Abstract
Introduction
About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2 to 4 days after birth, and resolves spontaneously after 1 to 2 weeks. Jaundice is caused by bilirubin deposition in the skin. Most jaundice in newborn infants is a result of increased red cell breakdown and decreased bilirubin excretion.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different wavelengths of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? What are the effects of different intensities of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? What are the effects of different total doses of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? What are the effects of starting hospital phototherapy at different thresholds in term and preterm infants? We searched Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
Fourteen studies were included. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of different wavelengths, intensities, total doses, and threshold for commencement of the following intervention: hospital phototherapy.
Key Points
About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2 to 4 days after birth, and resolves spontaneously after 1 to 2 weeks.
Jaundice is caused by bilirubin deposition in the skin. Most jaundice in newborn infants is a result of increased red cell breakdown and decreased bilirubin excretion.
Breastfeeding, haemolysis, and some metabolic and genetic disorders also increase the risk of jaundice.
Unconjugated bilirubin can be neurotoxic, causing an acute or chronic encephalopathy that may result in cerebral palsy, hearing loss, and seizures.
Hospital phototherapy is provided by conventional or fibreoptic lights as a treatment to reduce neonatal jaundice.
We assessed RCTs comparing light with different wavelengths used for hospital phototherapy for unconjugated hyperbilirubinaemia in term and preterm infants. Interventions compared included: conventional phototherapy (using halogen-quartz bulbs), daylight fluorescent lamps, standard blue fluorescent lamps, blue fluorescent lamps with a narrow spectral emission, green fluorescent lamps, blue-green fluorescent lamps, blue LED lamps, and blue-green LED lamps.
Blue-green fluorescent light may be more effective than blue fluorescent light at reducing the requirement for phototherapy after 24 hours in healthy low birth weight babies with hyperbilirubinaemia in the first 4 days of life.
Hospital phototherapy using blue LED lamps may be more effective at reducing the number of hours spent under phototherapy compared with conventional phototherapy (using halogen-quartz bulbs) in term and preterm infants.
Apart from these two comparisons, we found no difference between the other wavelengths of light on the duration of phototherapy required.
We don't know whether the various wavelengths of light studied differ in their effect on rate of decline in serum bilirubin levels.
One small RCT found no significant difference in blue LED lamps compared with conventional phototherapy at reducing mortality in preterm infants requiring phototherapy.
For different intensities of light:
Close phototherapy compared with distant light-source phototherapy may reduce the duration of phototherapy and mean serum bilirubin level in infants with hyperbilirubinaemia.
Double conventional phototherapy may be more effective than single conventional phototherapy at reducing the duration of treatment and mean serum bilirubin level in term infants of birth weight 2500 g or above with haemolysis included. However, we don't know if double phototherapy reduces the need for exchange transfusion.
We don't know whether there is any additional benefit of triple phototherapy compared to double phototherapy.
We assessed RCTs comparing light with different total doses used for hospital phototherapy for unconjugated hyperbilirubinaemia in term and preterm infants. Interventions included intermittent versus continuous phototherapy and increased skin exposure versus standard skin exposure phototherapy.
We don’t know whether there is any difference in effectiveness of intermittent phototherapy versus continuous phototherapy or increased skin exposure versus standard skin exposure phototherapy at reducing duration of phototherapy treatment or at improving the rate of decrease of serum bilirubin levels.
We assessed RCTs comparing different thresholds for commencement of hospital phototherapy. This included comparing prophylactic phototherapy (commencement of phototherapy routinely according to specific criteria other than level of serum bilirubin) with threshold phototherapy (commencement of phototherapy when the serum bilirubin was above a certain predefined level).
We only found one small RCT comparing prophylactic hospital phototherapy with threshold hospital phototherapy. It is generally accepted that phototherapy should only be applied once serum bilirubin levels reach predefined thresholds.
Lower thresholds compared with higher thresholds in extremely low birth weight infants may reduce the proportion of infants with neurodevelopmental impairment, profound impairment, and severe hearing loss.
Clinical context
General background
Neonatal jaundice is a common condition in newborn babies, affecting about 50% of term and 80% of preterm babies. Phototherapy is often used to reduce levels of unconjugated bilirubin that may result in acute or chronic encephalopathy. However, exchange transfusion is still the gold standard of treatment for severe hyperbilirubinaemia.
Focus of the review
The efficacy of phototherapy in the treatment of unconjugated hyperbilirubinaemia may be influenced by the wavelength of the light used, the intensity of the light source, the total dose of light received (time under phototherapy and amount of skin exposed), and/or the threshold at which phototherapy is commenced. In this review we try to determine the most safe and effective method for the delivery of phototherapy to decrease unconjugated bilirubin levels in the neonate.
Comments on evidence
Due to a large range of treatment options, the evidence is difficult to interpret. However, it is generally accepted that intensive phototherapy applied to infants with already high serum bilirubin levels or rapidly rising serum bilirubin levels has greatly reduced the need for exchange transfusions in infants with or without haemolysis. If there is a choice of blue-green or blue wavelengths, blue-green appears to be slightly more effective than blue. Using a lower threshold for the commencement of phototherapy in extremely low birth weight (ELBW) infants may improve neurodevelopmental outcome. Overall, there is a lack of RCT evidence on effectiveness of low versus high threshold for the commencement of phototherapy in babies other than those who are ELBW infants.
Search and appraisal summary
The update literature search for this review was carried out from the date of the last search, February 2010, to January 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. After deduplication and removal of conference abstracts, 75 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 56 studies and the further review of 19 full publications. Of the 19 full articles evaluated, one systematic review and three RCTs were added at this update. One RCT was added to the Comment section.
Additional information
If treatment is required for neonatal jaundice, phototherapy is generally accepted as first-line clinical management. Exchange transfusion should be reserved for those infants with very high serum bilirubin levels or rapidly rising serum bilirubin levels that are not responding to phototherapy.
About this condition
Definition
Neonatal jaundice refers to the yellow coloration of the skin and sclera of newborn babies that results from the deposition of bilirubin. This review focuses on phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants; however, exchange transfusion is still the gold standard of treatment for severe hyperbilirubinaemia. Jaundice is usually seen first in the face, and progresses caudally to the trunk and extremities. However, visual estimation of the bilirubin levels can lead to errors, and a low threshold should exist for measuring serum bilirubin. There are devices that measure transcutaneous bilirubin, but these are generally for screening purposes.
Incidence/ Prevalence
Jaundice is the most common condition requiring medical attention in newborn babies. About 50% of term and 80% of preterm babies develop jaundice in the first week of life. Jaundice is also a common cause of re-admission to hospital after early discharge of newborn babies. Jaundice usually appears 2 to 4 days after birth and disappears 1 to 2 weeks later, usually without the need for treatment.
Aetiology/ Risk factors
Jaundice occurs when there is accumulation of bilirubin in the skin and mucous membranes. In most infants with jaundice there is no underlying disease, and the jaundice is termed physiological. Physiological jaundice typically presents on the second or third day of life and results from the increased production of bilirubin (owing to increased circulating red cell mass and a shortened red cell lifespan) and the decreased excretion of bilirubin (owing to low concentrations of the hepatocyte binding protein, low activity of glucuronosyl transferase, and increased enterohepatic circulation) that normally occur in newborn babies. Breastfed infants are more likely to develop jaundice within the first week of life; this is thought to be an exacerbated physiological jaundice caused by a lower calorific intake and increased enterohepatic circulation of bilirubin. Prolonged unconjugated jaundice, persisting beyond the second week, is also seen in breastfed infants. The mechanism for this later 'breast milk jaundice syndrome' is still not completely understood. Non-physiological causes include blood group incompatibility (rhesus or ABO problems), other causes of haemolysis, sepsis, bruising, and metabolic disorders. Gilbert's and Crigler-Najjar syndromes are rare causes of neonatal jaundice.
Prognosis
In the newborn baby, unconjugated bilirubin can penetrate the blood-brain barrier and is potentially neurotoxic. Acute bilirubin encephalopathy consists of initial lethargy and hypotonia, followed by hypertonia (retrocollis and opisthotonus), irritability, apnoea, and seizures. Kernicterus refers to the yellow staining of the deep nuclei of the brain, namely, the basal ganglia (globus pallidus); however, the term is also used to describe the chronic form of bilirubin encephalopathy, which includes symptoms such as athetoid cerebral palsy, hearing loss, failure of upward gaze, and dental enamel dysplasia. The level at which unconjugated bilirubin becomes neurotoxic is unclear, and kernicterus at autopsy has been reported in infants in the absence of markedly elevated levels of bilirubin. Reports suggest a resurgence of kernicterus in countries in which this complication had virtually disappeared. This has been attributed mainly to early discharge of newborns from hospital.
Aims of intervention
To prevent the development of bilirubin-associated neurodevelopmental sequelae; to reduce serum bilirubin levels, with minimal adverse effects.
Outcomes
Mortality; neurological/neurodevelopmental outcomes (including neurodevelopmental delay; incidence of kernicterus and other neurodevelopmental sequelae; hearing loss; blindness; neurological sequlae [e.g., cerebral palsy]); need for exchange transfusion; duration of treatment (including duration of phototherapy, need for re-treatment with phototherapy, need for phototherapy due to treatment failure); serum bilirubin levels; adverse effects (including effects on parent-infant bonding). Wherever possible, we have reported on our prespecified clinical outcomes of interest such as neurodevelopmental delay or sequelae. However, many studies did not report on clinical outcomes, but on biochemical measures such as serum bilirubin levels. Hence, we have also reported these non-clinical outcomes.
Methods
BMJ Clinical Evidence search and appraisal January 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to January 2014, Embase 1980 to January 2014, and The Cochrane Database of Systematic Reviews 2014, issue 1 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, any level of blinding, and containing at least 20 individuals (at least 10 per arm), of whom at least 80% were followed up. There was no minimum length of follow-up. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the BMJ Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table 1.
GRADE evaluation of interventions for neonatal jaundice
| Important outcomes | Mortality, neurological/neurodevelopmental, need for exchange transfusion, duration of treatment, serum bilirubin levels, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of different wavelengths of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? | |||||||||
| 1 (72) | Duration of treatment | Fluorescent v blue fluorescent | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for no statistical analysis between groups |
| 1 (72) | Serum bilirubin levels | Fluorescent v blue fluorescent | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for no statistical analysis between groups |
| 1 (262) | Duration of treatment | Blue fluorescent v green fluorescent | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for restricted population |
| 2 (356) | Serum bilirubin levels | Blue fluorescent v green fluorescent | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for subgroup analysis (no overall analysis reported) in 1 RCT; directness point deducted for restricted population |
| 1 (40) | Duration of treatment | Blue-green fluorescent v blue fluorescent | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 3 (266) | Serum bilirubin levels | Blue-green fluorescent v blue fluorescent | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results; consistency point deducted for conflicting results |
| 1 (58) | Mortality | Blue LED v conventional quartz-halogen | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and unclear randomisation/allocation concealment |
| 2 (322) | Duration of treatment | Blue LED v conventional quartz-halogen | 4 | 0 | –1 | –1 | 0 | Low | Consistency point deducted for significant heterogeneity in meta-analysis; directness point deducted for variation in interventions and protocols for phototherapy affecting generalisability of results |
| 3 (261) | Serum bilirubin levels | Blue LED v conventional quartz-halogen | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results; directness point deducted for variation in interventions and protocols for phototherapy affecting generalisability of results |
| 1 (79) | Duration of treatment | Blue-green LED v conventional quartz-halogen | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (79) | Serum bilirubin levels | Blue-green LED v conventional quartz-halogen | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of different intensities of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? | |||||||||
| 1 (774) | Duration of treatment | Close phototherapy v distant light-source phototherapy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for small number of comparators |
| 1 (151) | Serum bilirubin levels | Close phototherapy v distant light-source phototherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (42) | Need for exchange transfusion | Double phototherapy v single phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of events (2 in total) indicating weak power to demonstrate difference between groups |
| 9 (749) | Duration of treatment | Double phototherapy v single phototherapy | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for inclusion of quasi-randomised trials, and variation in inclusion criteria and outcome criteria; directness point deducted for inconsistent interventions between trials (BiliBlanket, Wallaby, conventional phototherapy) |
| 10 (809) | Serum bilirubin levels | Double phototherapy v single phototherapy | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for inclusion of quasi-randomised trials, and variation in inclusion criteria and outcome criteria; directness point deducted for inconsistent interventions between trials (BiliBlanket, Wallaby, conventional phototherapy) |
| 1 (40) | Serum bilirubin levels | Triple phototherapy v double phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of comparators |
| What are the effects of different total doses of light in hospital phototherapy as treatment for unconjugated hyperbilirubinaemia in term and preterm infants? | |||||||||
| 1 (34) | Duration of treatment | Intermittent phototherapy v continuous phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for restricted population |
| 3 (228) | Serum bilirubin levels | Intermittent phototherapy v continuous phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results; directness point deducted for small number of events in some analyses (1 and 5 in two analyses) indicating weak power to demonstrate differences between groups |
| 1 (59) | Duration of treatment | Increased skin exposure v standard skin exposure phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of comparators |
| 1 (59) | Serum bilirubin levels | Increased skin exposure v standard skin exposure phototherapy | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data; directness point deducted for small number of comparators |
| What are the effects of starting hospital phototherapy at different thresholds in term and preterm infants? | |||||||||
| 1 (83) | Neurological/neurodevelopmental | Prophylactic v threshold phototherapy | 4 | –2 | 0 | –1 | 0 | Very low | Quality point deducted for sparse data and no intention-to-treat analysis; directness point deducted for composite outcome (death and cerebral palsy) |
| 1 (unclear, <96) | Duration of treatment | Prophylactic v threshold phototherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (at least 92) | Serum bilirubin levels | Prophylactic v threshold phototherapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (1974) | Mortality | Low threshold v high threshold phototherapy | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for composite outcome |
| 1 (1854) | Neurological/neurodevelopmental | Low threshold v high threshold phototherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for no intention-to-treat analysis |
| 1 (unclear) | Need for exchange transfusion | Low threshold v high threshold phototherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (unclear) | Duration of treatment | Low threshold v high threshold phototherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (unclear) | Serum bilirubin levels | Low threshold v high threshold phototherapy | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
Type of evidence: 4 = RCT.Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Paul Woodgate, Department of Neonatology, Mater Mothers' Hospital, Brisbane, Australia.
Luke Anthony Jardine, Department of Neonatology, Mater Mothers' Hospital, Brisbane, Australia.
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