもある。
研究の特性プレバイオティクスの経腸栄養法とプラセボ（蒸留水など）とを比較した3件の小規模研究（乳児154例）を対象とした。本エビデンスは2018年6月14日時点のものである。
主要な結果新生児のプレバイオティクスの効果を評価するには、科学的根拠（エビデンス）は不十分であった。利用可能なデータによると、新生児高ビリルビン血症の発症率（エビデンスの質は低い）と光線療法の必要性（エビデンスの質は低い）は、プレバイオティクスの経腸栄養法により減少したが、このアウトカムを報告したのは小規模の研究1件のみであった。
これらの小規模研究のメタアナリシスでは、プラセボと比較してプレバイオティクスの経腸栄養療法を受けた乳児において、入院期間の有意な短縮（エビデンスの質は低い）、排便回数の有意な増加（エビデンスの質は高い）が示された。さらにメタアナリシスでは、血漿ビリルビン値の最高値（エビデンスの質は低い）、光線療法の治療期間（エビデンスの質は低い）、新生児死亡（エビデンスの質は低い）に関して、群間の有意差は示されなかった。本レビューでは、プレバイオティクスとプラセボを比較したランダム化臨床試験が3件しか同定できなかった。今後もさらなる研究が必要である。
Authors' conclusions
Summary of findings
| Feeding supplementation with prebiotics compared to no prebiotics for the prevention of hyperbilirubinaemia in neonates | ||||||
| Patient or population: Neonates, including term neonates (gestational age ≥ 37 weeks), late preterm neonates (35 to 37 weeks' gestation) and preterm neonates (< 35 weeks' gestation) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no prebiotics | Risk with Feeding supplementation with prebiotics | |||||
| Incidence of hyperbilirubinaemia | Study population | RR 0.75 | 50 | ⊕⊕⊝⊝ | ||
| 960 per 1,000 | 720 per 1,000 | |||||
| Maximum plasma unconjugated bilirubin levels; | The mean maximum plasma unconjugated bilirubin levels; ranged from 7.6 to 8.1 mg/dL | MD 0.14 mg/dL higher | ‐ | 78 | ⊕⊕⊝⊝ | |
| Treatment with phototherapy | Study population | RR 0.75 | 50 | ⊕⊕⊝⊝ | ||
| 960 per 1,000 | 720 per 1,000 | |||||
| Stool frequency | The mean stool frequency; ranged from 1 to 3 | MD 1.18 higher | ‐ | 154 | ⊕⊕⊕⊕ | |
| Duration of phototherapy (days) | The mean duration of phototherapy (days); ranged from 2 to 3 days | MD 0.1 days higher | ‐ | 28 | ⊕⊕⊝⊝ | |
| Length of hospital stay (days) | The mean length of hospital stay (days); ranged from 29 to 72 days | MD 10.57 days lower | ‐ | 78 | ⊕⊕⊝⊝ | |
| Neonatal mortality | Study population | RR 0.94 | 78 | ⊕⊕⊝⊝ | ||
| 26 per 1,000 | 25 per 1,000 | |||||
| Acute bilirubin encephalopathy (encephalopathy) | Study population | not estimable | (0 RCTs) | ‐ | None of the included studies showed any acute bilirubin encephalopathy. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Exchange transfusion (exchange) | Study population | not estimable | (0 RCTs) | ‐ | There were no reports of the need for exchange transfusion in included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Chronic bilirubin encephalopathy or kernicterus (kernicterus) | Study population | not estimable | (0 RCTs) | ‐ | There were no reports of the incidence of chronic bilirubin encephalopathy in included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Major neurodevelopmental disability | Study population | not estimable | (0 RCTs) | ‐ | Major neurodevelopmental disability was not reported in any of the included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Side effects | Study population | not estimable | (0 RCTs) | ‐ | No side effects were reported in any of the included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level due to high risk of performance bias b Downgraded one level due to uncertainty about precision (one study) c Downgraded one level due to uncertainty about precision (small study) d Downgraded one level due to unclear risk of attrition bias (incomplete outcome data) | ||||||
Background
Description of the condition
Hyperbilirubinaemia occurs in approximately two‐thirds of all newborns during the first days of life (Lauer 2011). Mild elevations in bilirubin levels usually do not have serious side effects apart from recognisable jaundice (Maisels 2008).
The pathogenesis of jaundice in preterm infants is similar to term infants, but because of liver and gastrointestinal tract prematurity, hyperbilirubinaemia can be more dangerous during the late preterm period (Maisels 2012). Furthermore, because of complications related to prematurity, enteral feeding in late preterm infants is sometimes delayed. This, in turn, may limit intestinal flow and bacterial colonisation, resulting in more effective enterohepatic circulation, hence high serum bilirubin (Gartner 2001). The major complication of hyperbilirubinaemia ‐ kernicterus, or bilirubin‐induced encephalopathy ‐ can occur at high bilirubin levels. Severe haemolysis and certain diseases (e.g. isoimmune haemolytic disease, glucose‐6‐phosphate deficiency (G6PD), asphyxia, sepsis, acidosis, hypoalbuminaemia) are risk factors for kernicterus (Maisels 2009). This devastating neurological dysfunction can cause permanent neurodevelopmental handicaps (Xiong 2011). Although, nowadays, kernicterus is rarely seen to result from early aggressive phototherapy, it still occurs (Kaplan 2011). Neonatal jaundice can cause parental concern and can increase hospital costs due to hospital re‐admissions (Burke 2009). Therefore, proper and timely treatment of hyperbilirubinaemia is of critical importance.
Current recommendations for management of neonatal hyperbilirubinaemia focuses on determining age‐specific bilirubin levels before initiating phototherapy (Maisels 2012). 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 (Cetinkursun 2005; Ramy 2016; Roll 2005; Rosenstein 1984; Tatli 2008; Yahia 2014). Investigators have observed that hyperbilirubinaemia did not influence DNA damage and apoptosis, whereas phototherapy (both conventional and intensive types) was associated with DNA damage in full‐term infants (Ramy 2016; Tatli 2008; Yahia 2014) and induced apoptosis in peripheral blood lymphocytes (Yahia 2014). Therefore, other types of treatment for hyperbilirubinaemia are needed rather than phototherapy alone.
The increased enterohepatic circulation of bilirubin has a known role in the incidence of neonatal jaundice (Sato 2013), and interventions that reduce the enterohepatic circulation of bilirubin can be beneficial, as they reduce the production of bilirubin.
Prebiotics are observed to have favourable effects on the enterohepatic cycle, including better gastrointestinal motility and improved frequency and viscosity of stool (Indrio 2009; Westerbeek 2011). Thus, it has been hypothesised that with enteral feeding supplementation of prebiotics during enterohepatic circulation (when bilirubin circulates within the intestine), less conjugated bilirubin is converted to unconjugated bilirubin, leading to improvement in hyperbilirubinaemia status and reduction of jaundice among neonates. It is worth noting that the exact mechanism of action of prebiotics on hyperbilirubinaemia and how long it takes for prebiotics to delay onset of neonatal jaundice remain unclear.
Description of the intervention
Prebiotics are “non‐digestible food components that affect the host beneficially by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, thereby improving host health” (Gibson 1995). Oligosaccharides are the most common archetype of prebiotics. Lactulose and inulin are other types of prebiotics.
Our selected intervention consists of "enteral supplementation with any type of prebiotics". Prebiotics can take the form of galacto‐oligosaccharides (GOSs), fructo‐oligosaccharides (FOSs), acidic oligosaccharides (AOSs), lactulose, or inulin. The most frequently used prebiotics are oligosaccharides (Srinivasjois 2013), which are found in human breast milk (Armanian 2014; Srinivasjois 2013). They usually consist of a mixture of short‐chain carbohydrates (with a degree of polymerisation between 2 and 60) with long‐chain carbohydrates (9:1) that are non‐digestible by neonatal digestive systems (Cummings 2002). Oligosaccharides usually are given at a dosage of 0.5 to 1.5 g/kg/d initiated at day two to 10 after birth, added to neonatal enteral milk. Distilled water rarely has an effect on neonatal jaundice. Therefore, to eliminate the confounding effects of different types of placebo, use of distilled water is the best form of placebo.
As there are a limited number of papers available for usage of distilled water, we compared enteral supplementation of prebiotics added to milk versus distilled water, other forms of placebo, or no supplementation. Trials included in this review must have continued for at least seven days. For management of neonatal jaundice, all infants in both groups were treated according to the protocol for phototherapy described in guidelines of the American Academy of Pediatrics 2004.
How the intervention might work
The literature suggests positive effects of prebiotics on neonatal outcomes, such as gastrointestinal (GI) motility, frequency and viscosity of stool, enteral tolerance, and necrotizing enterocolitis (NEC) (Armanian 2014; Indrio 2009; Modi 2010; Srinivasjois 2013; Westerbeek 2011). Prebiotics mainly stimulate rapid growth of beneficial bacteria within the colon (Armanian 2016; Cummings 2002; Oozeer 2013; Sherman 2009). Oligosaccharides represent one type of prebiotic in the gut that is decomposed by microbial flora into short‐chain fatty acids, hydrogen, and carbon dioxide. Short‐chain fatty acids have a mild laxative effect because they reduce the pH level of the stool, making it more acidic (Rao 2009) and thus changing stool consistency and frequency of defecation. This could be beneficial in preventing production of bilirubin by enterohepatic circulation. As prebiotics enter the GI system, the enterohepatic circulation of bilirubin rotates slowly with better and faster GI evacuation. When bilirubin is evacuated faster from the GI system, the opportunity for conversion of conjugated bilirubin to unconjugated bilirubin is lessened, hence less jaundice occurs. Therefore, supplementation with prebiotics can reduce the production of unconjugated bilirubin. On the other hand, distilled water rarely has an effect on neonatal jaundice and can act as a preferred placebo.
Why it is important to do this review
Concerns about the use of phototherapy surround its potentially damaging effects on DNA (Ramy 2016; Tatli 2008; Yahia 2014) and increased mortality among term and particularly preterm infants (Tyson 2012) with intensive use. Investigators have evaluated other methods, such as administration of prebiotics, for management of hyperbilirubinaemia in neonates. However, to the best of our knowledge, no review has evaluated the impact of prebiotics on neonatal hyperbilirubinaemia.
To date, only three studies have examined effects of prebiotics on neonatal hyperbilirubinaemia (Armanian 2015; Bisceglia 2009; Riskin 2010). In two of these studies, lower bilirubin levels detected by transcutaneous bilirubinometry were associated with enteral feeding supplementation by oligosaccharides (Armanian 2015; Bisceglia 2009). On the other hand, it has been found that colonies of lactobacilli and bifidobacteria within the gut cannot convert bilirubin into excretory products (Bisceglia 2009), and some researchers have observed that Clostridium (a pathogenic microorganism that can be reduced by prebiotics) can convert bilirubin to non‐toxic excretory derivatives (Konickova 2012; Petit 1999; Vitek 2006). Hence, enteral feeding supplementation with prebiotics may lead to an unexpected increase in conversion of bilirubin into recyclable products. Therefore, researchers are interested in discerning the effects of prebiotics on neonatal hyperbilirubinaemia.
In summary, the literature is inconsistent in terms of effects of feeding supplementation with prebiotics on neonatal hyperbilirubinaemia. This review can shed light on clinical trials investigating effects of prebiotics on neonatal hyperbilirubinaemia.
Objectives
To determine whether administration of prebiotics reduces the incidence of hyperbilirubinaemia and bilirubin encephalopathy among term and preterm infants compared with enteral supplementation of milk with distilled water/placebo or no supplementation.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing enteral feeding supplementation with prebiotics versus distilled water/placebo or no supplementation were included.
Feedings could be entirely enteral or infants could be receiving parenteral nutrition.
Types of participants
We included all studies that enrolled neonates and categorised neonates into three groups: term neonates (gestational age ≥ 37 weeks); late preterm neonates (35 to < 37 weeks' gestation); and preterm neonates (< 35 weeks' gestation). We excluded all studies that enrolled infants with the following conditions: asphyxia, major congenital anomalies, Rhesus isoimmunisation, G6PD deficiency, inborn errors, proven sepsis or other infection, cephalohematoma, and subgaleal haemorrhage. We also excluded infants with enteral feeding supplementation with specific formulas, probiotics, or zinc.
Types of interventions
Enteral feeding supplementation given with prebiotics during the first ten days of life is the intervention under study. Prebiotics can be provided in the form of galacto‐oligosaccharides (GOSs), fructo‐oligosaccharides (FOSs), acidic oligosaccharides (AOSs), lactulose, or inulin. We included studies that initiated supplementation with prebiotics between days two and 10 of life at a dosage of 0.5 to 1.5 g/kg/d, with concentrations of 1% and 0.8 g/dL for oligosaccharides, lactulose, and inulin. To eliminate confounding effects of prebiotics in users of human breast milk and formula, we included studies that added these compounds to neonatal enteral feeding. We included studies of three types: trials that added prebiotics to breast milk in breast‐fed only infants; trials that added prebiotics to formula in bottle‐fed only infants; and trials providing mixed forms (i.e. adding prebiotics to both breast milk and formula). Investigators compared interventions versus enteral supplementation of milk with distilled water/placebo or no supplementation. We included in this review only trials that were continued for at least seven days. For management of neonatal jaundice, all infants in both groups were treated according to the protocol for phototherapy described in the guidelines of the American Academy of Pediatrics 2004.
Types of outcome measures
Primary outcomes
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Neonatal hyperbilirubinaemia: incidence of hyperbilirubinaemia at any time during the first ten days of life, considered as the primary outcome. Hyperbilirubinaemia is defined as follows:
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for term and late preterm neonates (gestational age ≥ 35 weeks) as total bilirubin (TB) level eligible for phototherapy, as described in the guidelines of the American Academy of Pediatrics 2004 (Figure 1), or as absolute TB level ≥ 15 mg/dL; and
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for preterm neonates (< 35 weeks’ gestation) as TB level that is eligible for phototherapy, as described in the guidelines of the American Academy of Pediatrics 2004 (Figure 2), or as absolute TB level > 1% of body weight.
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Guidelines for phototherapy in infants at ≥ 35 weeks' gestation.
(American Academy of Pediatrics Subcommittee on Hyperbilirubinaemia. Management of hyperbilirubinaemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297.)
Suggested guidelines for initiating phototherapy or exchange transfusion in preterm infants (< 35 weeks' gestation).
(Maisels MJ, Watchko JF, Bhutani VK, et al. An approach to the management of hyperbilirubinaemia in the preterm infant less than 35 weeks of gestation. Journal of Perinatology 2012;32:660‐664.)
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Acute bilirubin encephalopathy: defined as a clinical syndrome, in the presence of severe hyperbilirubinaemia, that ranges from the initial phase of lethargy, hypotonia, reduced movement, and poor sucking and suckling to the advanced phase of deep stupor, hypertonia, inability to feed, and shrill cry or seizures (Canadian Pediatric Society 2007).
Secondary outcomes
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Maximum plasma unconjugated bilirubin levels (at any time during study period)
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Treatment with phototherapy
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Duration of phototherapy (days)
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Exchange transfusion: receipt of any exchange transfusion (single or double volume)
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Chronic bilirubin encephalopathy or kernicterus: defined by a tetrad of choreoathetoid cerebral palsy, high‐frequency sensorineural hearing loss, palsy of vertical gaze and dental enamel hypoplasia assessed at six months' corrected age (Okumura 2009)
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Stool frequency: total number of defecations recorded per day during intervention
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Length of hospital stay (days)
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Neonatal mortality
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Major neurodevelopmental disability
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Major neurodevelopmental disabilities considered
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Cerebral palsy
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Developmental delay or intellectual impairment
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Bayley or Griffith assessment more than two standard deviations (SDs) below the mean, or intellectual impairment (IQ) > 2 SDs below the mean
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Neuromotor development (Bayley Scales of Infant Development ‐ Psychomotor Development Index (BSID PDI)) assessed among survivors
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Mental development (Bayley Scales of Infant Development ‐ Mental Development Index (BSID MDI)) assessed among survivors
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Blindness/vision (< 6/60 in both eyes)
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Sensorineural deafness requiring amplification
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The review evaluated these components of long‐term outcomes for all studies that evaluated children after 18 months' chronological age. The review authors considered separate analyses for children 18 to 24 months of age and 3 to 5 years of age.
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Side effects: diarrhoea (stool > 40 g/kg/d) and dehydration (weight loss > 10% birth weight) recorded during the intervention
Search methods for identification of studies
We used the criteria and standard methods of Cochrane and Cochrane Neonatal.
Electronic searches
We conducted a comprehensive search including: Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5) in the Cochrane Library; MEDLINE via PubMed (1966 to 14 June 2018); Embase (1980 to 14 June 2018); and CINAHL (1982 to 14 June 2018). We used the following search terms: (hyperbilirubinaemia [MeSH] OR jaundice[MeSH] OR (hyperbilirubinemia OR hyperbilirubinaemia OR jaundice OR icter*) AND (prebiotics[MeSH] OR prebiotic* OR oligosaccharides[Mesh] OR oligosaccharides), plus database‐specific limiters for RCTs and neonates (see Appendix 1 for the full search strategies for each database). We did not apply language restrictions.
We searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; the World Health Organization’s International Trials Registry and Platform www.whoint/ictrp/search/en/, and the ISRCTN Registry). We checked Proceedings of the Prenatal Society of Australia and New Zealand (PSANZ ‐ 2005 to 14 June 2018), the Society for Pediatric Research, and the European Society for Paediatric Research (2000 to 14 June 2018).
Searching other resources
We also searched the reference lists of any articles selected for inclusion in this review in order to identify additional relevant articles, and contacted authors of published articles to ask about possible unpublished trials.
Data collection and analysis
We employed standard methods of the Cochrane Collaboration, as described in the Cochrane Handbook for Systematic Reviews of Interventions, and of the Cochrane Neonatal Review Group (Higgins 2011).
Selection of studies
Two review authors (AA and NS) independently checked the titles and abstracts of all studies retrieved through the literature search to identify those that met the inclusion criteria, independently confirmed their eligibility by reviewing the full text of retrieved articles, and resolved disagreements through discussion. We consulted the Cochrane Neonatal Review Group for advice, when necessary.
Data extraction and management
We designed a data extraction form and evaluated its validity and reliability before use. At least two review authors independently extracted data and resolved differences in data interpretation with assistance provided by the trial authors. We resolved uncertainties regarding trial information and incomplete or missing data by contacting the trial authors. We entered data into Review Manager (RevMan 5.3) and checked them for accuracy.
Assessment of risk of bias in included studies
Two review authors (AA and NS) independently assessed the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2011) for the following domains:
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Sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants and personnel (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective reporting (reporting bias)
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Any other bias
Any disagreements were resolved by discussion or by a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain.
Measures of treatment effect
We presented pooled estimates of dichotomous outcomes as risk ratios (RRs) or risk differences (RDs) with corresponding 95% confidence intervals (CIs). For continuous outcomes, we used mean differences (MDs) along with 95% CIs to compare intervention and control groups. When outcomes were measured by different methods or by different scales, we used standardised mean differences (SMDs). If data were missing or incomplete and the RD statistic was statistically significant, we planned to present the number needed to treat for an additional beneficial or harmful outcome (NNTB/NNTH).
Unit of analysis issues
We considered the participating infant as the unit of analysis in clinical trials. We dealt with an approximate analysis as suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
If clarification of information or missing data was needed, we contacted the relevant study authors. We attempted to contact authors to complete the information about incidence of hyperbilirubinaemia, maximum plasma unconjugated bilirubin level, treatment with phototherapy, duration of phototherapy, length of hospital stay, and neonatal mortality, but unfortunately we did not receive any replies. We excluded from the meta‐analysis studies with a high dropout rate for which we could not obtain appropriate details of missing data and performed a sensitivity analysis to evaluate the impact of exclusion on the results of analysis. Those studies which reported missing data or dropout more than 20% were considered as high level of dropout and excluded from meta‐analysis.
Assessment of heterogeneity
We used the I2 statistic and the following categories to assess for heterogeneity among studies.
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Less than 25%: no heterogeneity.
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25% to 49%: low heterogeneity.
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50% to 74%: moderate heterogeneity.
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75% or greater: high heterogeneity.
We used Cochran's Chi2 Q test and the associated P value in evaluating heterogeneity. We considered P < 0.1 as an indication of the presence of heterogeneity. We performed a visual assessment to identify obvious overlaps and outliers. In cases of moderate or high heterogeneity, we explored potential sources of heterogeneity by performing sensitivity analysis and subgroup analyses. We intended to use a Galbraith plot for heterogeneity but it was deemed unnecessary.
Assessment of reporting biases
We planned to use funnel plots to assess possible reporting or publication bias and conduct Begg and Egger linear tests in evaluating publication bias. For funnel plots to be meaningful, ten or more trials must be included, however, there were insufficient studies to do this.
you planned to do x and y; however, there were insufficient studies to do this
Data synthesis
We applied standard methods of the Cochrane Neonatal Review Group and RevMan 5.3 for meta‐analyses. We used a fixed‐effect method in combining the effects of studies that were sufficiently similar. For estimates of combined risk ratio and risk difference, we used the Mantel‐Haenszel method. We used mean differences (MDs) to combine estimates of quantitative data as reported in clinical trials measuring the same outcome using the same scale. If trials reported outcomes using different scales or measurement methods, we planned to use standardised mean difference (SMDs). We reported risk ratios (RRs) and MDs along with 95% CIs, and based analysis on numbers needed to treat for additional beneficial and harmful outcomes.
Quality of evidence
We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the quality of evidence for the following clinically relevant outcomes: neonatal hyperbilirubinaemia, need for phototherapy, exchange transfusion, acute bilirubin encephalopathy/kernicterus, and stool frequency.
Two authors independently assessed the quality of the evidence for each of the outcomes above. We considered evidence from randomised controlled trials as high quality but downgraded the evidence one level for serious, or two levels for very serious, limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.
The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades:
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High: We are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
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Very low: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect
Subgroup analysis and investigation of heterogeneity
We ran a subgroup analysis based on the following.
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Gestational age (term neonates (gestational age ≥ 37 weeks), late preterm neonates (35 to 37 weeks' gestation), preterm neonates (< 35 weeks' gestation)).
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Birth weight (≥ 2500 grams, 1500 to 2500 grams, < 1500 grams).
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Type of prebiotic (oligosaccharide, lactulose, inulin).
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Type of feeding (only breast milk‐fed infants, only formula‐fed infants, infants given a mixed form of feeding).
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Duration of supplementation (≥ 7 days, < 7 days).
Sensitivity analysis
We planned to perform sensitivity analyses based on both outcomes and baseline characteristics to assess the impact of bias on the results of the meta‐analysis; however, there was no need to use the sensitivity analyses because none of the included studies had a high risk of bias.
Results
Description of studies
Results of the search
Overall, 85 records were identified through our search, of which 10 articles were assessed for eligibility. Of these, only three studies met the inclusion criteria (Figure 3).
Study flow diagram.
Included studies
Ten potential studies were identified, of which three were included in the review (Figure 3). These are described in detail in the Characteristics of included studies section (Armanian 2015; Bisceglia 2009; Riskin 2010).
Armanian 2015 performed a randomised double‐blinded clinical trial that enrolled 50 preterm neonates (< 1501 grams and/or < 34 weeks). Infants who had initially been on parenteral nutrition were entered into the study after the enteral feeding with breast milk was started and met the volume of 30 mL/kg/day. Researchers randomly assigned infants to receive the intervention short‐chain galacto‐oligosaccharides (scGOSs)/ long‐chain fructo‐oligosaccharides (lcFOSs) (scGOS/lcFOS) in a ratio of 9:1 or a placebo of distilled water with the same volume as of the prebiotic mixture, 25 infants in each group. The study’s primary outcomes were change in bilirubin level after intervention as well as average and peak bilirubin levels during the intervention. Secondary outcomes were change in stool frequency, average stool frequency, and meeting full enteral feeding, defined as a milk volume of 150 mL/kg/day during the study period.
Bisceglia 2009 performed a prospective, double‐blind, clinical trial which enrolled seventy‐six infants (healthy term infants). Whenever breast milk was not available, newborns were randomly assigned to receive a formula containing 0.8 g ⁄ dL of a mixture from scGOS and lcFOS (ratio 9:1) (39 infants), or maltodextrins as placebo (37 infants). The intervention period lasted for 28 days. The primary outcome measure was bilirubin concentrations as detected by transcutaneous measurements. Secondary outcomes included stool frequency and increase in weight, length, and head circumference.
Riskin 2010 performed a double‐blinded, placebo‐controlled pilot study on twenty‐eight infants with gestational age of 23 to 34 weeks without major congenital anomaly. Researchers randomly assigned infants to receive the intervention (i.e. lactulose, 15 infants received 1% lactulose in their entire mother’s breast milk or preterm formula feeds (1 gram per 100 mL feeds)) or placebo (i.e. dextrose, 13 infants received 1% dextrose with the same volume as the lactulose). The primary outcome was the growth of bacteria in stool cultures. The most important secondary outcome measure was the absence of adverse effects, especially diarrhoea. Other secondary outcome measures were neonatal jaundice (indirect hyperbilirubinaemia) and anaemia of prematurity.
Excluded studies
See Characteristics of excluded studies table.
We rejected the following studies because they did not report our desired outcomes (i.e. hyperbilirubinaemia etc.): ISRCTN87058658, Westerbeek 2010 and Kajzer 2016. We excluded the following two studies because they enrolled non‐neonate infants (i.e. outside of our age range for inclusion): NCT01515644 and NCT02363582. We also rejected Keuth 1977 because the article was found only as an abstract.
Risk of bias in included studies
Details are provided in the Characteristics of included studies table. As well, a graphical presentation of our individual judgements per item per study and a summary graph are indicated in Figure 4 and Figure 5, respectively.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
We determined that all included studies had low risk of bias, as Armanian 2015 and Bisceglia 2009 performed random allocation by using the table of random numbers, and Riskin 2010 performed the randomisation with sealed nontransparent envelopes assigned to the lactulose or placebo groups. Allocation concealment was also adequately done in all of them.
Blinding
All studies clearly described and achieved blinding of participants, study personnel and outcome assessors except for Bisceglia 2009 and Armanian 2015 for which methods of blinding outcome assessors were not described so uncertainty about blinding were exist.
Incomplete outcome data
Two studies described reasons for attrition and exclusion of participants (Armanian 2015; Bisceglia 2009) and one study did not (Riskin 2010).
Selective reporting
For two studies, the study protocol was not available to us (Bisceglia 2009; Riskin 2010) so we cannot judge if there were any deviations from their protocols. The other study was entered into a trial registry and seemed to have no major deviations from the protocol (Armanian 2015).
Other potential sources of bias
Because we did not enough data about other potential sources of bias, we judged the risk of other bias as unclear for all included trials.
Effects of interventions
See: summary of findings Table for the main comparison for the main comparison of feeding supplementation with prebiotics versus distilled water/placebo or no supplementation.
We included three studies in the comparison, involving a total of 154 infants.
Incidence of hyperbilirubinaemia (outcome 1.1)
In the one study that clearly reported the incidence of hyperbilirubinaemia, there was a significant reduction in the prebiotic group (RR 0.75, 95% CI 0.58 to 0.97; one study, 50 infants; low‐quality evidence) (Analysis 1.1) (Armanian 2015).
The single trial that evaluated this outcome had similar data for the following subgroups: gestational age (preterm neonates defined as < 35 weeks' gestation); birth weight (< 1500 grams); type of prebiotic (oligosaccharide); type of feeding (only breast milk‐fed infants); and therefore we presented only one forest plot.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (lactulose, inulin); type of feeding (only formula‐fed infants, infants given a mixed form of feeding); duration of supplementation.
Maximum plasma unconjugated bilirubin level (outcomes 1.2, 1.3)
Two studies reported this outcome (Armanian 2015; Riskin 2010). Infants in these two studies were preterm and had a birth weight of < 1500 grams. Maximum plasma unconjugated bilirubin level was higher in the prebiotic group in one of these studies (Riskin 2010) while it was significantly lower in the prebiotic group in the other study (Armanian 2015). The prebiotic was lactulose in Riskin 2010 and oligosaccharide in Armanian 2015. Overall, although there was a suggestion of high heterogeneity, the meta‐analysis of these two studies demonstrated no significant difference in maximum plasma unconjugated bilirubin levels in infants with prebiotic supplementation versus placebo (MD 0.14 mg/dL, 95% CI ‐0.91 to 1.20; 2 studies, 78 infants; I² = 81%, P = 0.79; low‐quality evidence) (Analysis 1.2, Analysis 1.3).
With meta‐analysis of these two studies similar data was obtaind for the following subgroups: a. gestational age (preterm neonates defined as < 35 weeks' gestation) and birth weight (< 1500 grams); b. type of prebiotic (lactulose, oligosaccharide) and type of feeding (only breast milk‐fed infants, infants given a mixed form of feeding). Therefore we presented only two forest plots for these similar analyses.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (inulin); type of feeding (only formula‐fed infants); duration of supplementation.
Acute bilirubin encephalopathy
None of the included studies reported any acute bilirubin encephalopathy.
Treatment with phototherapy (outcome 1.4)
Treatment with phototherapy was only clearly reported by Armanian 2015. There was a significant reduction in the rate of treatment with phototherapy in the prebiotic group (RR 0.75, 95% CI 0.58 to 0.97; one study, 50 infants; low‐quality evidence) (Analysis 1.4).
The single trial that evaluated this outcome had similar data for the following subgroups: gestational age (preterm neonates defined as < 35 weeks' gestation); birth weight (< 1500 grams); type of prebiotic (oligosaccharide); type of feeding (only breast milk‐fed infants). Therefore we presented only one forest plot for these similar analysis.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (lactulose, inulin); type of feeding (only formula‐fed infants, infants given a mixed form of feeding); duration of supplementation.
Stool frequency (outcomes 1.5 to 1.8)
All three studies reported the stool frequency, and there was a significant increase in stool frequency in the prebiotic groups. Meta‐analysis of all studies showed a significant increase in stool frequency in the prebiotic group in all subgroup analyses (MD 1.18, 95% CI 0.90 to 1.46; 3 studies, 154 infants; I² = 90%; high‐quality evidence) (Analysis 1.5, Analysis 1.6, Analysis 1.7, Analysis 1.8). While no diarrhoea was reported, this increase in stool frequency improves the movement of stool in the intestines.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (1500 to 2500 grams); type of prebiotic (inulin); duration of supplementation.
Duration of phototherapy (outcome 1.9)
Duration of phototherapy was only reported by Riskin 2010 who found no significant difference between the prebiotic and control groups (MD 0.10 days, 95% CI ‐2.00 to 2.20; one study, 28 infants; P = 0.93; low‐quality evidence) (Analysis 1.9) (Riskin 2010).
The single trial that evaluated this outcome had similar data for the following subgroups: gestational age (preterm neonates defined as < 35 weeks' gestation); birth weight (< 1500 grams); type of prebiotic (oligosaccharide); type of feeding (only breast milk‐fed infants). Therefore we presented only one forest plot for these similar analysis.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (lactulose, inulin); type of feeding (only formula‐fed infants, infants given a mixed form of feeding); duration of supplementation.
Length of hospital stay (outcomes 1.10, 1.11)
Two studies reported the length of hospital stay (Armanian 2015, Riskin 2010). In the meta‐analysis, both studies showed a significant reduction in the prebiotic group in all subgroup analyses. In the meta‐analysis, prebiotics resulted in a significant reduction in the mean 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) (Analysis 1.10, Analysis 1.11).
With meta‐analysis of these two studies similar data was obtaind for the following subgroups: a. gestational age (preterm neonates defined as < 35 weeks' gestation) and birth weight (< 1500 grams); b. type of prebiotic (lactulose, oligosaccharide) and type of feeding (only breast milk‐fed infants, infants given a mixed form of feeding). Therefore we presented only two forest plots for these similar analyses.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (inulin); type of feeding (only formula‐fed infants); duration of supplementation.
Exchange transfusion
There were no reports of the need for exchange transfusion in included studies.
Chronic bilirubin encephalopathy or kernicterus
There were no reports of the incidence of chronic bilirubin encephalopathy in included studies.
Major neurodevelopmental disability
Major neurodevelopmental disability was not reported in any of the included studies.
Neonatal mortality (outcomes 1.12, 1.13)
Neonatal mortality rate was reported by both Armanian 2015 and Riskin 2010. There was no significant difference between the prebiotic and placebo groups (typical RR 0.94, 95% CI 0.14 to 6.19; 2 studies; 28 infants; I² = 6%, P = 0.95; low‐quality evidence) (Analysis 1.12, Analysis 1.13).
With meta‐analysis of these two studies similar data was obtaind for the following subgroups: a. gestational age (preterm neonates defined as < 35 weeks' gestation) and birth weight (< 1500 grams); b. type of prebiotic (lactulose, oligosaccharide) and type of feeding (only breast milk‐fed infants, infants given a mixed form of feeding). Therefore we presented only two forest plots for these similar analyses.
We were unable to run the planned subgroup analysis for the following subgroups because there was no study with these target variables: gestational age (term neonates defined as gestational age ≥ 37 weeks, late preterm neonates defined as 35 to 37 weeks' gestation); birth weight (≥ 2500 grams, 1500 to 2500 grams); type of prebiotic (inulin); type of feeding (only formula‐fed infants); duration of supplementation.
Side effects
No side effects were found in any of the included studies.
Discussion
Summary of main results
There were only three studies that assessed the effectiveness of prebiotics on the incidence of neonatal jaundice, so the majority of the outcomes in this review could not be investigated and more studies should be done in this regard. However, the available data showed a significant decrease in the incidence of neonatal jaundice and the need for phototherapy in the prebiotic group, although there was no significant difference in the maximum plasma unconjugated bilirubin levels in the prebiotic and placebo groups. In all of the clinical trials that have been evaluated in this study, the frequency of faecal excretion (stool frequency) in the prebiotic group infants was significantly higher than that of the placebo group, which may indirectly lead to a reduction in jaundice in infants due to excretion of meconium containing high levels of bilirubin. Interestingly, the meta‐analysis found that supplementation of prebiotics in the prebiotic group infants reduced the duration of hospitalisation. There were no publications reporting the need for exchange transfusion, major neurodevelopmental disability, acute/chronic bilirubin encephalopathy, or any side effects in the included studies.
Overall completeness and applicability of evidence
Given that we performed an extensive search and consulted with experts in the field, which did not reveal any other studies, publication bias as an explanation of the limited number of studies is unlikely.
Only three small studies with different studied outcomes, enrolling between 28 and 79 infants were included in our review. The evidence from the meta‐analyses of the effects of prebiotics was only available for frequency of stool in neonates. This evidence clearly indicates a significant effect of the intervention under study, although these were based on small studies. For other outcomes, either non‐significant results were obtained, or there was no study or available data. It should be noted that because the sample size for the meta‐analysis is small, the clinical implications should be used with caution in infants with hyperbilirubinaemia. None of the included studies in our meta‐analyses showed serious side effects. The findings from another meta‐analysis (Deshmukh 2019) is in contrast with our study showing a significant effect of 'probiotics' on reducing the duration of phototherapy and total serum bilirubin level. The observed differences in terms of studied outcomes between our study and Deshmukh's systematic review could be attributed to different pathways through which probiotics and prebiotics work. Based on meta‐analyses conducted on limited quality data, particularly based on small and short‐term trials, it cannot be concluded that the routine use of prebiotics could be considered as an effective approach to prevent or treat neonatal hyperbilirubinaemia. Despite these systematic reviews and meta‐analyses, large well‐designed clinical trials are strongly recommended.
Quality of the evidence
According to the available data, the certainty of the evidence for the majority of outcomes was low with an exception of the outcome 'stool frequency' which was grade as relatively high quality (please see summary of findings Table for the main comparison).
The three included studies in our systematic review and meta‐analyses had good methodological quality such as random allocation, allocation concealment, and blinding. All the outcomes in the included trials had been measured objectively and all three studies indicated that sample size calculation had been performed. The potential confounding variables were balanced between prebiotics and placebo groups.Two major weaknesses limiting the quality of the included studies are high level of attrition bias or incomplete data and selective reporting. Despite the lack of major methodological issues in the included studies, due to their small sample size and short evaluation period, they could not provide reliable evidence about the effectiveness of prebiotics on hyperbilirubinaemia.
Potential biases in the review process
We are not aware of any potential biases in our review process. We would like to declare that the senior author of this review is also the first author of one of the included studies (Armanian 2015). To ensure bias did not occur, Dr. Armanian did not participate in the screening process, data abstraction or risk of bias assessments for his article.
Agreements and disagreements with other studies or reviews
To our knowledge, there is no review about the effectiveness of prebiotics on hyperbilirubinaemia.
Guidelines for phototherapy in infants at ≥ 35 weeks' gestation.
(American Academy of Pediatrics Subcommittee on Hyperbilirubinaemia. Management of hyperbilirubinaemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297.)
Suggested guidelines for initiating phototherapy or exchange transfusion in preterm infants (< 35 weeks' gestation).
(Maisels MJ, Watchko JF, Bhutani VK, et al. An approach to the management of hyperbilirubinaemia in the preterm infant less than 35 weeks of gestation. Journal of Perinatology 2012;32:660‐664.)
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 1 Incidence of hyperbilirubinaemia.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 2 Maximum plasma unconjugated bilirubin levels.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 3 Maximum plasma unconjugated bilirubin levels.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 4 Treatment with phototherapy.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 5 Stool frequency: gestational age.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 6 Stool frequency: birth weight.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 7 Stool frequency: type of prebiotic.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 8 Stool frequency: type of feeding.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 9 Duration of phototherapy (days).
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 10 Length of hospital stay (days).
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 11 Length of hospital stay (days).
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 12 Neonatal mortality.
Comparison 1 Feeding supplementation with prebiotics versus no prebiotics, Outcome 13 Neonatal mortality.
| Feeding supplementation with prebiotics compared to no prebiotics for the prevention of hyperbilirubinaemia in neonates | ||||||
| Patient or population: Neonates, including term neonates (gestational age ≥ 37 weeks), late preterm neonates (35 to 37 weeks' gestation) and preterm neonates (< 35 weeks' gestation) | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with no prebiotics | Risk with Feeding supplementation with prebiotics | |||||
| Incidence of hyperbilirubinaemia | Study population | RR 0.75 | 50 | ⊕⊕⊝⊝ | ||
| 960 per 1,000 | 720 per 1,000 | |||||
| Maximum plasma unconjugated bilirubin levels; | The mean maximum plasma unconjugated bilirubin levels; ranged from 7.6 to 8.1 mg/dL | MD 0.14 mg/dL higher | ‐ | 78 | ⊕⊕⊝⊝ | |
| Treatment with phototherapy | Study population | RR 0.75 | 50 | ⊕⊕⊝⊝ | ||
| 960 per 1,000 | 720 per 1,000 | |||||
| Stool frequency | The mean stool frequency; ranged from 1 to 3 | MD 1.18 higher | ‐ | 154 | ⊕⊕⊕⊕ | |
| Duration of phototherapy (days) | The mean duration of phototherapy (days); ranged from 2 to 3 days | MD 0.1 days higher | ‐ | 28 | ⊕⊕⊝⊝ | |
| Length of hospital stay (days) | The mean length of hospital stay (days); ranged from 29 to 72 days | MD 10.57 days lower | ‐ | 78 | ⊕⊕⊝⊝ | |
| Neonatal mortality | Study population | RR 0.94 | 78 | ⊕⊕⊝⊝ | ||
| 26 per 1,000 | 25 per 1,000 | |||||
| Acute bilirubin encephalopathy (encephalopathy) | Study population | not estimable | (0 RCTs) | ‐ | None of the included studies showed any acute bilirubin encephalopathy. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Exchange transfusion (exchange) | Study population | not estimable | (0 RCTs) | ‐ | There were no reports of the need for exchange transfusion in included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Chronic bilirubin encephalopathy or kernicterus (kernicterus) | Study population | not estimable | (0 RCTs) | ‐ | There were no reports of the incidence of chronic bilirubin encephalopathy in included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Major neurodevelopmental disability | Study population | not estimable | (0 RCTs) | ‐ | Major neurodevelopmental disability was not reported in any of the included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| Side effects | Study population | not estimable | (0 RCTs) | ‐ | No side effects were reported in any of the included studies. | |
| 0 per 1,000 | 0 per 1,000 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded one level due to high risk of performance bias b Downgraded one level due to uncertainty about precision (one study) c Downgraded one level due to uncertainty about precision (small study) d Downgraded one level due to unclear risk of attrition bias (incomplete outcome data) | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incidence of hyperbilirubinaemia Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.58, 0.97] |
| 1.1 gestational age preterm neonates (< 35 weeks' gestation); birth weight ( < 1500 grams); type of prebiotic (oligosaccharide); type of feeding (only breast milk‐fed infants) | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.58, 0.97] |
| 2 Maximum plasma unconjugated bilirubin levels Show forest plot | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.91, 1.20] |
| 2.1 gestational age preterm neonates (< 35 weeks' gestation), birth weight ( < 1500 grams) | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.91, 1.20] |
| 3 Maximum plasma unconjugated bilirubin levels Show forest plot | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 0.14 [‐0.91, 1.20] |
| 3.1 breastfed only infants, oligosaccharide | 1 | 50 | Mean Difference (IV, Fixed, 95% CI) | ‐0.90 [‐2.28, 0.48] |
| 3.2 given a mixed form of feeding, lactulose | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 1.60 [‐0.03, 3.23] |
| 4 Treatment with phototherapy Show forest plot | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.58, 0.97] |
| 4.1 gestational age preterm neonates (< 35 weeks' gestation); birth weight ( < 1500 grams); type of prebiotic (oligosaccharide); type of feeding (only breast milk‐fed infants) | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.58, 0.97] |
| 5 Stool frequency: gestational age Show forest plot | 3 | 154 | Mean Difference (IV, Fixed, 95% CI) | 1.18 [0.90, 1.46] |
| 5.1 term neonates (gestational age ≥ 37 weeks) | 1 | 76 | Mean Difference (IV, Fixed, 95% CI) | 1.7 [1.34, 2.06] |
| 5.2 preterm neonates (< 35 weeks' gestation) | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 0.4 [‐0.05, 0.85] |
| 6 Stool frequency: birth weight Show forest plot | 3 | 154 | Mean Difference (IV, Fixed, 95% CI) | 1.18 [0.90, 1.46] |
| 6.1 infants ≥ 2500 grams | 1 | 76 | Mean Difference (IV, Fixed, 95% CI) | 1.7 [1.34, 2.06] |
| 6.2 infants < 1500 grams | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | 0.4 [‐0.05, 0.85] |
| 7 Stool frequency: type of prebiotic Show forest plot | 3 | 154 | Mean Difference (IV, Fixed, 95% CI) | 1.18 [0.90, 1.46] |
| 7.1 oligosaccharide | 2 | 126 | Mean Difference (IV, Fixed, 95% CI) | 1.28 [0.98, 1.58] |
| 7.2 lactulose | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐0.44, 1.24] |
| 8 Stool frequency: type of feeding Show forest plot | 3 | 154 | Mean Difference (IV, Fixed, 95% CI) | 1.18 [0.90, 1.46] |
| 8.1 breastfed only infants | 1 | 50 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐0.13, 0.93] |
| 8.2 formula‐fed only infants | 1 | 76 | Mean Difference (IV, Fixed, 95% CI) | 1.7 [1.34, 2.06] |
| 8.3 given a mixed form of feeding | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.40 [‐0.44, 1.24] |
| 9 Duration of phototherapy (days) Show forest plot | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [0.00, 2.20] |
| 9.1 gestational age preterm neonates (< 35 weeks' gestation); birth weight ( < 1500 grams); type of prebiotic (lactulose); type of feeding (infants given a mixed form of feeding) | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | 0.10 [0.00, 2.20] |
| 10 Length of hospital stay (days) Show forest plot | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | ‐10.57 [‐17.81, ‐3.33] |
| 10.1 gestational age preterm neonates (< 35 weeks' gestation), birth weight ( < 1500 grams) | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | ‐10.57 [‐17.81, ‐3.33] |
| 11 Length of hospital stay (days) Show forest plot | 2 | 78 | Mean Difference (IV, Fixed, 95% CI) | ‐10.57 [‐17.81, ‐3.33] |
| 11.1 breastfed only infants, oligosaccharide | 1 | 50 | Mean Difference (IV, Fixed, 95% CI) | ‐10.2 [‐17.59, ‐2.81] |
| 11.2 given a mixed form of feeding, lactulose | 1 | 28 | Mean Difference (IV, Fixed, 95% CI) | ‐19.10 [‐54.58, 16.38] |
| 12 Neonatal mortality Show forest plot | 2 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.14, 6.19] |
| 12.1 gestational age preterm neonates (< 35 weeks' gestation), birth weight ( < 1500 grams) | 2 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.14, 6.19] |
| 13 Neonatal mortality Show forest plot | 2 | 78 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.94 [0.14, 6.19] |
| 13.1 breastfed only infants, oligosaccharide | 1 | 50 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 70.30] |
| 13.2 given a mixed form of feeding, lactulose | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.29 [0.01, 6.60] |
