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Cochrane Database of Systematic Reviews Protocol - Intervention

Intermittent phototherapy versus continuous phototherapy for neonatal jaundice

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effect of intermittent phototherapy compared with continuous phototherapy on the incidence of kernicterus and treatment failure in neonates with hyperbilirubinemia.

Background

Description of the condition

Jaundice is the yellow discolouration of the skin caused by the presence of bilirubin in the soft tissues and can result from high levels of conjugated or unconjugated bilirubin.  About 97% of full term and preterm neonates demonstrate a biochemical hyperbilirubinaemia (serum bilirubin level > 1 mg/dl) and about 65% appear clinically jaundiced (serum bilirubin > 5 mg/dl) (Maisels 1986; Keren 2008). Physiological jaundice results from a high level of circulating unconjugated bilirubin due to accelerated red cell break‐down, reduced liver bilirubin handling capacity and increased enterohepatic circulation (Horn 2006). Pathologic jaundice results from conditions such as haemolytic disease of the newborn, sepsis, and inborn errors of metabolism (Maisels 2005). Supplementary feeding, percentage weight loss, ABO incompatibility and vacuum extraction significantly increase the risk of jaundice (Bertini 2001).

Untreated indirect hyperbilirubinaemia may result in kernicterus. In the acute phase, the signs of kernicterus are poor feeding, lethargy, high‐pitched cry, hypertonia or hypotonia, opisthotonos and seizures. The chronic manifestations of kernicterus include athetoid cerebral palsy, motor delay, gaze palsy, dental dysplasia, mental retardation and sensorineural hearing loss. When neurological signs are evident in the infant, permanent damage has already occurred, leading to death or long‐ term disability (AAP 2004).

Description of the intervention

In 1985, the National Institute of Child Health and Human Development (NICHHD) reported that phototherapy was as effective as exchange transfusion in preventing neurological sequelae (NICHHD 1985). Since then, phototherapy has been widely adopted as the initial therapy of choice for neonatal jaundice (Knudsen 1991; Eberhard 1994). Phototherapy converts the bilirubin through structural photoisomerization and photo‐oxidation into excretable products. This molecular conversion occurs when bilirubin accumulating in the skin is exposed to light of wave‐lengths 425 ‐ 475 nm (blue‐green spectrum).The effectiveness of phototherapy is related to the area of skin exposed, the radiant energy, the sources and wave‐length of the light (Tan 1982; Thaithumyanon 2002), and the cause and severity of jaundice (Maisels 2008). The guidelines or protocols used to determine the need for phototherapy may vary from one study to the other. Lewis et al showed that early institution of phototherapy produced a more rapid decline in serum bilirubin levels compared to delayed phototherapy (Lewis 1982).

Side effects of phototherapy include temperature instability manifesting as either hyperthermia or hypothermia, dehydration (Oh 1972), gastrointestinal hypermotility, diarrhoea, drowsiness, and exanthemata (Knudsen 1991). Phototherapy has been linked to persistent ductus arteriosus (Clyman 1978; Rosenfeld 1986; Travadi 2006) and to increased incidence of atypical melanocytic naevi (Csoma 2007; Bauer 2004).

Continuous phototherapy involves maintaining the jaundiced neonate under phototherapy virtually all the time with only minimal interruptions (e.g. during feeding or cleaning) so as to maximize the time spent under radiant energy and hopefully minimize the duration of phototherapy and hospital stay. Intermittent phototherapy involves regular cessation of phototherapy at specific times and for specific duration to reduce exposure to radiant energy and allow ample time for parental‐infant interaction. There is no optimal time schedule for intermittent phototherapy defined in the literature and, therefore, different studies have looked at various time intervals for their effectiveness at lowering serum bilirubin while allowing ample time for parental‐infant interaction. A study by Vogl et al looked at three different intermittent schedules: fifteen minutes on and 15 minutes off phototherapy; 15 minutes on and 30 minutes off phototherapy; 15 minutes on and 60 minutes off phototherapy (Vogl 1978). A study by Hodgman looked at 12 hours on and 12 hours off phototherapy (Hodgman 1976). Jahrig et al also considered 12 hours on and 12 hours off phototherapy (Jahrig 1982).

The advantages and disadvantages of intermittent and continuous phototherapy remain controversial. Rubaltelli et al showed that continuous phototherapy was more effective than intermittent therapy in newborns greater than three days of age (Rubaltelli 1978). Rudenko and Kalinicheva showed that continuous phototherapy had the highest efficacy in prematures that was enhanced with the addition of alpha‐tocopherol acetate (Rudenko 1990). The study by Hodgman comparing intermittent versus continuous therapy showed that continuous phototherapy was more effective but was associated with higher metabolic demands (Hodgman 1976).

Other studies have supported the use of various schedules of intermittent phototherapy. Vogl et al showed that intermittent phototherapy was as effective as continuous phototherapy (Vogl 1978). Wu et al demonstrated that the subsequent catch‐up growth, after initial weight loss, was better in the intermittent compared to the continuous therapy group (Wu Py 1974). Roll observed that there was a marked reduction in the total light energy required to decrease serum bilirubin by a certain concentration. The ''dark periods'' of the intermittent therapy would allow for evaluation of the neonates’ skin colour, reduce stray light exposure to staff or parents, and facilitate feeding and parent‐child bonding. Increased apoptosis and necrosis was noted with longer exposure periods and was possibly due to increased photo‐oxidation and cell damage (Roll 2005).

Komar‐Szymborska et al showed that  the effectiveness of phototherapy depended on the initial bilirubinaemia and was similar in both continuous and intermittent groups (Komar‐Szymborska 1994). Intermittent therapy is convenient and best suited for home phototherapy in infants with no major risk factors (CIGNA 2008). Lau and Fung in their study noted that the chief advantage of intermittent treatment is the reduction of total irradiance. It was also simple and economically attractive for developing countries where the need is great and the resources are scarce (Lau 1984).

Why it is important to do this review

There is no consensus on whether intermittent phototherapy or continuous phototherapy is the preferred method of treatment. Intermittent therapy would be simple, economical, facilitate adequate feeding and bonding, home therapy, and have minimal adverse effects (Lau 1984; Roll 2005). Therefore, the aim of this review is to systematically assess the available evidence from randomized and quasi‐randomized controlled trials for the effect of intermittent phototherapy compared to continuous phototherapy in reducing the incidence of kernicterus and treatment failure.

Objectives

To assess the effect of intermittent phototherapy compared with continuous phototherapy on the incidence of kernicterus and treatment failure in neonates with hyperbilirubinemia.

Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi‐randomized controlled trials.

Types of participants

Infants (both term and preterm) up to the age of 30 days with jaundice or hyperbilirubinaemia assessed clinically by the primary physician as severe enough to require phototherapy.

Types of interventions

Intermittent phototherapy compared with continuous phototherapy by any method and at any dose and duration as defined by the authors.

Types of outcome measures

Primary outcomes

  • Kernicterus defined as either the pathological finding of deep‐yellow staining of neurons and neuronal necrosis of the basal ganglia and brainstem nuclei or acute or chronic neurological deficit including athetoid cerebral palsy, impaired upward gaze and deafness, isolated conditions like auditory neuropathy or dyssynchrony and subtle bilirubin‐induced neurological dysfunction.

  •  Rate of decline of serum bilirubin (mcmol/l/h).

Secondary outcomes

  • Treatment failure i.e. the need to restart phototherapy or exchange transfusion or both

  • Number of infants receiving an exchange transfusion

  • Infant growth parameters e.g. weight gain (g/kg/day) and/or length (cm/day)

  •  Length of hospital stay (days) during treatment for hyperbilirubinaemia

  • Infant feeding (defined as volume of feeds per day while receiving phototherapy) 

  • Infant mortality ‐ as a result of complications of hyperbilirubinaemia

  • Total duration of phototherapy ‐ total number of hours of phototherapy delivered

  • Duration of first episode of phototherapy (hours)

  • Parental satisfaction with care ‐ qualitative assessment of parental perception of effect of phototherapy

  • Medical staff satisfaction with care ‐ qualitative assessment of the perception of the medical staff on the effect of phototherapy

Side effects

  • Dehydration (as defined by the authors)     

  • Gastrointestinal motility (defined as number of stools passed per day)

  • Incidence of patent ductus arteriosus

  • Incidence of thrombocytopenia (defined as platelet count < 100,000)

  • Retinal damage

  • Melanocytic naevi

  • Temperature instability‐ hypothermia/ hyperthermia

  • Body rash

  • Drowsiness

  • Bronze discolouration of the skin

  • Interference with maternal‐infant interaction

Search methods for identification of studies

See: Cochrane Neonatal Group methods used in reviews

The standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library will be used. The following sources will be searched for eligible reports in any language:

Electronic searches

Electronic databases to be searched will include:

  • The Cochrane Central Register of Controlled Trials (CENTRAL).

  • MEDLINE (1966 to the present)

  • EMBASE(1980 to the present)

  • CINAHL (1982 to the present).

The search string for searching CENTRAL, and MEDLINE via PubMed, will include the following terms: Jaundice OR Hyperbilirubinemia OR Hyperbilirubinaemia OR Bilirubin encephalopathy OR Kernicterus OR High serum bilirubin AND Neonate OR Neonatal OR Baby OR Babies OR Child OR Infant OR Infants OR Neonates AND Phototherapy OR Phototherapeutic OR Phototherapeutics OR Light therapy OR Phototherapies.

A similar search string will be used for searching EMBASE and CINAHL via Ovid. The search terms will be adapted to the structured vocabulary, syntax, and limits required for these databases.

Searching other resources

Abstracts presented in the past years at the annual meetings of the European Society for Paediatric Research and The Society for Pediatric Research will be searched from the journal Pediatric Research and Abstracts On Line.

On‐going trials will be searched at the WHO clinical trials registry platform, and specifically at the following websites:http://www.clinicaltrials.gov and http://www.controlled‐trials.com.

Hand searches of the reference lists of all pertinent reviews and studies found will be done.

Where possible authors of identified trials will be contacted to find out if they are aware of other published or unpublished trials.

Data collection and analysis

Selection of studies

The lead review author will perform the search for trials with the assistance of the Cochrane Neonatal Review Group. Two review authors will independently screen the titles and abstracts obtained from the electronic searches to create a pool of eligible studies. The lead review author will obtain the full articles of the latter, which both review authors will then independently scrutinize for relevance using a standardized eligibility form with predefined inclusion criteria. The criteria for relevance will be based on the study design, participants, interventions and outcomes. Possible duplicate publications will be assessed by comparing author names, location and setting, specific details of the intervention, numbers of participants and their baseline data, date and duration of the study. We will attempt to obtain data sets that are as complete as possible.

Data extraction and management

For included studies, data will be extracted concerning study identity (title, authors, reference), design, methodology, eligibility, quality, clinical features of the population, interventions and outcomes, and treatment effects, using specially designed data collection forms. For studies that were initially considered eligible for inclusion, but which were excluded after reading the full report, the reason for exclusion will be documented.

All data will be extracted independently by two review authors, compared, and any discrepancies resolved by discussion or, if necessary, through contact with the primary investigators. Unresolved disagreements will be referred for arbitration by the third review author or mentor. We will request from the primary investigators any unreported data on study outcomes, if necessary. To the extent possible, outcome data will be extracted on all patients randomised.

Assessment of risk of bias in included studies

The risk of bias for each included trial will be assessed independently by two review authors using the Cochrane ''Risk of Bias'' tool, with any disagreement(s) resolved by discussion.

The risk of bias will be assessed based on the following:

  • Sequence generation

  • Allocation concealment

  • Blinding of participants, personnel and outcome assessors

  • Incomplete outcome data

  • Selective outcome reporting

  • Other potential sources of bias e.g. sources of funding

The judgement for each entry will involve answering a question, with answers 'Yes' for low risk of bias, 'No' for high risk of bias, and 'Unclear' for either lack of information or uncertainty over the potential for bias.

Measures of treatment effect

Data analysis will be done using the RevMan 5. If it is possible to conduct a meta‐analysis of identified trials, the effect measures for binary outcomes will be the relative risk (RR), and absolute risk difference (RD), each with 95% confidence interval (CI). For the primary outcome(s), number needed to treat (NNT), or number needed to harm (NNH), will be calculated. For continuous outcomes, the effect measures will be the weighted mean difference (WMD) or, if the scale of measurement differs across trials, the standardised mean difference (SMD), each with 95% CI.

Assessment of heterogeneity

If it is possible to conduct a meta‐analysis, the amount of heterogeneity of treatment effect across trials will be estimated using the I2 statistic and the chi‐squared statistic. If substantial heterogeneity is present, its source(s) will be explored, considering differences in design or clinical features of the trials.

Subgroup analysis and investigation of heterogeneity

Analyses will be performed among subgroups to determine if responses differ according to the following:

  • Gestational age: term ( ≥ 37 weeks) vs. preterm (< 37 weeks)

  • Aetiology of the jaundice (haemolytic vs. no identified hemolysis)

  • Radiant energy, as defined by the authors

  • Various regimens of intermittent phototherapy

  • Trial validity (industry funded vs. non‐industry funded trials)

Sensitivity analysis

The effect of risk of bias on the meta‐analysis and on studies with high risk of bias, will be examined by performing a sensitivity analysis. The aim will be to estimate how outcomes change according to small variations in the data and methods.