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Cochrane Database of Systematic Reviews Protocol - Intervention

Periodic change of body position under phototherapy in term and late preterm neonates with hyperbilirubinemia

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Abstract

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

To evaluate the effects of periodic change of body position during phototherapy as compared to no prescribed change in body position, in decreasing serum total bilirubin level and duration of treatment in neonates with unconjugated hyperbilirubinemia during the first 28 days of life.

The secondary objectives of the review include evaluation of the efficacy of periodic change of body position in hemolytic versus non‐hemolytic jaundice and in term versus preterm neonates.

Background

Description of the condition

Hyperbilirubinemia is a term commonly used to describe elevated levels of bilirubin in the blood. Nearly 97% of full term and preterm babies demonstrate biochemical hyperbilirubinemia (defined as serum bilirubin level > 1 mg/dl) and more than two‐thirds appear clinically jaundiced (serum bilirubin > 5mg/dl) (Maisels 1986). In the majority of cases, hyperbilirubinemia is physiological due to increased breakdown of red blood cells, decreased uptake and metabolism of bilirubin in the liver and increased enterohepatic circulation. However, the presence of conditions like blood group incompatibility, glucose‐6‐phosphate dehydrogenase enzyme deficiency, the presence of extravasated blood, and suboptimal feeding can cause an excessive rise of bilirubin (Wells 2013). Bilirubin is a potential neurotoxin and severe hyperbilirubinemia can result in neurological damage (Bhutani 2013; Cashore 1990).

The acute phase of bilirubin‐induced neurological damage (BIND) manifests clinically with poor feeding, lethargy, a high‐pitched cry, hypertonia or hypotonia, opisthotonos and seizures. The chronic manifestations include athetoid cerebral palsy, motor delay, gaze palsy, dental dysplasia, mental retardation and sensorineural hearing loss. Prematurity, lower postnatal age, ongoing hemolysis, hypo‐albuminemia and other co‐morbidities like asphyxia and sepsis increase the risk of BIND. Therefore, threshold bilirubin levels for initiating treatment for hyperbilirubinemia are based on gestation at birth, postnatal age and the presence of risk factors (AAP 2004).

Description of the intervention

Phototherapy is the standard method for treating neonatal hyperbilirubinemia (Maisels 2008; Polin 1990). Phototherapy is provided by placing the light source over the baby bassinet. Bilirubin present in the skin, subcutaneous tissue and peripheral capillaries absorbs light energy emitted by the phototherapy unit and, as a result of different photochemical reactions, is converted into more easily excretable photo‐isomers. If phototherapy fails to reduce bilirubin concentration below neurotoxic levels, exchange transfusion is performed. However, exchange transfusion is associated with risk of death (nearly 2%) or severe complications (12%) (Jackson 1997).

Various strategies employed to improve the efficacy of phototherapy include: using a high‐intensity light source, decreasing the distance between the baby and the light source, using double surface phototherapy (application of another panel angulated to the first panel) and increasing the surface area of skin exposed to phototherapy (Pratesi 1989; Vreman 2004). The posture of the baby under phototherapy is usually governed by nursing preferences and the hospital policy to decrease the risk of sudden infant death syndrome (SIDS) (Jeffery 1999). As a result, neonates are most likely to be nursed in a supine posture under phototherapy. Parts of the skin under phototherapy are in a state of continuous equilibrium with the actual 'bilirubin pool' of body in such a way that the bilirubin photo‐isomers (formed after phototherapy) are constantly being removed from the skin and added to the circulation pool and fresh unconjugated bilirubin circulating in the blood pool is being added to the skin (both along their respective concentration gradients). However, it can be hypothesized that periodically changing the body position from supine to prone or lateral positions may improve the efficiency of phototherapy by hastening the access of phototherapy light to bilirubin deposited in different parts of the skin and subcutaneous tissue.

How the intervention might work

The principal site of action of phototherapy is the outermost 2 mm of the skin (Vogl 1974). First, bilirubin in the skin is converted to its photo‐isomers, a process that occurs in nanoseconds (Cremer 1958). Bilirubin degradation includes configurational isomerization which is a very rapid process that changes bilirubin isomers to water‐soluble isomers; however this isomerization is not significantly influenced by light intensity (Dennery 2001; Maisels 2008). On the other hand, structural isomerization, which consists of intramolecular cyclization resulting in the formation of lumirubin, is enhanced by increasing the intensity of light. The second step is migration of these photo‐isomers into the circulation and, simultaneously, the reverse migration of non‐isomerized serum bilirubin into the skin (Cremer 1958; Maisels 2001). This second step is considered rate‐limiting and the time required is estimated at between one and three hours (Lau 1984; Vogl 1974). Assuming that this migration occurs only through skin‐blood‐skin bilirubin transfer and there is no lateral diffusion of bilirubin from unexposed skin to the adjacent exposed skin, phototherapy becomes less effective once the exposed skin is blanched. Hence, turning the infant over from the blanched side to the bilirubin‐loaded side (the side not receiving phototherapy) seems to be logical therapeutic maneuver for increasing the rate of bilirubin degradation and thereby improving efficacy of phototherapy (Lau 1984; Vogl 1978).

Why it is important to do this review

American Academy of Pediatrics (AAP) Subcommittee on Hyperbilirubinemia guidelines (AAP 2004) and the National Institute for Health and Clinical Excellence (NICE) guidelines on neonatal jaundice (NICE 2010) have not published any recommendation for or against changing the infant's position under phototherapy (AAP 2004; Rennie 2010). The NICE guidelines recommend supine positioning and the AAP guidelines do not recommend any specific position for infants. In view of conflicting evidence from studies and uncertain clinical practice regarding the optimal position of infants under phototherapy, the search for the optimal position during phototherapy remains an important research priority. Authors of a recent systematic review (Lee Wan Fei 2014) on the effect of turning versus supine position for neonates under phototherapy suggested that keeping the jaundiced newborns in the supine position throughout phototherapy is as effective as turning them. However, this systematic review excluded studies not available in the English language and studies with position changes more frequent than two‐ to three‐hourly (Yamuchi 1989). Any recommendation on change in body position during phototherapy also needs to consider a possible association with the risk of SIDS (Hunt 2003; Mitchell 1999).

Objectives

To evaluate the effects of periodic change of body position during phototherapy as compared to no prescribed change in body position, in decreasing serum total bilirubin level and duration of treatment in neonates with unconjugated hyperbilirubinemia during the first 28 days of life.

The secondary objectives of the review include evaluation of the efficacy of periodic change of body position in hemolytic versus non‐hemolytic jaundice and in term versus preterm neonates.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized and quasi‐randomized controlled trials. No language restrictions will be used. Trials reported in abstract form will be eligible for inclusion if methods are reported in enough detail to enable assessment of the study for inclusion and risk of bias.

Types of participants

Neonates (term and preterm) of either gender with unconjugated hyperbilirubinemia (irrespective of etiology and defined as hyperbilirubinemia with direct‐reacting component less than 2 mg/dl or less than 15% of serum total bilirubin) within the first 28 days of life.

Types of interventions

We will include studies comparing periodic change in body position of the infant under phototherapy with no prescribed change in body position. The infant’s position may include supine, prone or lateral body posture with the intervention prescribing periodic change in position. Periodicity for change in position may be based on time (every 30 minutes to 6 hours), handling of baby (e.g. after each breastfeeding session) or nursing shift (e.g. once during a shift).

Types of outcome measures

To be included, studies must use outcome measures identified a priori to evaluate the efficacy of phototherapy.

Primary outcomes

  • Duration of phototherapy (hours)

  • Rate of fall of serum bilirubin (mg/dL/hour)

Secondary outcomes

  • Need for exchange transfusion (proportion)

  • Number of exchange transfusions (mean number)

  • Incidence of bilirubin‐induced neurological damage (BIND) (proportion). BIND or subtle encephalopathy shall be defined as neurological, cognitive, learning, movement disorders, isolated hearing loss or auditory dysfunction in the presence of hyperbilirubinemia (Bergman 1985; Hyman 1969; Johnson 1974; Rubin 1979; Scheldt 1977)

  • Phototherapy side effects including skin rash

  • Kernicterus (Dennery 2001; Gkoltsiou 2008; Shapiro 2005)

  • Sudden infant death syndrome (SIDS) (proportion): SIDS will be defined as "the sudden death of an infant under one year of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history" (Willinger 1991).

Search methods for identification of studies

We will use the standard search strategy of the Cochrane Neonatal Review Group, as outlined in the Cochrane Library.

Electronic searches

  • Cochrane Central Register of Controlled Trials (CENTRAL)

  • MEDLINE and EMBASE electronic searches using the Cochrane Highly Sensitive Search Strategy for identifying randomized trials: sensitivity‐ and precision‐maximizing version (2008 revision); with Limits: Human, age < 1 month combined with jaundice, neonatal, phototherapy, body position, posture as text words using Boolean operators AND or OR with no language restrictions

  • We will search for any ongoing or recently completed and unpublished trials using www.who.int/ictrp, clinicaltrials.gov and the Australian/New Zealand Database of Clinical Trials up to and including 2014.

Searching other resources

  • Reference lists from relevant studies and review articles

  • Personal communication with primary authors of relevant studies to retrieve unpublished data related to published articles

  • Proceedings of annual meetings of The European Society for Pediatric Research and The Society for Pediatric Research and Pediatric Academic Societies Annual Meeting. Available at Abstracts2view from year 2000 onwards; up to and including 2014

  • Proceedings of the Perinatal Society of Australia and New Zealand (PSANZ)

Data collection and analysis

We will use the standard methods of the Cochrane Collaboration and the Cochrane Neonatal Review Group.

Selection of studies

All three authors will independently identify the studies to be included.

Data extraction and management

Two review authors (AT and DC) will independently extract data using a pre‐tested data extraction form. Differences will be resolved after discussion between all three authors.

Assessment of risk of bias in included studies

We will use the standard methods of the Cochrane Neonatal Review Group. AT and DC will independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving the remaining review authors.

The risk of bias of the studies will be assessed using the following criteria:

1. Sequence generation (checking for possible selection bias): For each included study, we will categorize the method used to generate the allocation sequence as:

a) low risk (any truly random process e.g. random number table; computer random number generator);

b) high risk (any non‐random process e.g. odd or even date of birth; hospital or clinic record number);

c) unclear risk.

2. Allocation concealment (checking for possible selection bias): For each included study, we will categorize the method used to conceal the allocation sequence as:

a) low risk (e.g. telephone or central randomization; consecutively‐numbered sealed opaque envelopes);

b) high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

c) unclear risk.

3. Blinding (checking for possible performance bias): It is not feasible to blind health professionals providing care during phototherapy; therefore we will not subject participant and caregiver blinding to sensitivity analysis. We will compare the results with or without trials by addressing adequate randomization, adequate concealed allocation, outcome assessor blinding, standard management and co‐interventions applied equally across groups, and loss to follow up of less than 20% with an intention‐to‐treat analysis. Blinding will be assessed separately for different outcomes or classes of outcomes. We will categorize the methods as:

a) low risk, high risk or unclear risk for outcome assessors.

4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations): For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re‐include missing data in the analyses. We will categorize the methods as:

a) low risk (< 20% missing data);

b) high risk (≥ 20% missing data);

c) unclear risk.

5. Selective reporting bias, assessed by:

a) Comparison of the outcomes reported in the published report and in protocol, if the latter is available in the public domain (clinical trial registries).

b) Comparison of outcomes listed in the methods section of the included study with those whose results are reported.

For each included study, we will describe how we investigated the possibility of selective outcome reporting bias and what we found. We will assess the methods as:

a) low risk (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

b) high risk (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

c) unclear risk.

6. Other sources of bias: For each included study, we will describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data‐dependent process and/or interim analyses issues). We will assess whether each study was free of other problems that could put it at risk of bias as:

a) low risk;

b) high risk;

c) unclear risk.

We will make explicit judgements regarding whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. If needed, we plan to explore the impact of the level of bias through undertaking sensitivity analyses (see Sensitivity analysis below).

Quality of evidence

We will assess the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodological approach considers evidence from randomized controlled trials as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates and presence of publication bias. (Guyatt 2011a). The GRADE approach results in an assessment of the quality of a body of evidence in one of four grades: 1) High: We are very confident that the true effect lies close to that of the estimate of the effect; 2) Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; 3) Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect; 4) Very Low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect (Schünemann 2013).

The review authors will independently assess the quality of the evidence found for following outcomes identified as critical or important for clinical decision making: duration of phototherapy, rate of fall of serum bilirubin and need for exchange transfusion.

In cases where we consider the risk of bias arising from inadequate concealment of allocation, randomized assignment, complete follow‐up or blinded outcome assessment to reduce our confidence in the effect estimates, we will downgrade the quality of evidence accordingly (Guyatt 2011b). Consistency will be evaluated by similarity of point estimates, extent of overlap of confidence intervals and statistical criteria including measurement of heterogeneity (I2). The quality of evidence will be downgraded when inconsistency across studies' results is large and unexplained (i.e. some studies suggest important benefit, and others, no effect or harm, without a clinical explanation) (Guyatt 2011d). Precision will be assessed according to the 95% confidence interval around the pooled estimate (Guyatt 2011c). When trials were conducted in populations other than the target population, we will downgrade the quality of evidence because of indirectness (Guyatt 2011e).

Data (i.e. pooled estimates of the effects and corresponding 95% confidence Intervals) and explicit judgments for each of the above aspects assessed will be entered into the Guideline Development Tool, the software used to create 'Summary of findings' (SoF) tables. All judgements involving the assessment of the study characteristics described above will be explained in footnotes or comments in the SoF table.

Measures of treatment effect

For categorical data we will calculate the relative risk (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) and number needed to treat for an additional harmful outcome (NNTH) with 95% confidence intervals. Continuous data will be analyzed using mean difference (MD).

Unit of analysis issues

We will compare prescribed change in body position. The infant’s position may include supine, prone or lateral body posture with the intervention prescribing periodic change in position. Periodicity for change in position may be based on time (every 30 minutes to 6 hours), handling of baby (e.g. after each breastfeeding session) or nursing shift (e.g. once during a shift). Repeated measurements in a group or measurements done in a cross‐over design will not be included. Cluster trials will not be eligible for inclusion.

Dealing with missing data

In the case of missing data, we will contact the original investigators to request the data are provided if feasible. In addition, we are aware that requests for missing data from trial authors may or may not be successful. In the first instance, we will contact the study authors to source missing data. If the study author either does not respond or it is not possible to contact them, we will include the trial in question in the review but will analyze its inclusion and exclusion for overall effect on the results as part of the sensitivity analysis.

Assessment of heterogeneity

We will examine heterogeneity between trials by first assessing differences in trial methodologies and clinical heterogeneity. We will use the following cut‐offs and labels for results of the I2 test: < 25% no heterogeneity, 25% to 49% low, 50% to 74% moderate, and greater than 75% high heterogeneity. We will then inspect the forest plots and quantify the impact of heterogeneity using the I2 statistic. If heterogeneity is noted, we plan to explore the possible causes of statistical heterogeneity using pre‐specified subgroup analysis (for example term versus preterm neonates and hemolytic versus non‐hemolytic jaundice).

Assessment of reporting biases

We will use funnel plots to investigate publication bias if there are at least 10 trials included in a meta‐analysis.

Data synthesis

We will tabulate studies that meet the inclusion criteria to enable comparison of trial characteristics and individual components of the quality assessment. We will also tabulate the bibliographic details of trials excluded from the review with specific reason for exclusion documented. We will review the summary tables of included trials to identify clinical heterogeneity amongst trials. If there are two or more randomized trials with comparable populations undergoing similar interventions, we will implement a meta‐analysis with a random effects model using RevMan 5.3 software. If there is clear evidence of heterogeneity amongst the trials, we will undertake a narrative summary of the findings (Sutton 2008). For dichotomous outcomes we will use relative risk (RR), risk difference (RD) and if the RD is significant we will report on the number needed to treat for an additional beneficial outcome (NNTB) and the number needed to treat for an additional harmful outcome (NNTH), all with 95% confidence intervals. We will use mean difference with 95% confidence intervals for continuous outcomes. We will conduct a meta‐analysis of pooled data to provide a summary statistic of effect if the combined data have minimal statistical heterogeneity. (Higgins 2011)

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analysis for term versus preterm neonates and hemolytic versus non‐hemolytic jaundice. In addition subgroup analysis will be carried out if studies have reported different regimens of change in position (e.g. frequency of change in position or change in position under a single‐surface versus double‐surface phototherapy).

Sensitivity analysis

We will perform sensitivity analyses to test the robustness of the decisions if a sufficient number of trials are found. A sensitivity analysis will be performed to determine if the findings were affected by including only studies of adequate methodology (low risk of bias), defined as adequate randomization and allocation concealment, blinding of intervention and outcome measurement, and less than 10% loss‐to‐follow‐up.