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.
Main 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. Clofibrate has been withdrawn from the market in some countries and is no longer in use in adults (the primary indication) because of safety concerns. As such, we will no longer be updating this review.
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.
Clofibrate has been withdrawn from the market in some countries and is no longer in use in adults (the primary indication) because of safety concerns. As such, we will no longer be updating this review.
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.
Editor's note: Clofibrate has been withdrawn from the market in some countries and is no longer in use in adults (the primary indication) because of safety concerns (Oliver 1984). As such, we will no longer be updating this review.
Objectives
In patients with unconjugated hyperbilirubinaemia requiring treatment:
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to determine the effects of clofibrate in combination with phototherapy versus phototherapy alone on:
bilirubin levels (specifically bilirubin levels after initiation of phototherapy);
duration of phototherapy;
frequency of exchange transfusion;
incidence of bilirubin encephalopathy and long‐term neurodevelopmental impairment associated with unconjugated hyperbilirubinaemia;
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:
preterm (less than 37 completed weeks of gestation) and term (37 weeks or more of gestation) neonates;
haemolytic versus non‐haemolytic causes of hyperbilirubinaemia;
studies that used different dosages of clofibrate;
studies that used phototherapy at serum bilirubin levels less than 255 µmol/L.
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
Mean change in bilirubin levels (mg/dL or µmol/L) over 24 hours, 48 hours, 72 hours.
Mean duration of treatment with phototherapy (hours).
Number of exchange transfusions needed.
Any adverse effects of clofibrate.
Bilirubin encephalopathy.
Neonatal mortality.
Secondary outcomes
Parental anxiety.
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
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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:
low risk (any truly random process, e.g. random number table; computer random number generator);
high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear.
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Allocation concealment (Did the study conceal the allocation adequately?) For each included study, we categorised the method used to conceal the allocation sequence as:
low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk (open random allocation; unsealed or non‐opaque envelopes, alternation, date of birth);
unclear.
Performance bias
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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:
low risk, high risk or unclear for participants;
low risk, high risk or unclear for personnel;
low risk, high risk or unclear for outcome assessors.
Attrition bias
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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:
low risk (less than 20% missing data);
high risk (20% or more missing data);
unclear risk.
Selective reporting bias
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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:
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);
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);
unclear risk.
Other sources of bias
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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:
yes;
no;
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).
1.
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.
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:
preterm (less than 37 completed weeks of gestation) and term (37 weeks or more of gestation) neonates;
studies that used different dosages (100 mg/kg and greater versus less than 100 mg/kg);
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.
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.
2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
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
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
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
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 tunityhis 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%).
1.1. Analysis.
Comparison 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates, Outcome 1 Mean total serum bilirubin (mg/dL) after 24 hours.
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%).
1.2. Analysis.
Comparison 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates, Outcome 2 Mean total serum bilirubin (mg/dL) after 48 hours.
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%).
1.3. Analysis.
Comparison 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates, Outcome 3 Mean duration of phototherapy (hours).
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%).
2.1. Analysis.
Comparison 2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates, Outcome 1 Mean total serum bilirubin (mg/dL) after 24 hours.
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%).
2.2. Analysis.
Comparison 2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates, Outcome 2 Mean total serum bilirubin (mg/dL) after 48 hours.
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%).
2.3. Analysis.
Comparison 2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates, Outcome 3 Mean duration of phototherapy (hours).
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.
3.1. Analysis.
Comparison 3 Phototherapy + clofibrate 25 mg/kg versus phototherapy alone in term neonates, Outcome 1 Mean total serum bilirubin (mg/dL) after 24 hours.
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.
3.2. Analysis.
Comparison 3 Phototherapy + clofibrate 25 mg/kg versus phototherapy alone in term neonates, Outcome 2 Mean duration of phototherapy (hours).
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.
What's new
| Date | Event | Description |
|---|---|---|
| 10 January 2019 | Review declared as stable | Clofibrate has been withdrawn from the market in some countries and is no longer in use in adults (the primary indication) because of safety concerns. As such, we will no longer be updating this review. |
History
Protocol first published: Issue 3, 2011 Review first published: Issue 12, 2012
| Date | Event | Description |
|---|---|---|
| 25 October 2018 | Amended | Units for serum bilirubin levels in "Data and analyses" corrected (should be mg/dL and NOT micromol/L as originally labelled). |
Notes
Clofibrate has been withdrawn from the market in some countries and is no longer in use in adults (the primary indication) because of safety concerns (Oliver 1984). As such, we will no longer be updating this review.
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.
Appendices
Appendix 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 |
Appendix 2. The Cochrane Library (1st quarter 2010) search strategy
| Clofibrat* |
| Atromid |
Appendix 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 |
Appendix 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*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 50 |
| S15 | MH KERNICTERUS | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 130 |
| S14 | (TI jaundice*) | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 358 |
| S13 | MH JAUNDICE | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 286 |
| S12 | (AB "hyperbilirubin*" N3 "encephalopath*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 4 |
| S11 | (TI "hyperbilirubin*" N3 "encephalopath*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 0 |
| S10 | (AB "bilirubin*" N3 "encephalopath*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 30 |
| S9 | (TI "bilirubin*" N3 "encephalopath*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 10 |
| S8 | (TI "bilirubinaemia" OR "bilirubinemia") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 7 |
| S7 | (TI "hyperbilirubinemia" or "hyperbilirubinaemia") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 225 |
| S6 | MH HYPERBILIRUBINEMIA | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 269 |
| S5 | S1 or S2 or S3 or S4 | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 52074 |
| S4 | (TI "newborn*" or "neonate*") or (AB "newborn*" or "neonate*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 12020 |
| S3 | MH INFANT, NEWBORN | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 45595 |
| S2 | (TI "preterm*") or (AB "preterm*") | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 6817 |
| S1 | MH INFANT, PREMATURE | Search modes ‐ Find all my search terms | Interface ‐ EBSCOhost Search Screen ‐ Advanced Search Database ‐ CINAHL with Full Text | 754 |
Appendix 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 |
Appendix 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) | |
Data and analyses
Comparison 1. Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Mean total serum bilirubin (mg/dL) after 24 hours | 10 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1 Preterm (< 37 weeks' GA) | 2 | 128 | Mean Difference (IV, Fixed, 95% CI) | 0.55 [‐0.48, 1.58] |
| 1.2 Term (37 or more weeks' GA) | 8 | 522 | Mean Difference (IV, Fixed, 95% CI) | ‐2.14 [‐2.53, ‐1.75] |
| 2 Mean total serum bilirubin (mg/dL) after 48 hours | 8 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 Preterm (< 37 weeks' GA) | 2 | 128 | Mean Difference (IV, Fixed, 95% CI) | ‐1.37 [‐2.19, ‐0.55] |
| 2.2 Term (37 or more weeks' GA) | 6 | 358 | Mean Difference (IV, Fixed, 95% CI) | ‐1.82 [‐2.25, ‐1.38] |
| 3 Mean duration of phototherapy (hours) | 6 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 Preterm (< 37 weeks' GA) | 2 | 128 | Mean Difference (IV, Fixed, 95% CI) | ‐23.82 [‐30.46, ‐17.18] |
| 3.2 Term (37 or more weeks' GA) | 4 | 270 | Mean Difference (IV, Fixed, 95% CI) | ‐25.40 [‐28.94, ‐21.86] |
| 4 Number of exchange transfusions needed | 5 | 261 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.07, 15.26] |
| 5 Adverse effects of clofibrate | 8 | 491 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
1.4. Analysis.
Comparison 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates, Outcome 4 Number of exchange transfusions needed.
1.5. Analysis.
Comparison 1 Phototherapy + clofibrate 100 mg/kg versus phototherapy alone in preterm and term neonates, Outcome 5 Adverse effects of clofibrate.
Comparison 2. Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Mean total serum bilirubin (mg/dL) after 24 hours | 3 | 180 | Mean Difference (IV, Fixed, 95% CI) | ‐3.54 [‐3.96, ‐3.12] |
| 2 Mean total serum bilirubin (mg/dL) after 48 hours | 2 | 120 | Mean Difference (IV, Fixed, 95% CI) | ‐3.41 [‐3.91, ‐2.91] |
| 3 Mean duration of phototherapy (hours) | 2 | 120 | Mean Difference (IV, Fixed, 95% CI) | ‐10.85 [‐12.48, ‐9.23] |
| 4 Number of exchange transfusion needed | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.87] |
| 5 Adverse effects of clofibrate | 3 | 180 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.0 [0.25, 99.95] |
2.4. Analysis.
Comparison 2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates, Outcome 4 Number of exchange transfusion needed.
2.5. Analysis.
Comparison 2 Phototherapy + clofibrate 50 mg/kg versus phototherapy alone in term neonates, Outcome 5 Adverse effects of clofibrate.
Comparison 3. Phototherapy + clofibrate 25 mg/kg versus phototherapy alone in term neonates.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Mean total serum bilirubin (mg/dL) after 24 hours | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐4.7 [‐5.25, ‐4.15] |
| 2 Mean duration of phototherapy (hours) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐11.10 [‐12.73, ‐9.47] |
| 3 Adverse effects of clofibrate | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
3.3. Analysis.
Comparison 3 Phototherapy + clofibrate 25 mg/kg versus phototherapy alone in term neonates, Outcome 3 Adverse effects of clofibrate.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
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 | ||
| 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) All outcomes | Unclear risk | Not clear on outcomes |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No statement on blinding |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | No drop‐outs reported |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | "Patients and physicians allocated to the intervention group we aware of the allocation" |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | No drop‐outs reported |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | 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) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | 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) All outcomes | 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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 ≥ 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | 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: ≥ 2500 g Born from an uncomplicated pregnancy TSB: ≥15 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 | ||
| 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) All outcomes | Low risk | All participants accounted for |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not reported |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | Not reported |
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 [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Bourget 1995 | No placebo‐control group |
| Flores 1996 | Study examining the use of clofibrate to prevent hyperbilirubinaemia |
| Lindenbaum 1981 | Study examining the use of clofibrate to prevent hyperbilirubinaemia |
| Lindenbaum 1985 | Study examining the use of clofibrate to prevent hyperbilirubinaemia |
| Mohammadzadeh 2008 | Study examining the use of clofibrate to prevent hyperbilirubinaemia |
| Morcos 2006 | Case control study |
| Zahedpasha 2009 | Study includes children with prolonged jaundice (Jaundice > 14 days of age) only |
Characteristics of studies awaiting assessment [ordered by study ID]
Kumar 2017.
| Methods | This randomized controlled trial was done in the level III neonatal intensive care unit (NICU) of a tertiary care hospital. Ninety term neonates with unconjugated hyperbilirubinemia with serum bilirubin 15‐25 mg/dl were randomized to either intervention group (single dose of clofibrate in a dose of 50 mg/kg prior to starting phototherapy) or standard care group (only phototherapy). Primary outcome was absolute fall in bilirubin by 48 h. Secondary outcomes were duration of phototherapy, absolute fall in bilirubin levels at 12, 24, 36, 48 h, need for exchange transfusion and incidence of side‐effects. |
| Participants | |
| Interventions | |
| Outcomes | After 48 h of intervention, significantly lower bilirubin levels were noted in the intervention group compared to standard care group with a mean difference of 7 mg/dl (95% CI 6.7 mg/dl to 7.2 mg/dl). Duration of phototherapy required was less in the intervention group compared to standard care group with mean difference of 23.82 h (95% CI 30.46 h to 17.18 h). Exchange transfusion was needed for 4 neonates in the standard care group and none in the intervention group. No side‐effects were noted with clofibrate. |
| Notes |
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.
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.
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
-
National Institute for Health Research, UK.
Editorial support for Cochrane Neonatal has been funded with funds from a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health.
Declarations of interest
MG: none known.
HM and RL: were members of NCC‐WCH technical team responsible for NICE Neonatal Jaundice guideline.
Stable (no update expected for reasons given in 'What's new')
References
References to studies included in this review
Alipour 2011 {published data only}
- 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. [Google Scholar]
Badeli 2008 {published data only}
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Caballero‐Noguéz 2001 {published data only}
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Eghbalian 2007 {published data only}
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Eyvazzadeh 2011 {published data only}
- 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. [Google Scholar]
Fallah 2012 {published data only}
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