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Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia

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Authors

Maryam Gholitabar1, Hugh McGuire1, Janet Rennie2, Donal Manning3, Rosalind Lai4

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1National Collaborating Centre for Women's and Children's Health, London, UK [top]
2University College London Hospitals NHS Foundation Trust, London, UK [top]
3Wirral University Teaching Hospital NHS Foundation Trust, Wirral, UK [top]
4NLH Primary Care Q & A Service, Aberystwyth, UK [top]

Citation example: Gholitabar M, McGuire H, Rennie J, Manning D, Lai R. Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD009017. DOI: 10.1002/14651858.CD009017.pub2.

Contact person

Hugh McGuire

National Collaborating Centre for Women's and Children's Health
4th Floor, King's Court
2-16 Goodge Street
London
W1T 2QA
UK

E-mail: hmcguire@ncc-wch.org.uk

Dates

Assessed as Up-to-date: 02 April 2012
Date of Search: 02 April 2012
Next Stage Expected: 02 April 2014
Protocol First Published: Issue 3, 2011
Review First Published: Issue 12, 2012
Last Citation Issue: Issue 12, 2012

Abstract

Background

There are many pathological conditions leading to an elevated unconjugated bilirubin level (hyperbilirubinaemia) in neonates. Currently the standard therapies for unconjugated hyperbilirubinaemia include phototherapy and exchange transfusion. In addition to phototherapy, clofibrate has been studied as a treatment for hyperbilirubinaemia in several countries.

Objectives

To determine the efficacy and safety of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinaemia.

Search methods

Randomised controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases. All searches were re-run on 2 April 2012.

Selection criteria

We included trials where neonates with hyperbilirubinaemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy.

Data collection and analysis

Data were extracted and analysed independently by two review authors (MG and HM). Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality. Study authors were contacted for additional information. Studies were analysed for methodological quality in a 'Risk of bias' table.

Results

Fifteen studies (two including preterm neonates and 13 including term neonates) were included in this review. All but one of the included studies were conducted in Iran. For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95% CI -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95% CI -36 µmol/L to -9 µmol/L) after 48 hours. For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95% CI -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95% CI -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L), respectively.

There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95% CI -30.46 hours to -17.18 hours) and -25.40 hours (95% CI -28.94 hours to -21.86 hours), respectively.

None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions.

Authors' conclusions

There are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinaemia to make recommendations for practice. There is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinaemia.

Plain language summary

Clofibrate for neonatal jaundice

Jaundice is a common problem in the neonatal period typically in the first week of life. It is treated quite effectively using phototherapy whereby the baby is placed under special lights for up to three to four days. Clofibrate is used in some countries in combination with phototherapy to reduce the time the baby needs to spend under lights thereby reducing parental anxiety and improved parent-baby bonding opportunities.

We have reviewed the evidence using systematic literature searches and have synthesised outcome data to see if clofibrate does has an effect on time spent under lights. We identified 12 studies and the use of clofibrate reduced time spent under lights by an average of 23 hours for both term and preterm babies.

However, most of the studies were carried out in one country, Iran, so these findings may not be generalisable to other countries. Further research is needed in other countries before the use of clofibrate can be recommended.

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Background

Description of the condition

Bilirubin is a naturally occurring antioxidant in the human body (Hammerman 1998); however, elevated levels of bilirubin, or 'hyperbilirubinaemia', is a neonatal complication that if treated promptly can usually be resolved in three to four days. This is a common problem in the neonatal period, occurring in around 60% of newborns (Maisels 1992). It is the most common cause of re-admissions to the hospital after early hospital discharge of term neonates (Escobar 2005). It is more common in preterm infants than in term infants, mainly because of a delay in the expression of hepatic glucuronyl transferase, the enzyme that conjugates bilirubin (Gartner 1994).

Bilirubin production and excretion follows a specific pathway. When the reticuloendothelial system breaks down old red blood cells, bilirubin is one of the waste products. This unconjugated bilirubin is in a lipid-soluble form that must be made water-soluble in order to be excreted. The unconjugated bilirubin is carried by albumin to the liver, where it is converted or conjugated and made water soluble. Once it is conjugated into a water-soluble form, bilirubin can be excreted in the urine.

There are many pathological conditions leading to an elevated unconjugated bilirubin level in neonates and these can be broadly grouped into haemolytic and non-haemolytic conditions. Under certain circumstances unconjugated bilirubin can be toxic to the central nervous system, resulting in encephalopathy and neurological impairment (Gourley 1997). Factors influencing bilirubin toxicity to the brain cells of newborn infants are complex and incompletely understood; they include those that affect the serum albumin concentration and those that affect the binding of bilirubin to albumin, the penetration of bilirubin into the brain, and the vulnerability of brain cells to the toxic effects of bilirubin. It is not known at what bilirubin concentration or under what circumstances significant risk of brain damage occurs or when the risk of damage exceeds the risk of treatment (AAP 1994).

Currently the standard therapies for hyperbilirubinaemia include phototherapy and exchange transfusion. These therapies aim to reduce high levels of unconjugated bilirubin or prevent the development of such high levels, and are usually instituted at different levels of bilirubin in different categories of infants, based on the recommendations of experts (AAP 1994; RCOG 2010).

Description of the intervention

Clofibrate is a fibric acid derivative used in the treatment of hyperlipoproteinaemia Type III and severe hypertriglyceridaemia. Clofibrate acts an activator of peroxisome proliferated activated receptors (PPARs), and thus it affects lipid metabolism. It acts to lower elevated serum lipids by reducing the very low-density lipoprotein fraction (Sf 20-400) rich in triglycerides. Serum cholesterol may be decreased, particularly in those patients whose cholesterol elevation is because of the presence of low-density lipoprotein as a result of Type III hyperlipoproteinaemia (DrugBank 2012).

It has been studied as a treatment for hyperbilirubinaemia in France, Iran, Mexico and Spain. It has been used to prevent the need for phototherapy and as an adjunct to phototherapy. It is usually given as a syrup or in liquid form via orogastric tube. The dosage commonly used for neonates is 100 mg/kg given in a single dose and its safety profile at this dosage has been examined (Bourget 1995). In adults (500 mg every six to 12 hours) its adverse effects include nausea and pruritus. No adverse effects have been noted in trials on neonates but, to date, no long-term follow-up has been carried out.

How the intervention might work

Phototherapy is the first-line treatment for neonatal hyperbilirubinaemia and reduces serum bilirubin levels by converting bilirubin into a water-soluble, more easily excretable form. This molecular conversion occurs when bilirubin accumulating in the skin of jaundiced infants is exposed to light of wavelengths 425 nm to 475 nm (blue-green spectrum) (Tan 1982). Phototherapy devices emit special light within this range and this is often referred to as 'special' lights. Clofibrate potentially aids this by increasing bilirubin conjugation and excretion via induction of glucuronyl transferase activity (Bourget 1995). Glucuronyl transferase is a liver enzyme that changes bilirubin into a water-soluble form that can be excreted in the bile. In Gilbert's syndrome, clofibrate decreases serum total bilirubin concentrations by increasing the glucuronidation of bilirubin, thus promoting the overall hepatic transport of bilirubin (Kutz 1984).

Why it is important to do this review

One review of English-language papers on the effectiveness of clofibrate in combination with phototherapy for neonatal hyperbilirubinaemia recommended that research be carried out into the effectiveness of clofibrate for unconjugated hyperbilirubinaemia (RCOG 2010). This review indicates that clofibrate could potentially result in a clinically significant reduction in the duration of phototherapy. If this is demonstrated in the current review, this would have huge potential in terms of healthcare costs owing to reduced stays in paediatric units or neonatal intensive care units. It would also be important for neonates and their parents or carers by reducing separation and associated anxiety and increasing bonding opportunities in the neonatal period. To this end a review of all studies, not just English-language papers, of clofibrate in combination with phototherapy in neonatal hyperbilirubinaemia is warranted.

Objectives

In patients with unconjugated hyperbilirubinaemia requiring treatment:

  1. to determine the effects of clofibrate in combination with phototherapy versus phototherapy alone on:
    1. bilirubin levels (specifically bilirubin levels after initiation of phototherapy);
    2. duration of phototherapy;
    3. frequency of exchange transfusion;
    4. incidence of bilirubin encephalopathy and long-term neurodevelopmental impairment associated with unconjugated hyperbilirubinaemia;
  2. to determine the frequency and nature of side effects of clofibrate when used to treat unconjugated hyperbilirubinaemia in neonates.

We intended to perform the following subgroup analyses:

  1. preterm (less than 37 completed weeks of gestation) and term (37 weeks or more of gestation) neonates;
  2. haemolytic versus non-haemolytic causes of hyperbilirubinaemia;
  3. studies that used different dosages of clofibrate;
  4. studies that used phototherapy at serum bilirubin levels less than 255 µmol/L.

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Methods

Criteria for considering studies for this review

Types of studies

We included only randomised and quasi-randomised controlled trials. We included only studies with individual participant allocation and did not include cross-over studies. We excluded studies of prophylactic phototherapy.

Types of participants

We included studies of term and preterm neonates with unconjugated hyperbilirubinaemia requiring phototherapy as defined by the author.

Types of interventions

We included studies in which participants received clofibrate (of any dosage) in combination with phototherapy in the treatment arm(s), and received either phototherapy alone or placebo clofibrate in combination with phototherapy in the comparison arm(s).

We did not include studies where phototherapy was given after relapse of hyperbilirubinaemia following successful phototherapy (rebound jaundice).

Types of outcome measures

Primary outcomes
  1. Mean change in bilirubin levels (mg/dL or µmol/L) over 24 hours, 48 hours, 72 hours.
  2. Mean duration of treatment with phototherapy (hours).
  3. Number of exchange transfusions needed.
  4. Any adverse effects of clofibrate.
  5. Bilirubin encephalopathy.
  6. Neonatal mortality.
Secondary outcomes
  1. Parental anxiety.
  2. Clinical staff satisfaction with treatment.

Search methods for identification of studies

Electronic searches

We developed a search strategy designed to capture all systematic reviews, and randomised or quasi-randomised controlled clinical trials assessing the effectiveness of clofibrate to treat jaundice in neonates.

The population stem of the search strategy consisted of both subject descriptors and text words describing newborn infants with high levels of bilirubin, those diagnosed with jaundice or the associated complications of encephalopathy or kernicterus. Likewise, we searched for the intervention clofibrate as a subject heading where available and as a text word (Appendix 1).

We developed the search initially in the MEDLINE database (Appendix 1) and then ran across all years to the present (1950 to April 2012) before being translated for use in The Cochrane Library (Appendix 2), EMBASE (1980 to April 2012) (Appendix 3) and CINAHL (Appendix 4) databases. Since we were unable to identify a validated methodology filter for retrieving systematic reviews and controlled clinical trials in the CINAHL database, we planned to run only the population and intervention parts of the strategy.

We ran searches in the MEDLINE In-Process database (Appendix 5) and in CENTRAL to capture the latest studies.

Clinical trials registries

We searched the following clinical trials registries on 2 April 2012 using terms 'clofibrate' and 'atromid':

Searching other resources

We did not conduct any handsearching of journals or conference proceedings for this review.

We checked the reference list of all included studies and of systematic reviews on this topic.

We carried out an internet search using both Google and Google Scholar. Last checked on 2 April 2012.

Data collection and analysis

Selection of studies

Two reviewer authors (HM and MG) reviewed all citations and abstracts. A third review author (JR) was available to resolve any disagreement by discussion or adjudication, or both, was not needed. We obtained full-text papers, and then two review authors (HM and MG) selected those that met the inclusion criteria and again a third review author (JR) was available to resolve any disagreement by discussion or adjudication, or both.

Data extraction and management

Two review authors (HM and MG) extracted data independently using standardised data extraction sheets (e.g. Appendix 6) and both entered the data into Review Manager (RevMan) 5.1 (RevMan 5.1).

Assessment of risk of bias in included studies

The review authors based their criteria for quality assessment on the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) . We assessed the bias and complete the 'Risk of bias' table. We were interested in the following types of bias:

Selection bias
  1. Sequence generation (Did the study generate the allocation sequence adequately?)For each included study, we categorised the method used to generate the allocation sequence as:
    1. low risk (any truly random process, e.g. random number table; computer random number generator);
    2. high risk (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
    3. unclear.
  2. Allocation concealment (Did the study conceal the allocation adequately?) For each included study, we categorised the method used to conceal the allocation sequence as:
    1. low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    2. high risk (open random allocation; unsealed or non-opaque envelopes, alternation, date of birth);
    3. unclear.
Performance bias
  1. Blinding (Did the authors conceal knowledge of the allocated intervention adequately during the study? At study entry? At the time of outcome assessment?) For each included study, we categorised the methods used to blind study personnel from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes. We categorised the methods as:
    1. low risk, high risk or unclear for participants;
    2. low risk, high risk or unclear for personnel;
    3. low risk, high risk or unclear for outcome assessors.
Attrition bias
  1. Incomplete outcome data (Did the study address incomplete outcome data adequately?) For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether the study reported attrition and exclusions, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion (where reported), and whether the authors balanced missing data across groups or related to outcomes.Where the trial authors reported or supplied sufficient information, we re-included missing data in the analyses. We categorised the methods as:
    1. low risk (less than 20% missing data);
    2. high risk (20% or more missing data);
    3. unclear risk.
Selective reporting bias
  1. Incomplete reporting (Are reports of the study free of suggestion of selective outcome reporting?) For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    1. low risk (where it is clear that the trial authors have reported all of the study's pre-specified outcomes and all expected outcomes of interest to the review);
    2. high risk (where the trial's authors have not reported all the study's pre-specified outcomes; they did not pre-specify one or more reported primary outcomes; they reported outcomes of interest incompletely so that they cannot be used; study failed to include results of a key outcome that the authors should have reported);
    3. unclear risk.
Other sources of bias
  1. Other sources of bias (Was the study apparently free of other problems that could put it at a high risk of bias?) For each included study, we described any important concerns we had about other possible sources of bias (e.g. whether there was a potential source of bias related to the specific study design or whether the trial was stopped early owing to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    1. yes;
    2. no;
    3. unclear.

We planned to explore the impact of the level of bias through undertaking sensitivity analyses if needed.

Measures of treatment effect

We originally planned to use weighted mean difference (WMD) when analysing continuous data and risk ratio (RR) when analysing dichotomous data. However, based on the advice in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) we opted to use mean endpoint scores instead of mean change from baseline.

We also planned to calculate the number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH) for significant risks, but as no adverse effects were reported we did not do this.

Unit of analysis issues

We planned to combine data from the treatment arms of studies with multiple treatment arms and compare them with placebo but made a post-hoc decision to report as separate comparisons based on dosage of clofibrate used.

Dealing with missing data

In cases where adequate information was not available within the papers, we contacted the investigators and asked them to supply additional information using a standardised form. Where the investigators provided no further usable data, we imputed missing data using formulae from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We carried out sensitivity analyses to examine the effect of including these studies.

If bilirubin levels were reported as milligrams per decilitre (mg/dL), we used these data in the meta-analyses and added conversion to micromoles per litre (µmol/L) by multiplying by a factor of 17.1 (JAMA 2001) in brackets.

Assessment of heterogeneity

We assessed heterogeneity between studies using the I2 statistic and by visual inspection of the results. We stated that if heterogeneity was present then we would re-examine the studies to see if there was a clinical explanation for it. We used I2 > 50% to be indicative of moderate heterogeneity (Higgins 2003) .

Assessment of reporting biases

We performed a funnel plot analysis to check for small study effects, including publication bias (see Figure 1).

Data synthesis

For dichotomous outcomes, we calculated RR and their 95% confidence intervals (CIs). We used a fixed-effect model for analyses as recommended by the Cochrane Neonatal Group (Cochrane Neonatal Review Group 2011).

For continuous outcomes, we had planned to calculate the mean difference (MD) of change from baseline to end point using a fixed-effect model but we made a post-hoc decision to use end point scores based on advice in Cochrane handbook (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

While we accept that we should perform and interpret subgroup analyses with caution because multiple analyses can lead to false-positive conclusions (Davey Smith 2008), we carried out the intended subgroup analyses as follows:

  1. preterm (less than 37 completed weeks of gestation) and term (37 weeks or more of gestation) neonates;
  2. studies that used different dosages (100 mg/kg and greater versus less than 100 mg/kg);
  3. studies that used phototherapy at serum bilirubin levels less than 255 µmol/L.

We did not find any studies that examined haemolytic hyperbilirubinaemia.

Sensitivity analysis

Planned sensitivity analysis: we did not use imputed data so we did not carry out this planned sensitivity analysis.

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Results

Description of studies

Results of the search

Nineteen published studies were identified. Twelve studies met the inclusion criteria. Seven trials were excluded. A total of 739 neonates were included in these studies (range 40 to 90 neonates per study). The details of each of these studies are given in the Characteristics of Included Studies table.

Included studies

All studies were single-centre studies and all except one were carried out in Iran. Neonates in one study received phototherapy at home while in the other 11 studies phototherapy was given in the hospital. Clofibrate was mostly given orally in a single dose and in two studies enteral water was given as placebo to the control group.

Nearly all of the studies used bilirubin level, duration of phototherapy, adverse effects and number of exchange transfusions as outcomes while parental or healthcare professional satisfaction was not reported in any study.

Subgroup analyses

One study was quasi-randomised (Badeli 2008) and sensitivity analysis was performed after excluding this study instead of the planned subgroup analysis.

Two studies (Mohammadzadeh 2009; Sakha 2009) exclusively included preterm infants and were analysed separately from the other 10 studies (Caballero-Noguéz 2001; Mohammadzadeh 2005; Eghbalian 2007; Moslehi 2007; Zahedpasha 2007; Badeli 2008; Zahedpasha 2008; Ghotbi 2009; Sharafi 2010; Eyvazzadeh 2011) including term neonates.

We did not identify any studies that included neonates with haemolytic hyperbilirubinaemia so this a priori subgroup analysis was not carried out.

One study (Sharafi 2010) specified a minimum entry level of 239 µmol/L and one study (Sakha 2009) did not report on minimum bilirubin entry levels. In both studies the mean baseline bilirubin levels were greater than 291 µmol/L so the planned subgroup analysis of studies using phototherapy at serum bilirubin levels less than 255 µmol/L was not carried out. .

Excluded studies

Four of the studies were excluded because they examined clofibrate as prophylactic intervention for neonatal jaundice/hyperbilirubinaemia. The fifth study was a case-control study. The sixth and seventh studies were excluded because there was no placebo-control group in one study and the population in other study consisted only of neonates with prolonged jaundice (> 14 days).

Risk of bias in included studies

See Figure 2 for full 'Risk of bias' table.

Allocation (selection bias)

Three of the studies (Badeli 2008; Ghotbi 2009; Eyvazzadeh 2011) allocated neonates alternately to the treatment groups and so were considered to be quasi-randomised studies. The remaining studies used either random-numbers tables (Caballero-Noguéz 2001; Mohammadzadeh 2005; Eghbalian 2007; Moslehi 2007; Sakha 2009) or did not state how the randomisation was carried out (Zahedpasha 2007; Zahedpasha 2008; Mohammadzadeh 2009; Sharafi 2010).

Blinding (performance bias and detection bias)

One of the studies (Mohammadzadeh 2009) was double-blinded and the remainder did not report on blinding of patient, outcome assessor or clinical staff.

Incomplete outcome data (attrition bias)

In the nine studies that used random allocation of interventions, no neonates were excluded after randomisation, so there were no missing data in any of these studies.

Selective reporting (reporting bias)

One study (Eghbalian 2007) claimed that all infants were examined at the second day after discharge for any probable pharmacological side effect, but the outcome of this assessment was not reported in the results section.

Other potential sources of bias

No other potential sources of bias were identified.

Serum bilirubin was assessed in all included studies. The blood test was performed before treatment and repeated 12 hours after treatment and then daily until phototherapy was discontinued. It is not clear who performed the blood test in the all included studies.

Effects of interventions

Phototherapy plus clofibrate 100 mg/kg versus phototherapy or phototherapy plus placebo group (Comparison 1)

Ten studies were included in this comparison. Two studies Mohammadzadeh 2009; Sakha 2009) included preterm neonates and the remaining eight studies (Mohammadzadeh 2005; Eghbalian 2007; Zahedpasha 2007; Badeli 2008; Zahedpasha 2008; Ghotbi 2009; Eyvazzadeh 2011; Habibi 2012) included term neonates.

Mean total serum bilirubin 24 hours after initiation of treatment (Outcome 1.1)
Preterm neonates

Two studies (Mohammadzadeh 2009; Sakha 2009) contributed to this analysis. There was no significant difference between the treatment groups for the preterm neonates after 24 hours of treatment (WMD 0.55 mg/dL; 95% CI -0.48 mg/dL to 1.58 mg/dL [9 µmol/L; 95% CI -8 µmol/L to 27 µmol/L]) (Analysis 1.1). Heterogeneity was high (I2 = 72%).

Term neonates

Eight studies (Mohammadzadeh 2005; Eghbalian 2007; Zahedpasha 2007; Badeli 2008; Zahedpasha 2008; Ghotbi 2009; Eyvazzadeh 2011; Habibi 2012) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -2.14 mg/dL; 95% CI -2.53 mg/dL to -1.75 mg/dL [-37 µmol/L; 95% CI -43 µmol/L to -30 µmol/L]) (Analysis 1.1). Heterogeneity was high (I2 = 71%). After the quasi-randomised studies (Badeli 2008; Ghotbi 2009; Eyvazzadeh 2011) were excluded from the analysis the MD was -1.67 mg/dL (95% CI -2.27 mg/dL to -1.08 mg/dL [-29 µmol/L; 95% CI -39 µmol/L to -18 µmol/L]). Heterogeneity was high (I2 = 72%).

Mean total serum bilirubin 48 hours after initiation of treatment (Outcome 1.2)
Preterm neonates

Two studies (Mohammadzadeh 2009; Sakha 2009) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -1.37 mg/dL; 95% CI -2.19 mg/dL to -0.55 mg/dL [-23 µmol/L; 95% CI -37 µmol/L to -9 µmol/L]) (Analysis 1.2). Heterogeneity was high (I2 = 94%).

Term neonates

Six studies (Mohammadzadeh 2005; Eghbalian 2007; Zahedpasha 2007; Zahedpasha 2008; Ghotbi 2009; Eyvazzadeh 2011) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -1.82 mg/dL; 95% CI -2.25 mg/dL to -1.38 mg/dL [-31 µmol/L; 95% CI -38 µmol/L to -24 µmol/L]) (Analysis 1.2). Heterogeneity was low (I2 = 18%). After the quasi-randomised studies (Eyvazzadeh 2011; Ghotbi 2009) were excluded from the analysis the MD was -1.70 mg/dL; 95% CI -2.29 mg/dL to -1.10 mg/dL [-29 µmol/L; 95% CI -39 µmol/L to -19 µmol/L]). Heterogeneity was low (I2 = 42%).

Mean duration of phototherapy (hours) (Outcome 1.3)
Preterm neonates

Two studies (Mohammadzadeh 2009; Sakha 2009) contributed to this analysis. There was a significantly lower duration of phototherapy in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -23.82 hours; 95% CI -30.46 hours to -17.18 hours) (Analysis 1.3). There was no heterogeneity (I2 = 0%).

Term neonates

Four studies (Alipour 2011; Badeli 2008; Eghbalian 2007; Mohammadzadeh 2005) contributed to this analysis. There was a significantly lower duration of phototherapy in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -25.40 hours; 95% CI -28.94 hours to -21.86 hours) (Analysis 1.3). Heterogeneity was high (I2 = 64%). After the quasi-randomised studies (Alipour 2011; Ghotbi 2009) were excluded from the analysis the WMD was -20.22 hours (95% CI -26.39 hours to -14.03 hours). Heterogeneity was moderate (I2 = 48%).

Number of exchange transfusions needed (Outcome 1.4)

Five studies (Caballero-Noguéz 2001; Eghbalian 2007; Eyvazzadeh 2011; Mohammadzadeh 2005; Mohammadzadeh 2009) reported on this outcome and no exchange transfusions were required in four of the studies. In one study (Mohammadzadeh 2009) two neonates needed an exchange transfusion during treatment, one in the clofibrate group and the other in the placebo group.

Adverse effects of clofibrate (Outcome 1.5)

Eight studies (Caballero-Noguéz 2001; Mohammadzadeh 2005; Eghbalian 2007; Badeli 2008; Zahedpasha 2008; Ghotbi 2009; Mohammadzadeh 2009; Eyvazzadeh 2011) reported on this outcome and no adverse effects were reported. There are no summary statistics so subgroup analyses for this outcome.

None of the studies reported the mean total serum bilirubin after 72 hours after initiation of treatment, bilirubin encephalopathy, neonatal mortality, parental anxiety and clinical staff satisfaction with treatment.

Phototherapy plus clofibrate 50 mg/kg versus phototherapy alone or plus placebo (Comparison 2)

Mean total serum bilirubin 24 hours after initiation of treatment (Outcome 2.1)
Preterm neonates

None of the studies reported the mean total serum bilirubin levels after 24 hours in preterm neonates.

Term neonates

Three studies (Moslehi 2007; Sharafi 2010; Fallah 2012) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -3.70; 95% CI -4.11 mg/dL to -3.30 mg/dL [-63 µmol/L; 95% CI -70 µmol/L to -56 µmol/L]) (Analysis 2.1). Heterogeneity was high (I2 = 95%).

Mean total serum bilirubin 48 hours after initiation of treatment (Outcome 2.2)
Preterm neonates

None of the studies reported the mean total serum bilirubin levels after 48 hours in preterm neonates.

Term neonates

Two studies (Sharafi 2010; Fallah 2012) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -3.41 mg/dL; 95% CI -3.91 mg/dL to -2.91 mg/dL [-58 µmol/L; 95% CI -67 µmol/L to -50 µmol/L]) (Analysis 2.2). Heterogeneity was high (I2 = 85%).

Mean duration of phototherapy (hours) (Outcome 2.3)
Preterm neonates

None of the studies reported the mean duration of phototherapy in preterm neonates.

Term neonates

Two studies (Fallah 2012; Moslehi 2007) contributed to this analysis. There was a significantly shorter duration of phototherapy in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -10.85 hours; 95% CI -12.48 hours to -9.23 hours) (Analysis 2.3). Heterogeneity was moderate (I2 = 47%).

Number of exchange transfusions needed (Outcome 2.4)
Preterm neonates

None of the studies reported the number of exchange transfusions in preterm neonates.

Term neonates

One study (Fallah 2012) contributed to this analysis. There was a single exchange transfusion in the control group. Heterogeneity was not applicable.

Adverse effects of clofibrate (Outcome 2.4)

Three studies (Moslehi 2007; Sharafi 2010; Fallah 2012) reported on this outcome and two adverse effects of clofibrate were report. No summary statistics were available.

None of the studies reported mean total serum bilirubin after 72 hours of treatment, bilirubin encephalopathy, neonatal mortality, parental anxiety and clinical staff satisfaction with treatment.

Phototherapy plus clofibrate 25 mg/kg versus phototherapy alone or plus placebo (Comparison 3)

One study (Moslehi 2007) contributed to this analysis.

Mean total serum bilirubin 24 hours after initiation of treatment (Outcome 3.1)
Preterm neonates

No studies were identified for mean total serum bilirubin levels after 24 hours in preterm neonates.

Term neonates

One study (Moslehi 2007) contributed to this analysis. There was a significantly lower bilirubin level in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -4.70 mg/dL; 95% CI -5.25 mg/dL to -4.15 mg/dL [-80 µmol/L; 95% CI -90 µmol/L to -71 µmol/L]) (Analysis 3.1). Heterogeneity was not applicable.

Mean duration of phototherapy (hours) (Outcome 3.2)
Preterm neonates

No studies were identified for this subgroup

Term neonates

One study (Moslehi 2007) contributed to this analysis. There was a significantly shorter duration of phototherapy in the phototherapy plus clofibrate group compared to the phototherapy alone or plus placebo group (WMD -11.10 hours; 95% CI -12.73 hours to -9.47 hours) (Analysis 3.2). Heterogeneity was not applicable.

Adverse effects of clofibrate (Outcome 3.3)

One study (Moslehi 2007) reported on this outcome and no exchange transfusions were required. There were no summary statistics for this outcome.

None of the studies reported the mean total serum bilirubin after 48 and 72 hours of treatment, bilirubin encephalopathy, neonatal mortality, parental anxiety and clinical staff satisfaction with treatment.

Discussion

Summary of main results

Seven studies (Mohammadzadeh 2005; Eghbalian 2007; Zahedpasha 2007; Badeli 2008; Zahedpasha 2008; Ghotbi 2009; Eyvazzadeh 2011) reported that clofibrate in combination with phototherapy was more effective than phototherapy alone in term neonates at reducing bilirubin levels 24 and 48 hours after start of phototherapy.Two studies (Mohammadzadeh 2009; Sakha 2009) reported that the addition of clofibrate to phototherapy did not improve the effectiveness of phototherapy in preterm neonates.No adverse effects were reported in any of the studies.There were no reported exchange transfusions in the majority of studies. One study (Mohammadzadeh 2009) reported that two neonates needed an exchange transfusions during treatment; one in the clofibrate plus phototherapy group and the other in the phototherapy only group.None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions.

Overall completeness and applicability of evidence

The objective of this review was to compare the effectiveness of clofibrate in combination with phototherapy for the treatment of neonatal hyperbilirubinaemia. All nine included studies reported on at least one of the four primary outcomes but none report on the remaining outcomes. We believe this review provides a relevant answer to the question of effectiveness of clofibrate in combination with phototherapy, but the evidence is susceptible to bias. In particular, there was no evidence on severe outcomes such as bilirubin encephalopathy or neonatal mortality. Trial settings, care providers and the study populations were comparable in the studies and the findings of these trials are generalisable. However, our planned subgroup analyses by bilirubin less than 255 µmol/L or by haemolytic hyperbilirubinaemia were not possible.

Quality of the evidence

The quality of evidence was low to moderate in all but one of the studies, with high risk of bias resulting from a lack of blinding.

Potential biases in the review process

Although our search was extensive, we cannot exclude the possibility that we have missed relevant evidence. We tried to contact the authors of the original studies but no responses were received. Our search of grey literature, the pursuit of trials listed in clinical trial registers and the fact that we applied no restrictions based on language or publication status aimed to avoid publication bias, location bias, citation bias, language bias and outcome reporting bias. Multiple publication bias did not occur but there was one case of duplicate publication that resulted in the journal withdrawing the published article.

Agreements and disagreements with other studies or reviews

We found no other systematic reviews examining the use of clofibrate in combination with phototherapy to treat neonatal hyperbilirubinaemia.

Authors' conclusions

Implications for practice

There is evidence that clofibrate in combination with phototherapy has a beneficial effect on the duration of phototherapy needed for neonates with hyperbilirubinaemia. However, it is unclear if these results, mainly from studies in a single country, are generalisable to other countries. The rates of exchange transfusion were quite low with only three neonates requiring an exchange transfusion in all the studies, which is to be expected with the effectiveness of phototherapy. As the indications for exchange transfusions may differ from country to country, we would need to replicate these findings in other countries before a conclusion could be made for this outcome. Adverse effect data from the randomised controlled trials of clofibrate are limited, and no definite recommendations based on available data can be made. Similarly no cases of either bilirubin encephalopathy or neonatal mortality were reported in any study so no definite recommendations for these outcomes can be made.

Implications for research

It is important that clofibrate in combination with phototherapy be examined in other countries before it can be assessed as effective and safe for use in all countries. Any such study should include outcome measures other than need for or duration of phototherapy and serum bilirubin levels, such as length of hospital stay, re-admission with jaundice and perhaps health economics analysis.

Acknowledgements

The authors would like to thank:

  • the National Institute for Health and Clinical Excellence (NICE) Neonatal Jaundice Guideline Development Group for their support and advice;
  • the National Collaborating Centre for Women's and Children's Health (NCC-WCH) technical team who supported this piece of work;
  • the Cochrane Neonatal Group who provided valuable comments and advice at protocol and review stages.

Contributions of authors

HM: planned the review; selected studies, extracted data, entered data and analysed results.

MG: planned the review; selected studies, extracted data, entered data and analysed results.

RL: carried out searches.

JR: advised and commented on protocol and review and wrote the implications for practice and research.

DM: advised and commented on protocol and review and wrote the implications for practice and research.

Declarations of interest

MG: none known.

HM and RL: were members of NCC-WCH technical team responsible for NICE Neonatal Jaundice guideline.

Differences between protocol and review

Types of participants:

In the protocol we stated "We will include neonates with prolonged hyperbilirubinaemia (greater than 14 days of age for term neonates and greater than 21 days of age for preterm neonates)".

We changed this in the full review and excluded one study that examined clofibrate plus phototherapy for prolonged jaundice.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Alipour 2011

Methods

Design: CCT
Blinding: not reported
Randomisation: alternation
Follow-up: not reported

Inclusion criteria
Term neonates with hyperbilirubinaemia

Exclusion criteria
Congenital anomalies

Haemolytic disease

Dehydration
Infection
G6PD deficiency

Participants

Phototherapy plus clofibrate group
Gender: male 29, female 11
Mean age at baseline: 6 ± 2 days
Mean bilirubin at baseline: not reported
Mean GA at birth: not reported
Mean birthweight: 3260 ± 400 g

Phototherapy group
Gender: male 21, female 11
Mean age at baseline: 5 ± 2 days
Mean bilirubin at baseline: not reported
Mean GA at birth: not reported
Mean birthweight: 3231 ± 370 g

Interventions

Phototherapy plus clofibrate group

4 (250 W) lamps positioned 30 cm above the baby + single dose of 100 mg/kg clofibrate

Phototherapy group

4 (250 W) lamps positioned 30 cm above the baby

Outcomes

Bilirubin levels

Adverse effects

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

"Infants were randomly divided by two groups .. by alternate time of admission"

Allocation concealment (selection bias) Unclear risk

No statement on blinding

Incomplete outcome data (attrition bias) Unclear risk

Not clear on outcomes

Blinding of participants and personnel (performance bias) Unclear risk

No statement on blinding

Blinding of outcome assessment (detection bias) Unclear risk

No statement on blinding

Badeli 2008

Methods

Design: CCT
Blinding: not reported
Randomisation: alternation
Follow-up: 1 month

Inclusion criteria
All selected neonates were born at term (with GA of 38 to 41 weeks), breastfed, had TSB levels between 15 mg/dL and 29.9 mg/dL and body weight 2500 g and 4000 g

Exclusion criteria
Dehydration
Infection
ABO or Rh incompatibility
G6PD deficiency
Conjugated bilirubin above 2 mg/dL or exceeding 15% of TSB
Congenital anomalies

Participants

Phototherapy plus clofibrate group
Gender: 26 male, 19 female
Mean age at baseline: 120 ± 36 hours
Mean bilirubin at baseline: 18.4 ± 1.4 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3190 ± 268 g

Phototherapy group
Gender: 24 male, 21 female
Mean age at baseline: 134 ± 50 hours
Mean bilirubin at baseline: 18.4 ± 1.8 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3151 ± 289 g

Interventions

Phototherapy plus clofibrate group

4 special white 420 to 480 nm lamps being used less than 240 hours and adjusted to about 30 cm above neonate + single dose of 100 mg/kg clofibrate

Phototherapy group
4 special white 420 to 480 nm lamps being used less than 240 hours and adjusted to about 30 cm above neonate

Outcomes

TSB and indirect bilirubin were measured every 12 hours till the end of phototherapy

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

"Were randomly allocated to clofibrate group (G1) and control group (G2) alternately; i.e. the first patient to group G1, the second one to G2, and so on"

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Caballero-Noguéz 2001

Methods

Design: RCT
Blinding: not reported
Randomisation: random numbers
Follow-up: not reported

Inclusion criteria
All selected neonates were born more than 28 weeks GA with an 1-minute Apgar 7 or greater

Exclusion criteria
Digestive tract problems
Blood group incompatibility (ABO or Rh)
Obstetric trauma
Sepsis
Congenital malformations
Diabetic mother
Erythrocyte changes
Polycythaemia

Participants

Phototherapy plus clofibrate group
Gender: 8 male, 4 female
Mean age at baseline: 113 ± 46 hours
Mean bilirubin at baseline: 18.6 ± 3.7 mg/dL
Mean GA at birth: 35.5 ± 3.1 weeks
Mean birthweight: 2341 ± 0.69 g

Phototherapy group
Gender: 7 male, 2 female
Mean age at baseline: 101 ± 41 hours
Mean bilirubin at baseline: 16.6 ± 4.1 mg/dL
Mean GA at birth: 36.0 ± 2.1 weeks
Mean birthweight: 2454 ± 0.66 grams

Interventions

Phototherapy plus clofibrate group
6 fluorescent white lamps positions 50 cm above neonate + single oral dose of 100 mg/kg clofibrate

Phototherapy group
6 fluorescent white lamps positioned 50 cm above neonate

Outcomes

TSB
Indirect bilirubin

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"números aleatorios" (random numbers)

Allocation concealment (selection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

No blinding

Blinding of outcome assessment (detection bias) High risk

No blinding

Eghbalian 2007

Methods

Design: RCT
Blinding: not reported
Randomisation: random numbers table
Follow-up: 2 days

Inclusion criteria
All selected neonates were born at health breastfed term with TSB levels between 15 and 25 mg/dL and body weight above 2500 g

Exclusion criteria
Dehydration
Signs of sepsis
Haemolytic diseases (ABO or Rh incompatibility)
Congenital anomalies
Requiring an exchange transfusion

Participants

Phototherapy plus clofibrate group
Gender: 15 male, 15 female
Mean age at baseline: not reported
Mean bilirubin at baseline: 20.8 ± 2.9 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Phototherapy group
Gender: 21 male, 9 female
Mean age at baseline: not reported
Mean bilirubin at baseline: 20.9 ± 4.3 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Interventions

Phototherapy plus clofibrate group
8 blue lamps (wavelength 420 to 450 nm) 25 cm above the cot + a single 100 mg/kg oral dose of clofibrate

Phototherapy group
8 blue lamps (wavelength 420 to 450 nm) 25 cm above the cot

Outcomes

Bilirubin levels
Duration of phototherapy
Number of exchange transfusions needed
Adverse effects of clofibrate
Rebound jaundice

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Using a table of random numbers"

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Eyvazzadeh 2011

Methods

Design: CCT
Blinding: not reported
Randomisation: alternation
Follow-up: 1 month

Inclusion criteria

Term neonates with jaundice

Exclusion criteria

Congenital anomalies

Haemolytic disease

Dehydration

Infection

G6PD deficiency

Participants

Phototherapy plus clofibrate group
Gender: Not reported on per group basis - overall 31 were male and 29 female
Mean age at baseline: not reported
Mean bilirubin at baseline: 17.22 ± 3.03 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Phototherapy group
Mean age at baseline: not reported
Mean bilirubin at baseline: 17.86 ± 3.04 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Interventions

Phototherapy plus clofibrate group

Phototherapy methods not specified + single dose of 100 mg/kg clofibrate

Phototherapy group
Phototherapy methods not specified

Outcomes

TSB

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

"Infants were randomly divided by two group…by a alternate allocation method"

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Fallah 2012

Methods

Design: RCT
Blinding: single blind
Randomisation: computerised randomisation
Follow-up: not stated

Inclusion criteria:
Body weight: 2500 to 4000 g
GA: 38 to 42 weeks
Breastfed
TSB: 17 to 29.9 mg/dL
Normal vaginal delivery

Exclusion criteria:
Sepsis
Anaemia
Severe asphyxia
Haemolytic diseases
Indirect hyperbilirubinaemia
Major congenital anomalies
Underlying hepatic disorders

Participants

Phototherapy plus clofibrate group
Gender: 16 male, 14 female
Mean bilirubin at baseline: 19.54 ± 3.07 mg/dL
Mean GA at birth: 38.23 ± 0.971 weeks
Mean birthweight: 3202 ± 370 g

Phototherapy group
Gender: 14 male, 16 female
Mean age at baseline: 4.97 ± 2.16 days
Mean bilirubin at baseline: 19.5 ± 2.21 mg/dL
Mean GA at birth: 37.87 ± 1.07 weeks
Mean birthweight: 3193.67 ± 369 g

Interventions

Phototherapy plus clofibrate group
4 special blue lamps (Phillips) 20 cm above the cot + a single 50 mg/kg oral dose of clofibrate

Phototherapy group
4 special blue lamps (Phillips) 20 cm above the cot

Outcomes

Duration of phototherapy

Adverse effects

Notes

Phototherapy stopped after bilirubin was below 14 mg/dL

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Simple randomisation was by a computer generated random number list"

Allocation concealment (selection bias) Low risk

List was prepared by "an investigator with no clinical involvement in the trial"

Incomplete outcome data (attrition bias) Low risk

No drop-outs reported

Blinding of participants and personnel (performance bias) High risk

"Patients and physicians allocated to the intervention group we aware of the allocation"

Blinding of outcome assessment (detection bias) Low risk

"Outcome assessors and data analysts were kept blinded to the allocation"

Ghotbi 2009

Methods

Design: CCT
Blinding: not reported
Randomisation: alternation
Follow-up: not reported

Inclusion criteria

Healthy breastfed babies

GA: 38 to 41 weeks

Birthweight 2500 to 4000 g

TSB 14 to 19.9 mg/dL

Exclusion criteria
Dehydration
Infection
ABO or Rh incompatibility
G6PD deficiency
Conjugated bilirubin above 2 mg/dL or exceeding 15% of TSB
Congenital anomalies

Participants

Phototherapy plus clofibrate group
Gender: 26 male, 19 female
Mean age at baseline: 120 ± 36 hours
Mean bilirubin at baseline: 18.4 ± 1.4 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3190 ± 268 g

Phototherapy group
Gender: 24 male, 21 female
Mean age at baseline: 134 ± 50 hours
Mean bilirubin at baseline: 18.4 ± 1.8 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3151 ± 289 g

Interventions

Phototherapy plus clofibrate group

4 special white 420 to 480 nm lamps being used less than 240 hours and adjusted to about 30 cm above neonate +

single dose of 100 mg/kg clofibrate

Phototherapy group
4 special white 420 to 480 nm lamps being used less than 240 hours and adjusted to about 30 cm above neonate

Outcomes

TSB and indirect bilirubin were measured every 12 hours to the end of phototherapy

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Not reported

Allocation concealment (selection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Habibi 2012

Methods

Design: RCT
Blinding: not reported
Randomisation: random numbers table
Follow-up: not stated

Inclusion criteria
Term neonate (GA 38 to 41 weeks)
Weight: 2500 to 4000 g
Age: 2 to 7 days
Serum total bilirubin level: 17 to 26 mg/dL with priority of unconjugated bilirubin
Level of direct bilirubin: less than 2 mg/dL or less than 15% of TSB
Exclusive breastfeeding

Exclusion criteria
Premature neonates
Sepsis
Meningitis
Congenital anomalies
Dehydration
Haemolytic diseases
Conjugated hyperbilirubinaemia

Participants

Phototherapy plus clofibrate group

Gender: 15 male, 11 female
Mean age at baseline: 3.3 ± 1.1 days
Mean bilirubin at baseline: 20.78 ± 2.38 mg/dL
Mean GA at birth: not reported
Mean Birthweight: 3057 ± 301 g

Phototherapy group

Gender: 15 male, 11 female
Mean age at baseline: 3.19 ± 0.98 days
Mean bilirubin at baseline: 20.52 ± 2.44 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3105 ± 337 g

Interventions

Phototherapy plus clofibrate group
8 lamped set (Tusan model using 20-watt Phillips bulbs) and adjusted to 25 cm above the infant's cot + a single oral dose of clofibrate (100 mg/kg birthweight)

Phototherapy group
8 lamped set (Tusan model using 20-watt Phillips bulbs) and adjusted to 25 cm above the infant's cot

Outcomes

Duration of phototherapy

Bilirubin level

Adverse effects

Notes

Phototherapy stopped once bilirubin level reached 14 mg/dL

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Placing in case or control, groups was based on a random numbers table"

Allocation concealment (selection bias) Unclear risk

Not reported

Incomplete outcome data (attrition bias) Low risk

No drop-outs reported

Blinding of participants and personnel (performance bias) Unclear risk

Not reported

Blinding of outcome assessment (detection bias) Unclear risk

Not reported

Mohammadzadeh 2005

Methods

Design: RCT
Blinding: not reported
Randomisation: random numbers table
Follow-up: 2 days

Inclusion criteria
Healthy, breast fed neonates

Delivered between 38th and 41 weeks GA after an uncomplicated pregnancy

TSB 17 and 29.9 mg/dL

Exclusion criteria
Any congenital anomaly
Haemolytic disease (Rh or ABO incompatibility and a positive Coombs' test)
Infection (congenital or acquired)
Dehydration
G6PD deficiency
Conjugated bilirubin > 2.0 mg/dL or exceeding 15% of TSB

Participants

Phototherapy plus clofibrate group

Gender: 20 male, 10 female
Mean age at baseline: 235 ± 99 hours
Mean bilirubin at baseline: 22.35 ± 3.35 mg/dL
Mean GA at birth: 38.7 ± 0.85 weeks
Mean birthweight: 3257 ± 473.87 g

Phototherapy group

Gender: 14 male, 16 female
Mean age at baseline: 197 ± 88 hours
Mean bilirubin at baseline: 23.81 ± 3.38 mg/dL
Mean GA at birth: 38.76 ± 0.89 weeks
Mean birthweight: 3262 ± 496.02 g

Interventions

Phototherapy plus clofibrate group
6 special white lamps and adjusted to 20 cm above the infant's cots. The lamps were changed regularly after 250 hours of usage plus

a single oral dose of clofibrate (100 mg/kg birthweight)

Phototherapy group
6 special white lamps and adjusted to 20 cm above the infant's cots. The lamps were changed regularly after 250 hours of usage

Outcomes

Bilirubin levels
Duration of phototherapy
Number of exchange transfusions needed
Adverse effects of clofibrate

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Using a table of random numbers"

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Mohammadzadeh 2009

Methods

Design: RCT
Blinding: double-blind
Randomisation: not reported
Follow-up: 2 days

Inclusion criteria
Healthy, breastfed

Birthweight: less than 2500 g

Exclusion criteria
Any congenital anomaly
Haemolytic disease (Rh or ABO incompatibility and a positive Coombs' test)
Infection (congenital or acquired)
Dehydration
G6PD deficiency
History of phenobarbital intake either by mother or infant

Participants

Phototherapy plus clofibrate group

Gender: 12 male, 18 female
Mean age at baseline: 209 ± 138 hours
Mean bilirubin at baseline: 22.7 ± 5.28 mg/dL
Mean GA at birth: 31.46 ± 1.44 weeks
Mean birthweight: 2186 ± 243.3 g

Phototherapy group

Gender: 20 male, 10 female
Mean age at baseline: 230 ± 122 hours
Mean bilirubin at baseline: 19.5 ± 4.7 mg/dL
Mean GA at birth: 31.5 ± 1.6 weeks
Mean birthweight: 2042 ± 386.5 g

Interventions

Phototherapy plus clofibrate group
4 special blue lamps (Philips Co., Germany) and adjusted to 25 cm above the infants' cots plus

single-dose clofibrate 100 mg/kg via orogastric tube

Phototherapy group
4 special blue lamps (Philips Co., Germany) and adjusted to 25 cm above the infants' cots plus

sterile water as clofibrate volume via orogastric tube

Outcomes

Bilirubin levels
Duration of phototherapy
Number of exchange transfusions needed
Adverse effects of clofibrate
Rebound jaundice

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Not reported

Allocation concealment (selection bias) Low risk

"The clofibrate and placebo were coded, nor physician neither laboratories known about type of treatment and selection of case and control group was randomly"

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) Low risk

"The clofibrate and placebo were coded, nor physician neither laboratories known about type of treatment and selection of case and control group was randomly"

Blinding of outcome assessment (detection bias) Low risk

"The clofibrate and placebo were coded, nor physician neither laboratories known about type of treatment and selection of case and control group was randomly"

Moslehi 2007

Methods

Design: RCT
Blinding: not reported
Randomisation: random numbers table
Follow-up: 2 days

Inclusion criteria

Healthy, full term neonates (between 38th and 41st week of GA)

Birthweight of 2500 to 3500 g

Breastfed

TSB: 17 to 24.9 mg/dL

Exclusion criteria

Presence of any congenital anomaly
Haemolytic disease (Rh or ABO incompatibility and a positive Coombs' test)
infection (congenital or acquired)
Dehydration
G6PD deficiency
Conjugated bilirubin > 2.0 mg/dL
TSB > 25 mg/dL

Participants

Phototherapy plus clofibrate group 1 (50 mg/kg)

Gender: 14 male, 16 female
Mean age at baseline: 124 ± 49 hours
Mean bilirubin at baseline: 17.6 ± 1.5 mg/dL
Mean GA at birth: 38.8 ± 1.9 weeks
Mean birthweight: 2525 ± 628 g

Phototherapy plus clofibrate group 2 (25 mg/kg)

Gender: 17 male, 13 female
Mean age at baseline: 126 ± 48 hours
Mean bilirubin at baseline: 17.7 ± 1.3 mg/dL
Mean GA at birth: 38.4 ± 1.5 weeks
Mean birthweight: 2564 ± 428 g

Phototherapy group

Gender: 16 male, 14 female
Mean age at baseline: 127 ± 45 hours
Mean bilirubin at baseline: 17.6 ± 1.4 mg/dL
Mean GA at birth: 39.3 ± 1.2 weeks
Mean birthweight: 2539 ± 585 g

Interventions

Phototherapy plus clofibrate group 1

6 special white lamps 20 cm above the infant's cot. The lamps were changed regularly after 250 hours of usage plus

single oral dose of clofibrate (50 mg/kg) in a mixture of corn-oil 20 minutes before breastfeeding

Phototherapy plus clofibrate group 2

6 special white lamps 20 cm above the infant's cot. The lamps were changed regularly after 250 hours of usage plus

single oral dose of clofibrate (25 mg/kg) in a mixture of corn-oil 20 minutes before breastfeeding

Phototherapy group

6 special white lamps 20 cm above the infant's cot. The lamps were changed regularly after 250 hours of usage

Outcomes

Bilirubin levels
Duration of phototherapy
Adverse effects of clofibrate

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"Using a table of random numbers."

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Sakha 2009

Methods

Design: RCT
Blinding: double-blind
Randomisation: random-numbers table
Follow-up: 1 week

Inclusion criteria
Healthy late preterm newborns (GA 34 to 37 weeks)
Non-haemolytic jaundice
Did not need urgent exchange transfusion

Exclusion criteria:
Major congenital anomalies
Haemolytic disorders
G6PD deficiency diagnosed by qualitative, visual, colorimetric test
Sepsis
Significant accompanying illness requiring NICU admission

Participants

Phototherapy plus clofibrate group

Gender: 20 male, 10 female
Mean age at baseline: 149 ± 63 hours
Mean bilirubin at baseline: 20.05 ± 2.82 mg/dL
Mean GA at birth: 35.04 ± 1.56 weeks
Mean birthweight: not reported

Phototherapy group

Gender: 18 male, 12 female
Mean age at baseline: 145 ± 75 hours
Mean bilirubin at baseline: 19.72 ± 1.79 mg/dL
Mean GA at birth: 35.16 ± 1.44 weeks
Mean birthweight: not reported

Interventions

Phototherapy plus clofibrate group
8 special blue fluorescent tubes labelled TL 52/20 w (Philips, Eindhoven, the Netherlands) adjusted at a 20-cm distance above the infant. Lamps of phototherapy units were changed regularly after 1500 hours of usage plus

single dose of clofibrate 100 mg/kg was administered orally within 12 hours of admission

Phototherapy group
8 special blue fluorescent tubes labelled TL 52/20 w (Philips, Eindhoven, the Netherlands) adjusted at a 20-cm distance above the infant. Lamps of phototherapy units were changed regularly after 1500 hours of usage

Outcomes

Bilirubin levels
Duration of phototherapy
Adverse effects of clofibrate
Rebound jaundice

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

"By a random-number table sequence"

Allocation concealment (selection bias) Low risk

"The allocation notes were kept in opaque sequentially numbered sealed envelops"

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) Low risk

"Based on the numerical order of sealed envelopes clofibrate or placebo was administered to patients by a nurse who was not involved in the care of the infant"

Blinding of outcome assessment (detection bias) Low risk

"By a physician who did not know the infant's group allocation. Duration of phototherapy was recorded by a nurse who was not involved in drug administration"

Sharafi 2010

Methods

Design: RCT
Blinding: not reported
Randomisation: not reported
Follow-up: 2 days

Inclusion criteria:
Body weight: 2500 to 4000 g
GA: 38 to 41 weeks
Breastfed
TSB: 14 to 20 mg/dL
Postnatal age above 72 hours

Exclusion criteria:
ABO or Rh incompatibility
G6PD deficiency
Conjugated hyperbilirubinaemia
Any concomitant disease

Participants

Phototherapy plus clofibrate group

Gender: 12 males, 18 females
Mean age at baseline: 163 ± 78 hours
Mean bilirubin at baseline: 17.24 ± 1.48 mg/dL
Mean GA at birth: not reported
Mean Birthweight: 3107 ± 394.89 g

Phototherapy group

Gender: 13 males, 17 females
Mean age at baseline: 158 ± 60 hours
Mean bilirubin at baseline: 17.42 ± 1.44 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3150 ± 469.40 g

Interventions

Phototherapy plus clofibrate group
4 special blue tubes placed 40 cm above the infant as home phototherapy plus a

single dose of 50 mg/kg clofibrate before starting phototherapy

Phototherapy group
4 special blue tubes placed 40 cm above the infant as home phototherapy

Outcomes

Decrease in bilirubin
Duration of phototherapy
Adverse effects of clofibrate

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Not reported

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Zahedpasha 2007

Methods

Design: RCT
Blinding: not reported
Randomisation: not reported
Follow-up: 1 week

Inclusion criteria:
Healthy, breast-fed

GA: 38 and 41 weeks
Uncomplicated pregnancy
TSB: 15 to 25 mg/dL
Body weight of greater than/or equal to 2500 g

Exclusion criteria:
Haemolytic disease
Rh or ABO incompatibility

Positive Coombs' test
G6PD deficiency
Conjugated bilirubin > 1.5 mg/dL or 15% of TSB
Dehydration
Infection (congenital or acquired)
History of phenobarbital intake either by mother or infant

Participants

Phototherapy plus clofibrate group

Gender: 14 male, 16 female
Mean age at baseline: 136 ± 44 hours
Mean bilirubin at baseline: 18.21 ± 1.85 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Phototherapy group

Gender: 14 male, 16 female
Mean age at baseline: 153 ± 90 hours
Mean bilirubin at baseline: 17.50 ± 2.34 mg/dL
Mean GA at birth: not reported
Mean birthweight: not reported

Interventions

Phototherapy plus clofibrate group

4 special blue lamps (Philips Co., Germany) adjusted to 25 cm above the infant's cot plus single oral dose of clofibrate 100 mg/kg

Phototherapy group
4 special blue lamps (Philips Co., Germany) adjusted to 25 cm above the infant's cot

The control group received distilled water in an equal amount and colour as placebo.

Outcomes

Decrease in bilirubin
Duration of phototherapy
Number of exchange transfusions needed
Adverse effect

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Not reported

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Zahedpasha 2008

Methods

Design: RCT
Blinding: not reported
Randomisation: not reported
Follow-up: 7 days

Inclusion criteria
G6PD-deficient jaundiced babies
GA: 38 to 41 weeks

Birthweight: greater than/or equal to 2500 g
Born from an uncomplicated pregnancy
TSB: greater than/or equal to15 and < 20 mg/dL at > 48 hours after birth

Exclusion criteria
Haemolytic disease (Rh or ABO incompatibility)
Positive Coombs' test
Conjugated bilirubin > 1.5 mg/dL or 15% of TSB
Dehydration
Infection (congenital or acquired)

History of phenobarbital intake by mother or infant

Participants

Phototherapy plus clofibrate group

Gender: not reported
Mean age at baseline: 139 ± 61 hours
Mean bilirubin at baseline: 18.40 ± 2.41 mg/dL
Mean GA at birth: not reported
Mean Birthweight: 3, 195.2 ± 403.7 g

Phototherapy group

Gender: not reported
Mean age at baseline: 105 ± 42 hours
Mean bilirubin at baseline: 17.49 ± 1.03 mg/dL
Mean GA at birth: not reported
Mean birthweight: 3326.3 ± 553.6 g

Interventions

Phototherapy plus clofibrate group

4 special blue lamps (made by Philips, Germany) adjusted to 25 cm above the infant cot plus

a single oral dose of clofibrate (100 mg/kg)

Phototherapy group
4 special blue lamps (made by Philips, Germany) adjusted to 25 cm above the infant cot

Outcomes

Bilirubin levels

Duration of phototherapy

Number of exchange transfusions needed

Adverse effects of clofibrate

Notes

-

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) High risk

Not reported

Allocation concealment (selection bias) High risk

Not reported

Incomplete outcome data (attrition bias) Low risk

All participants accounted for

Blinding of participants and personnel (performance bias) High risk

Not reported

Blinding of outcome assessment (detection bias) High risk

Not reported

Footnotes

CCT: clinical controlled trial; G6PD: glucose-6-phosphate dehydrogenase; GA: gestational age; NICU: neonatal intensive care unit; RCT: randomised controlled trial; TSB: total serum bilirubin.

Characteristics of excluded studies

Bourget 1995

Reason for exclusion

No placebo-control group

Flores 1996

Reason for exclusion

Study examining the use of clofibrate to prevent hyperbilirubinaemia

Lindenbaum 1981

Reason for exclusion

Study examining the use of clofibrate to prevent hyperbilirubinaemia

Lindenbaum 1985

Reason for exclusion

Study examining the use of clofibrate to prevent hyperbilirubinaemia

Mohammadzadeh 2008

Reason for exclusion

Study examining the use of clofibrate to prevent hyperbilirubinaemia

Morcos 2006

Reason for exclusion

Case control study

Zahedpasha 2009

Reason for exclusion

Study includes children with prolonged jaundice (Jaundice > 14 days of age) only

[top]

References to studies

Included studies

Alipour 2011

Alipour AA, Babaee H, Masoud Borghaee SA, Hashemian AH, Azizi M. The effect of clofibrate and phototherapy on physiological jaundice in term newborns. Behbood 2011;15(4):233-7.

Badeli 2008

Badeli MR, Sharafi R, Sajedi SA. The effect of clofibrate on neonatal hyperbilirubinemia in uncomplicated jaundice. Iranian Journal of Pediatrics 2008;18(1):20-4.

Caballero-Noguéz 2001

Caballero-Noguéz B, Hernández Peralta S, Bucheli Jiménez ER, Quiróz Maldonado M, Flores Colín. Effect of clofibrate associated with phototherapy on bilirubin levels in newborn infants [Efecto del clofibrato asociado a fototerapia sobre la concentración de bilirrubina en niños recién nacidos]. Revista Mexicana de Pediatria 2001;68(5):176-80.

Eghbalian 2007

Eghbalian F, Poorhosain A. Effect of clofibrate in non-hemolytic indirect hyperbilirubinemia in full term neonates. The Internet Journal of Pediatrics and Neonatology 2008;8(1):No pag.

Eghbalian F, Pourhossein A, Zandevakili H. Effect of clofibrate in non-hemolytic indirect hyperbilirubinemia in full term neonates. Indian Journal of Pediatrics 2007;74(11):1003-6.

Eyvazzadeh 2011

Eyvazzadeh E. Determination of clofibrate effect in treatment of jaundice full-term neonates in neonatal ward Boali Hospital [PhD thesis]. Ardabil: Ardabil Medical University, 2011.

Fallah 2012

Fallah R, Islami Z, Lotfi SR. Single dose of 50 mg/kg clofibrate in jaundice of healthy term neonates: randomised clinical trial of efficacy and safety. Indian Journal of Pediatrics 2012;79(2):194-7.

Ghotbi 2009

Ghotbi F, Tghiloo M, Gashb A. The effect of clofibrate on neonatal jaundice. Pejouhesh 2009;33(1):31-4.

Habibi 2012

Habibi M, Mahyar A, Ayazi P, Ahmadabadi F, Javadi A. The effect of clofibrate on hyperbilirubinemia of term neonates. Acta Medica Iranica 2012;50(1):21-5.

Mohammadzadeh 2005

Mohammadzadeh A, Farhat AS, Iranpour R. Effect of clofibrate in jaundiced term newborns. Indian Journal of Pediatrics 2005;72(2):123-6.

Mohammadzadeh 2009

Mohammadzadeh A, Farhat AS, Amiri R, Esmaely H, Bagheri S. Treatment effect of clofibrate in jaundiced low birth weight neonates. International Journal of Hematology and Oncology 2009;19(2):100-5.

Moslehi 2007

Moslehi MA, Pishva N. Determination of effect of low dose vs moderate dose clofibrate on decreasing serum bilirubin in healthy term neonates. Iranian Journal of Pediatrics 2007;17(2):108-12.

Sakha 2009

Sakha SP, Gharehbaghi MM, Rahbani ME. The effect of clofibrate with phototherapy in late pre-term newborns with non-hemolytic jaundice. Indian Journal of Medical Sciences 2009;63(5):174-9.

Sharafi 2010

Sharafi R, Mortazavi Z, Sharafi S, Parashkouh RM. The effect of clofibrate on decreasing serum bilirubin in healthy term neonates under home phototherapy. Iranian Journal of Pediatrics 2010;20(1):48-52.

Zahedpasha 2007

Zahedpasha Y, Ahmadpour-Kacho M, Hajiahmadi M, Naderi S. Effect of clofibrate in jaundiced full-term infants: a randomized clinical trial. Archives of Iranian Medicine 2007;10(3):349-53.

Zahedpasha Y, Ahmadpour-Kacko M, Hajiahmadi M, Naderi S. Effect of clofibrate in jaundiced infant at term. Archives of Disease in Childhood 2008;93:305.

Zahedpasha 2008

Zahedpasha Y, Ahmadpour-Kacho M, Hajiahmadi M, Naderi S, Abbas AK. Efficacy of clofibrate on severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency (a randomized clinical trial). Southeast Asian Journal of Tropical Medicine and Public Health 2008;39(3):557-61.

Excluded studies

Bourget 1995

Bourget P, Broise I, Quinquis-Desmaris V, Gabilan JC. Pharmacokinetics of clofibrate in jaundiced newborn infants at term [Pharmacocinetique du clofibrate chez le nouveau-ne a terme icterique]. Archives de pediatrie: organe officiel de la Societe francaise de pediatrie 1995;2(8):722-8.

Flores 1996

Flores NG, Vargas PC, Lopez PM, Escobedo CE. Clofibrate in the prevention of neonatal hyperbilirubinemia [ADMINISTRACION PROFILACTICA DE CLOFIBRATO EN NEONATOS CON RIESGO DE HIPERBILIRRUBINEMIA]. Practica Pediatrica 1996;5(5):40-6.

Lindenbaum 1981

Lindenbaum A, Hernandorena X, Vial M, Benattar C, Janaud JC, Dehan M, et al. Clofibrate for the treatment of hyperbilirubinemia in neonates born at term: a double blind controlled study [Traitement curatif de l'ictere du nouveau-ne a terme par le clofibrate. Essai therapeutique controle en double aveugle]. Archives Francaises de Pediatrie 1981;38(Suppl 1):867-73.

Lindenbaum 1985

Lindenbaum A, Delaporte B, Benattar C, Dehan M, Magny JF, Gerbet D, et al. Preventive treatment of jaundice in premature newborn infants with clofibrate. Double‐blind controlled therapeutic trial [Traitement preventif de l'ictere du nouveau-ne premature par le clofibrate. Essai therapeutique controle en double aveugle]. Archives Francaises de Pediatrie 1985;42(9):759-63.

Mohammadzadeh 2008

Mohammadzadeh A, Farhat A, Jafarzadeh M, Mirzarahimi M, Esmaeli H, Amiri R. Prophylactic effect of clofibrate in low birth weight neonates' hyperbilirubinemia. Journal of Chinese Clinical Medicine 2008;3(3):140-4.

Morcos 2006

Morcos AM. Treatment of jaundice in full term newborn infants with clofibrate. Medical Journal of Cairo University 2006;74(3):253-6.

Zahedpasha 2009

Zahedpasha Y, Ahmadpour Kacho M, Lookzadeh MH, Mazloomi A. Effect of clofibrate on prolonged jaundice of term neonates. Journal of Babol University of Medical Sciences 2009;11(5):No pag.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

AAP 1994

American Academy of Pediatrics, Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94(4):558-65.

Cochrane Neonatal Review Group 2011

Cochrane Neonatal Review Group. http://neonatal.cochrane.org/. (accessed 8 August 2012).

Davey Smith 2008

Davey Smith G, Egger M. Going beyond the grand mean: subgroup analysis in meta-analysis of randomised trials. In: Systematic Reviews in Health Care. 2nd edition. London: BMJ Publishing Group, 2008:143-56.

DrugBank 2012

DrugBank. Clofibrate. http://www.drugbank.ca/drugs/DB00636. Accessed 9 August 2012).

Escobar 2005

Escobar GJ, Greene JD, Hulac P, Kincannon E, Bischoff K, Gardner MN, et al. Rehospitalisation after birth hospitalisation: patterns among infants of all gestations. Archives of Diseases in Childhood 2005;90(2):125-31.

Gartner 1994

Gartner LM. Neonatal jaundice. Pediatrics in Review 1994;15(11):422-32.

Gourley 1997

Gourley GR. Bilirubin metabolism and kernicterus. Advances in Pediatrics 1997;44:173-229.

Hammerman 1998

Hammerman C, Goldstein R, Kaplan M, Eran M, Goldschmidt D, Eidelman AI, et al. Bilirubin in the premature: toxic waste or natural defense? Clinical Chemistry 1998;44(12):2551-3.

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60.

Higgins 2011a

Higgins JPT, Deeks JJ, Altman DG (editors). Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane Handbook of Systematic Reviews of Interventions. Version 5.1.0. [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

Higgins 2011b

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

JAMA 2001

Instructions to authors. http://jama.ama-assn.org/content/vol295/issue1/images/data/103/DC6/JAMA_auinst_si.dtl.

Kutz 1984

Kutz K, Kandler H, Gugler R, Fevery J. Effect of clofibrate on the metabolism of bilirubin, bromosulphophthalein and indocyanine green and on the biliary lipid composition in Gilbert's syndrome. Clinical Science 1984;66(4):389-97.

Maisels 1992

Maisels MJ. Neonatal jaundice. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. New York: Oxford University Press, 1992:507-61.

RCOG 2010

National Institute for Health and Clinical Excellence. Neonatal jaundice, 2010. http://guidance.nice.org.uk/CG/Wave14/82. (accessed 8 August 2012).

RevMan 5.1

Review Manager (RevMan) [Computer program]. Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Tan 1982

Tan KL. The pattern of bilirubin response of phototherapy for neonatal hyperbilirubinemia. Pediatric Research 1982;16(8):670-4.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

[top]

Data and analyses

1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Mean total serum bilirubin (µmol/L) after 24 hours 10 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.1.1 Preterm (< 37 weeks' GA) 2 128 Mean Difference (IV, Fixed, 95% CI) 0.55 [-0.48, 1.58]
1.1.2 Term (37 or more weeks' GA) 8 522 Mean Difference (IV, Fixed, 95% CI) -2.14 [-2.53, -1.75]
1.2 Mean total serum bilirubin (µmol/L) after 48 hours 8 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.2.1 Preterm (< 37 weeks' GA) 2 128 Mean Difference (IV, Fixed, 95% CI) -1.37 [-2.19, -0.55]
1.2.2 Term (37 or more weeks' GA) 6 358 Mean Difference (IV, Fixed, 95% CI) -1.82 [-2.25, -1.38]
1.3 Mean duration of phototherapy (hours) 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.3.1 Preterm (< 37 weeks' GA) 2 128 Mean Difference (IV, Fixed, 95% CI) -23.82 [-30.46, -17.18]
1.3.2 Term (37 or more weeks' GA) 4 270 Mean Difference (IV, Fixed, 95% CI) -25.40 [-28.94, -21.86]
1.4 Number of exchange transfusions needed 5 261 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.07, 15.26]
1.5 Adverse effects of clofibrate 8 491 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Mean total serum bilirubin (µmol/L) after 24 hours 3 180 Mean Difference (IV, Fixed, 95% CI) -3.54 [-3.96, -3.12]
2.2 Mean total serum bilirubin (µmol/L) after 48 hours 2 120 Mean Difference (IV, Fixed, 95% CI) -3.41 [-3.91, -2.91]
2.3 Mean duration of phototherapy (hours) 2 120 Mean Difference (IV, Fixed, 95% CI) -10.85 [-12.48, -9.23]
2.4 Number of exchange transfusion needed 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.87]
2.5 Adverse effects of clofibrate 3 180 Risk Ratio (M-H, Fixed, 95% CI) 5.00 [0.25, 99.95]

3 Phototherapy + clofibrate 25 mg/kg versus phototherapy alone in term neonates

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup".

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
3.1 Mean total serum bilirubin (µmol/L) after 24 hours 1 60 Mean Difference (IV, Fixed, 95% CI) -4.70 [-5.25, -4.15]
3.2 Mean duration of phototherapy (hours) 1 60 Mean Difference (IV, Fixed, 95% CI) -11.10 [-12.73, -9.47]
3.3 Adverse effects of clofibrate 1 60 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

[top]

Figures

Figure 1 (Analysis 1.2)

Refer to figure 1 caption below.

Funnel plot of comparison: 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone, outcome: 1.2 Mean total serum bilirubin (µmol/L) after 48 hours (Figure 1 description).

Figure 2

Refer to figure 2 caption below.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study (Figure 2 description).

Sources of support

Internal sources

  • NCC-WCH, UK

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human
  • Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

Appendices

1 Ovid MEDLINE(R) (1950 to February week 1 2010) search strategy

#

Searches

Results

1

randomised controlled trial.pt.

280513

2

controlled clinical trial.pt.

80002

3

DOUBLE BLIND METHOD/

103453

4

SINGLE BLIND METHOD/

13459

5

RANDOM ALLOCATION/

66578

6

RANDOMIZED CONTROLLED TRIALS/

64306

7

or/1-6

474442

8

((single or double or triple or treble) adj5 (blind$ or mask$)).tw, sh.

101460

9

clinical trial.pt.

452866

10

exp CLINICAL TRIAL/

591222

11

exp CLINICAL TRIALS AS TOPIC/

223082

12

(clinic$ adj5 trial$).tw, sh.

145934

13

PLACEBOS/

28300

14

placebo$.tw, sh.

132216

15

random$.tw, sh.

607002

16

or/8-15

1055967

17

or/7, 16

1060637

18

META ANALYSIS/

23078

19

META ANALYSIS AS TOPIC/

9814

20

meta analysis.pt.

23078

21

(metaanaly$ or meta-analy$ or (meta adj analy$)).tw, sh.

40640

22

(systematic$ adj5 (review$ or overview$)).tw, sh.

23231

23

(methodologic$ adj5 (review$ or overview$)).tw, sh.

2221

24

or/18-23

57629

25

review$.pt.

1495163

26

(medline or medlars or embase or cinahl or cochrane or psycinfo or psychinfo or psychlit or psyclit or "web of science" or "science citation" or scisearch).tw.

36961

27

((hand or manual$) adj2 search$).tw.

3979

28

(electronic database$ or bibliographic database$ or computeri?ed database$ or online database$).tw, sh.

6466

29

(pooling or pooled or mantel haenszel).tw, sh.

32720

30

(peto or dersimonian or der simonian or fixed effect).tw, sh.

1635

31

or/26-30

71991

32

and/25, 31

32023

33

or/24, 32

75297

34

letter.pt.

668939

35

case report.tw.

146613

36

comment.pt.

400828

37

editorial.pt.

249552

38

historical article.pt.

261273

39

or/34-38

1374875

40

17 not 39

1020563

41

33 not 39

71078

42

or/40-41

1057044

43

INFANT, PREMATURE/

33473

44

preterm$.ti, ab.

31298

45

INFANT, NEWBORN/

426290

46

(newborn$ or neonate$).ti, ab.

141897

47

or/43-46

486369

48

HYPERBILIRUBINEMIA/

3433

49

HYPERBILIRUBINEMIA, NEONATAL/

255

50

hyperbilirubin?emia$.ti.

2227

51

bilirubin?emia$.ti.

147

52

((bilirubin$ or hyperbilirubin$) adj3 encephalopath$).ti, ab.

313

53

exp JAUNDICE/

10036

54

jaundice$.ti.

9666

55

KERNICTERUS/

917

56

kernicterus.ti, ab.

684

57

or/48-56

20622

58

CLOFIBRATE/

3592

59

clofibrate$.ti, ab.

2821[r2]

60

or/58-59

4318

61

and/57, 60

22

62

and/42, 61

10

2 The Cochrane Library (1st quarter 2010) search strategy

  1. Clofibrat*
  2. Atromid

3 EMBASE (1980 to 2010 week 6) search strategy

#

Searches

Results

1

CLINICAL TRIALS/

577791

2

(clinic$ adj5 trial$).ti, ab, sh.

138910

3

SINGLE BLIND PROCEDURE/

9037

4

DOUBLE BLIND PROCEDURE/

76095

5

RANDOM ALLOCATION/

27508

6

CROSSOVER PROCEDURE/

22410

7

PLACEBO/

137708

8

placebo$.ti, ab, sh.

190524

9

random$.ti, ab, sh.

469120

10

RANDOMIZED CONTROLLED TRIALS/

181145

11

((single or double or triple or treble) adj (blind$ or mask$)).ti, ab, sh.

97844

12

randomi?ed control$ trial$.tw.

38829

13

or/1-12

943711

14

META ANALYSIS/

37104

15

((meta adj analy$) or metaanalys$ or meta-analy$).ti, ab, sh.

49578

16

(systematic$ adj5 (review$ or overview$)).ti, sh, ab.

33041

17

(methodologic$ adj5 (review$ or overview$)).ti, ab, sh.

1866

18

or/14-17

70511

19

review.pt.

993257

20

(medline or medlars or embase).ab.

27767

21

(scisearch or science citation index).ab.

886

22

(psychlit or psyclit or psychinfo or psycinfo or cinahl or cochrane).ab.

11407

23

((hand or manual$) adj2 search$).tw.

3183

24

(electronic database$ or bibliographic database$ or computeri?ed database$ or online database$).tw.

5319

25

(pooling or pooled or mantel haenszel).tw.

27532

26

(peto or dersimonian or "der simonian" or fixed effect).tw.

1111

27

or/20-26

60512

28

and/19, 27

22455

29

or/18, 28

82263

30

(book or conference paper or editorial or letter or note or proceeding or short survey).pt.

1845008

31

13 not 30

809185

32

29 not 31

38239

33

or/31-32

847424

34

PREMATURITY/

31811

35

preterm$.ti, ab.

29096

36

NEWBORN/

186962

37

(newborn$ or neonate$).ti, ab.

103282

38

or/34-37

252955

39

HYPERBILIRUBINEMIA/

6367

40

NEWBORN JAUNDICE/

1918

41

hyperbilirubin?emi$.ti.

1239

42

bilirubin?emi$.ti.

18

43

(bilirubin$ or hyperbilirubin$).ti, ab.

19247

44

jaundice$.ti.

3840

45

KERNICTERUS/

788

46

kernicterus.ti, ab.

439

47

or/39-46

26053

48

CLOFIBRATE/

5241

49

clofibrate$.ti, ab.

2004

50

or/48-49

5545

51

and/47, 50

81

52

and/33, 51

19

4 CINAHL Ebsco (14 May 14 2010) search strategy

#

Query

Limiters/Expanders

Last Run Via

Results

S23

S18 and S22

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

0

S22

S19 or S20 or S21

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

18

S21

TI (atromid*) or AB (atromid*)

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

0

S20

TI (clofibrate) or AB (clofibrate)

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

14

S19

(MH "Clofibric Acid")

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

4

S18

S5 and S17

Search modes - Boolean/Phrase

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

548

S17

S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16

Search modes - Find all my search terms

Interface - EBSCOhost
Search Screen - Advanced Search
Database - CINAHL with Full Text

924

S16

(TI "kernicterus*")

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Database - CINAHL with Full Text

50

S15

MH KERNICTERUS

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Database - CINAHL with Full Text

130

S14

(TI jaundice*)

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Database - CINAHL with Full Text

358

S13

MH JAUNDICE

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Database - CINAHL with Full Text

286

S12

(AB "hyperbilirubin*" N3 "encephalopath*")

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Database - CINAHL with Full Text

4

S11

(TI "hyperbilirubin*" N3 "encephalopath*")

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Database - CINAHL with Full Text

0

S10

(AB "bilirubin*" N3 "encephalopath*")

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Database - CINAHL with Full Text

30

S9

(TI "bilirubin*" N3 "encephalopath*")

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Database - CINAHL with Full Text

10

S8

(TI "bilirubinaemia" OR "bilirubinemia")

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Database - CINAHL with Full Text

7

S7

(TI "hyperbilirubinemia" or "hyperbilirubinaemia")

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Database - CINAHL with Full Text

225

S6

MH HYPERBILIRUBINEMIA

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Database - CINAHL with Full Text

269

S5

S1 or S2 or S3 or S4

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Database - CINAHL with Full Text

52074

S4

(TI "newborn*" or "neonate*") or (AB "newborn*" or "neonate*")

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Database - CINAHL with Full Text

12020

S3

MH INFANT, NEWBORN

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Database - CINAHL with Full Text

45595

S2

(TI "preterm*") or (AB "preterm*")

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Database - CINAHL with Full Text

6817

S1

MH INFANT, PREMATURE

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Database - CINAHL with Full Text

754

5 Ovid MEDLINE(R) In-Process and other non-indexed citations (12 February 2010) search strategy

#

Searches

Results

1

(prematur$ adj3 infant$).ti, ab.

211

2

preterm$.ti, ab.

863

3

(newborn$ or neonate$).ti, ab.

2464

4

or/1-3

3223

5

hyperbilirubin?emi$.ti, ab.

96

6

bilirubin?emi$.ti, ab.

2

7

bilirubin$.ti, ab.

491

8

jaundice$.ti, ab.

491

9

kernicterus.ti, ab.

8

10

or/5-9

957

11

and/4, 10

85

12

clofibrate$.ti, ab.

19

13

"atromid-s".ti, ab.

0

14

and/11-12

0

6 Data extraction form


Study ID

Initials of person extracting data

Type of report (e.g. peer reviewed journal article, full report, brief report, letter, unpublished data)

Language of report

Full citation

Design of study (e.g. controlled trial, cross-over trial)

Site of intervention (e.g. single site, multiple sites, country)

Setting of intervention (e.g. urban, rural, mixed)

Ethics committee approval

Age of participants (e.g. mean, SD, range)

Sex of participants

Ethnicity and other demographics of participants

Baseline characteristics

Mean GA:

Mean BW:

Mean TSB:

Inclusion criteria

Exclusion criteria

Description of intervention(s) (including control condition, placebo, treatment as usual etc.)

Duration of intervention(s)

Total number of participants randomised

Unit of allocation

Power calculation or sample size estimate

Prospectively stated outcome(s)


This review is published as a Cochrane review in The Cochrane Library, Issue 12, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.