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Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants

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Authors

Charles I Okwundu1, Christy AN Okoromah2, Prakeshkumar S Shah3

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


1Centre for Evidence-Based Health Care, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa [top]
2Department of Paediatrics and Child Health, College of Medicine, University of Lagos, Lagos, Nigeria [top]
3Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto, Canada [top]

Citation example: Okwundu CI, Okoromah CAN, Shah PS. Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD007966. DOI: 10.1002/14651858.CD007966.pub2.

Contact person

Charles I Okwundu

Centre for Evidence-Based Health Care
Faculty of Health Sciences, Stellenbosch University
Tygerberg
South Africa

E-mail: ciokwundu@sun.ac.za

Dates

Assessed as Up-to-date: 31 March 2011
Date of Search: 31 March 2011
Next Stage Expected: 01 April 2013
Protocol First Published: Issue 3, 2009
Review First Published: Issue 1, 2012
Last Citation Issue: Issue 1, 2012

Abstract

Background

Low birth weight and premature infants are at major risk for exaggerated hyperbilirubinaemia and jaundice that can lead to bilirubin encephalopathy. Phototherapy is the most common treatment for neonatal hyperbilirubinaemia and could be most effective in preventing the sequelae of hyperbilirubinaemia if initiated prophylactically.

Objectives

To evaluate the efficacy and safety of prophylactic phototherapy for preterm (< 37 weeks gestational age) or low birth weight infants (birth weight < 2500 g).

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, T he Cochrane Library, Issue 3) on 31 March 2011, MEDLINE (1950 to 31 March 2011), EMBASE (1980 to 31 March 2011) and CINAHL (1982 to 31 March 2011).

Selection criteria

Randomised controlled trials or quasi-randomised controlled studiesevaluating the effects of prophylactic phototherapy for preterm or low birth weight infants.

Data collection and analysis

Two authors independently obtained data from published articles. We performed fixed-effect meta-analysis for the outcomes: rate of exchange transfusion, cerebral palsy or other neurodevelopmental impairment, peak serum bilirubin level and all-cause mortality.

Results

Nine studies of 3449 participants were included. The rate of exchange transfusion was reduced in one study with liberal transfusion criteria (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) but not in the other two more recent studies with stringent criteria (typical RR 0.66; 95% CI 0.19 to 2.28). There was no statistically significant difference in the rate of cerebral palsy (typical RR 0.96; 95% CI 0.50 to 1.85; two studies, 756 participants). However, one large study that reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment with prophylactic phototherapy (RR 0.85; 95% CI 0.74 to 0.99; 1804 participants). The prophylactic phototherapy group had lower peak bilirubin levels (mean difference (MD) -2.73; 95% CI -2.89 to -2.57; six studies, 2319 participants) and had fewer neonates with peak unconjugated serum bilirubin levels > 10 mg/dl (typical RR 0.27; 95% CI 0.22 to 0.33; three studies, 1090 participants) or peak unconjugated serum bilirubin levels > 15 mg/dl (typical RR 0.13; 95% CI 0.07 to 0.23; four studies, 1116 participants). There was no statistically significant difference in the rate of all-cause mortality between the two groups (typical RR 1.08; 95% CI 0.93 to 1.26; four studies, 3044 participants).

Authors' conclusions

Prophylactic phototherapy helps to maintain a lower serum bilirubin concentration and may have an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment. However, further well-designed studies are needed to determine the efficacy and safety of prophylactic phototherapy on long-term outcomes including neurodevelopmental outcomes.

Plain language summary

Prophylactic phototherapy for preventing jaundice in preterm very low birth weight infants

Preterm (< 37 weeks gestational age) or low birth weight (LBW; birth weight < 2500 g) infants have a greater risk of developing jaundice compared to term or normal birth weight infant. This can be concerning because jaundice (caused by high levels of serum unconjugated bilirubin) could lead to permanent brain damage and/or death.

In this review we evaluated the efficacy and safety of prophylactic phototherapy in preventing jaundice in preterm or LBW infants. A total of nine clinical trials representing 3449 infants were included. The findings suggest that phototherapy initiated soon after birth (within 36 hours) for preterm or low birth weight infants may prevent the serum bilirubin from reaching a level that would require exchange transfusion and may reduce the risk of impairment of brain and central nervous system development. However, further well-designed studies are needed to evaluate the effects of prophylactic phototherapy on brain and central nervous system development and other long-term outcomes.

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Background

Description of the condition

Neonatal jaundice is the yellow discolouration of the skin and sclera of neonates caused by hyperbilirubinaemia. Bilirubin is a yellow pigment that is produced in the body during the normal recycling of aging red blood cells. About 50% of term and 80% of preterm infants develop jaundice in the first week of life (Kumar 1999). Jaundice is a common cause of readmission to hospital after early discharge of newborn infants (Gale 2001). The most common form of hyperbilirubinaemia observed in neonates is due to unconjugated or unbound bilirubin. High levels of unconjugated bilirubin are managed by treatment of the underlying cause (e.g. dehydration and sepsis), provision of phototherapy, administration of immunoglobulin (in certain cases of haemolytic anaemia) and, in very severe cases, exchange transfusion. If left untreated, extreme elevation of unconjugated bilirubin can lead to permanent brain damage and/or death (Hansen 2005).

Several risk factors have been identified for the occurrence of exaggerated or severe unconjugated hyperbilirubinaemia. Low birth weight and preterm birth are major risk factors for exaggerated hyperbilirubinaemia. Clinically significant levels that warrant treatment occur in approximately 50% to 80% of preterm neonates (Almeida 2004). Preterm infants are at risk of bilirubin encephalopathy at lower total serum bilirubin levels than mature infants.

High levels of unconjugated serum bilirubin can cross the blood brain barrier and can be deposited in the basal ganglia of the brain resulting in a condition termed kernicterus. Clinically, the term kernicterus is used to describe the chronic form of bilirubin encephalopathy and includes symptoms such as athetoid cerebral palsy (uncontrollable movement of the face, body, arms and legs), hearing loss, failure of upward gaze and dental enamel dysplasia. The exact level of unconjugated serum bilirubin that is neurotoxic is unclear. There is marked variability in the level of bilirubin at which kernicterus will occur. Kernicterus has been reported at autopsy in infants in the absence of markedly elevated levels of unconjugated serum bilirubin (Turkel 1980).

Description of the intervention

Phototherapy is the most common treatment for unconjugated hyperbilirubinaemia in neonates. Phototherapy leads to photoisomerisation of bilirubin into a water-soluble form that can be excreted by the kidney. Phototherapy effectively decreases the unconjugated bilirubin and decreases the need for exchange transfusion (Maisels 1998). Generally, phototherapy is considered a safe intervention. However, it is associated with complications such as 'bronze baby syndrome' if used in patients with conjugated hyperbilirubinaemia and it may result in dehydration due to insensible water loss. It may also cause damage to developing retina (Rubaltelli 1983). The major counter argument to the use of prophylactic phototherapy is that bilirubin is a powerful antioxidant (McDonagh 1990) and may have a physiological role in neonates (Hegyi 1994). It has also been suggested that the low levels of bilirubin achieved by the use of prophylactic phototherapy reduce the antioxidant level and may lead to the development of retinopathy of prematurity. Several other neonatal outcomes such as chronic lung disease and neurological injury (intraventricular haemorrhage, periventricular leukomalacia) could be affected by lack of antioxidant activity. In addition, alteration of fluid homeostasis associated with the use of phototherapy may affect closure of a patent ductus arteriosus.

How the intervention might work

Unconjugated hyperbilirubinaemia is very common in preterm and low birth weight neonates and because there is no way to predict a safe level of bilirubin in very low birth weight (VLBW) infants, prophylactic use of phototherapy immediately after birth has been suggested. It has been hypothesised that phototherapy could be used to prevent unconjugated hyperbilirubinaemia and clinical jaundice, thereby leading to improved neurodevelopmental outcomes.

Why it is important to do this review

Treatment of neonatal hyperbilirubinaemia is usually based on the measurement of the total serum bilirubin levels (Bratlid 2001) and the serum bilirubin level used as an indication for treatment varies across healthcare institutions, from country to country and across continents. The use of prophylactic phototherapy in preterm or low birth weight infants is not an uncommon practice (Hansen 1996). However, there is currently no evidence to support the use of phototherapy for the prevention of jaundice caused by unconjugated hyperbilirubinaemia.

Objectives

To evaluate the efficacy and safety of prophylactic phototherapy in preterm or low birth weight infants.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled studies that have evaluated the effects of prophylactic phototherapy in preterm and/or low birth weight infants.

Types of participants

  • Preterm infants (< 37 weeks gestation).
  • Low birth weight infants(< 2500 grams), within the first 36 hours of birth.

Originally (in the protocol) the focus of the review was narrower (to include very low birth weight infants; < 1500 g birth weight), however, in order not to lose valuable information, we made a post hoc decision to include any study that involved low birth weight (< 2500 g birth weight) or preterm infants.

We excluded studies of infants with a known cause that can lead to significant hyperbilirubinaemia, such as ABO incompatibility, Rh incompatibility, minor blood group incompatibility or G-6PD deficiency.

Types of interventions

We included studies in which prophylactic phototherapy was compared with control. We defined prophylactic phototherapy as initiation of phototherapy before the bilirubin has reached a pre-specified level (according to the study criteria) at which therapeutic use of phototherapy is indicated.

The control refers to the standard treatment whereby phototherapy is started when the serum bilirubin has reached to a pre-specified level (according to the study criteria) or no use of prophylactic phototherapy.

Types of outcome measures

Primary outcomes
  • Clinical kernicterus.
  • Pathological kernicterus.
  • Need for exchange blood transfusion.
  • Long-term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language or behavioural/school/socialinteraction/adaptation test.
Secondary outcomes
  • Highest serum bilirubin level during first seven days of life (mg/dl).
  • Duration of phototherapy in hours.
  • Fluid intake/requirement (cc/kg/day) in the first week after birth.
  • Bronze baby syndrome.
  • Patent ductus arteriosus (PDA) (clinical diagnosis) or PDA requiring treatment with cyclo-oxygenase inhibitor or surgery.
  • Retinopathy of prematurity (ROP) (any stage and severity (stages 3 or 4) defined according to the International Classification of Retinopathy of Prematurity).
  • Intraventricular haemorrhage (IVH) (any grade and severity (grade 3 or 4) as defined by Papile) (Papile 1978).
  • Periventricular leukomalacia (PVL) (diagnosed by ultrasound or magnetic resonance imaging (MRI)).
  • Duration of hospital stay (days).
  • Mortality during neonatal intensive care unit (NICU) stay: kernicterus-related mortality; all-cause mortality.

Search methods for identification of studies

See: Cochrane Neonatal Group methods used in reviews External Web Site Policy.

We formulated a comprehensive and exhaustive search strategy in order to identify all relevant studies, regardless of language or publication status (published, unpublished, in press and in progress).

Electronic searches

We searched the following electronic databases until 31 March 2011.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3).
  2. MEDLINE (1966 to 31 March 2011).
  3. EMBASE (from 1980 to 31 March 2011).
  4. CINAHL (from 1982 to 31 March 2011).

The search strategy included the search terms "Prophylactic" AND "phototherapy" AND "prevention" AND "jaundice" OR "hyperbilirubinemia" OR "hyperbilirubinaemia" "preterm" OR "premature" AND "very low birth weight" OR "VLBW and "infants" OR "neonates.

There were no language restrictions in the searches.

Searching other resources

We performed handsearches of the reference lists of all pertinent reviews and studies. We contacted the National Institute of Child Health and Human Development (NICHD) experts in the field for unpublished and any ongoing studies. We also searched for any ongoing or prospective studies in registries using the websites of ClinicalTrials.gov and Controlled-Trials.com External Web Site Policy.

Data collection and analysis

Selection of studies

See Figure 1 for details of the study selection process. Two review authors (CO and CAN) independently read the titles, abstracts and descriptor terms of the search output from the different databases to identify potentially eligible studies. We obtained full-text articles for all citations identified as potentially eligible. Both review authors (CO and CAN) independently inspected these to establish the relevance of the articles according to the prespecified criteria. We reviewed studies for relevance based on study design, types of participants, interventions and outcome measures. We gave reasons for excluding potentially relevant studies in an excluded studies table. We resolved discrepancies by consensus and involving third author (PS).

Data extraction and management

We designed a data extraction form. CO and CAN independently extracted data into the data extraction form individually. We extracted the following characteristics from each included study.

  • Administrative details: author(s); published or unpublished; year of publication; year in which study was conducted; details of other relevant papers cited.
  • Details of the study: study design; type, duration and completeness of follow-up; country and location of study informed consent and ethics approval.
  • Details of participants: age, birth weight and number of participants.
  • Details of intervention: age when phototherapy was commenced in both the intervention and control arm, duration of phototherapy, serum bilirubin level at which phototherapy was commenced or stopped, wavelength and light intensity.
  • Details of outcomes: peak serum bilirubin, mean serum bilirubin, exchange blood transfusions, duration of hospital stay, duration of phototherapy, long-term neurodevelopmental outcomes, deaths and any adverse events.

Assessment of risk of bias in included studies

Two review authors independently used the Cochrane Collaboration tool for assessing the risk of bias for each individual study. For trials, the Cochrane tool assesses risk of bias in individual studies across six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other potential biases. We judged the risk of bias for the different domains in each included study as 'high risk of bias', 'low risk of bias' or 'unclear risk of bias'.

Sequence generation

  • Low risk: investigators described a random component in the sequence generation process such as the use of a random number table, coin tossing, cards or envelope shuffling, etc.
  • High risk: investigators described a non-random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number.
  • Unclear risk: insufficient information to permit judgement of the sequence generation process.

Allocation concealment

  • Low risk: participants and the investigators enrolling participants cannot foresee assignment (e.g. central allocation; or sequentially numbered, opaque, sealed envelopes).
  • High risk: participants and investigators enrolling participants can foresee upcoming assignment (e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or non­opaque or not sequentially numbered).
  • Unclear risk: insufficient information to permit judgement of the allocation concealment or the method not described.

Blinding

  • Low risk: blinding of the participants, key study personnel and outcome assessor, and unlikely that the blinding could have been broken, or lack of blinding unlikely to introduce bias. No blinding in the situation where non-blinding is not likely to introduce bias.
  • High risk: no blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding.
  • Unclear risk: insufficient information to permit judgement of the adequacy or otherwise of the blinding.

Incomplete outcome data

  • Low risk: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups.
  • High risk: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data.
  • Unclear risk: insufficient reporting of attrition or exclusions.

Selective reporting

  • Low risk: a protocol is available which clearly states the primary outcome as the same as in the final trial report.
  • High risk: the primary outcome differs between the protocol and final trial report.
  • Unclear risk: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.

Other forms of bias

  • Low risk: there is no evidence of bias from other sources.
  • High risk: there is potential bias present from other sources (e.g. early stopping of trial, fraudulent activity, extreme baseline imbalance or bias related to specific study design).
  • Unclear risk: insufficient information to permit judgement of the adequacy or otherwise of other forms of bias.

Measures of treatment effect

We conducted measures of treatment effect data analysis using Review Manager (RevMan) version 5.0.15 (RevMan 2008). We calculated outcome measures for dichotomous data (e.g. exchange transfusion, death, peak serum bilirubin > 10 mg/dl) as a risk ratio with 95% confidence intervals. We calculated continuous data (e.g. peak serum bilirubin concentration, duration of phototherapy, duration of hospital stay) using the mean difference and standard deviations.

Assessment of heterogeneity

Where studies were found to be methodologically or clinically comparable, we pooled trial results in a meta-analysis. As we anticipated the presence of statistical heterogeneity, we combined data using the random-effects model. We calculated whether statistical heterogeneity is present using the Chi² test for homogeneity (P < 0.1 was considered significant). We quantified the impact of statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies due to heterogeneity rather than sampling error (Higgins 2003). We explored possible causes of significant heterogeneity by looking critically at the characteristics of the various studies.

Data synthesis

We summarised all eligible studies in RevMan 5. The two review authors extracted the data and entered all data into the current version of RevMan 5. Both review authors rechecked all of the entries. We conducted meta-analysis where appropriate and if the studies were found to be clinically homogenous. For comparable studies, we summarised the findings using a random-effects model. We calculated summary estimates, when applicable: risk ratio (RR) and risk difference (RD) for dichotomous outcome measures and mean difference (MD) for continuous outcomes, with their respective 95% confidence intervals (CI). If an intervention was beneficial or harmful, we calculated number needed to treat to benefit (NNTB) or harm (NNTH).

Subgroup analysis and investigation of heterogeneity

We carried out subgroup analysis where appropriate. For one of the outcomes, we stratified participants according to birth weight (very low birth weight and extremely low birth weight infants). We also performed a sensitivity analysis to explore the effect of trial quality on the results by excluding those studies with high risk of bias and assessed the effect of this on the overall results.

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Results

Description of studies

See: Characteristics of Included Studies; Characteristics of excluded studies.

Results of the search

See: Prisma flow diagram Figure 1 for details of the search output from each of the databases. We identified nine studies that met our inclusion criteria. These studies included 3449 participants with a median trial sample size of 96 (ranging from 22 (Curtis 1985) to 1974 participants (Morris 2008).

Included studies

A total of nine studies were included in this review (Lucey 1968; Giunta 1969; Hodgman 1970; Brown 1985; Curtis 1985; Leite 2004; Tripathi 2006; Jangaard 2007; Morris 2008). We have included details for each trial in the table Characteristics of Included Studies. Six of the studies were conducted in the USA (Lucey 1968; Giunta 1969; Hodgman 1970; Brown 1985; Curtis 1985; Morris 2008), while the others were conducted in Brazil (Leite 2004), Canada (Jangaard 2007) and India (Tripathi 2006). The most recent trial was conducted between 2002 and 2007 (Morris 2008), while the oldest trial was conducted before 1967 (Lucey 1968). Four studies (Lucey 1968; Giunta 1969; Hodgman 1970; Brown 1985) were conducted in the late 1960s and early 1970s. There were two multicentre studies (Brown 1985; Morris 2008) and these had the highest number of study participants (922 and 1974 respectively).

Types of participants

All the included studies evaluated the efficacy of phototherapy in preventing jaundice in preterm (< 37 weeks gestational age) low birth weight infants (< 2500 g). The upper limit of birth weight of the study participants differed in the different studies (< 2500 g for Giunta 1969 and Lucey 1968, < 2000 g for Brown 1985; Leite 2004; and Hodgman 1970, < 1500 g for Jangaard 2007, < 1250 g for Tripathi 2006 and Curtis 1985, and < 1000 g (Morris 2008). The mean gestational ages of the study participants were as follows: 27.3 weeks for Curtis 1985, 251 and 254 days (phototherapy and control group respectively) for Giunta 1969, 34.4 and 34.3 weeks (phototherapy and control group respectively) for Hodgman 1970, 28.1 and 28.7 weeks (phototherapy and control group respectively) for Jangaard 2007, < 37 weeks (all participants) for Leite 2004 and Brown 1985, 36 and 35 weeks (phototherapy and control group respectively) for Lucey 1968, and 26 weeks (all participants) for Morris 2008.

Types of intervention

For most of the studies (Lucey 1968; Giunta 1969; Curtis 1985; Leite 2004; Tripathi 2006; Jangaard 2007) phototherapy was started within 12 hours of age in the intervention group. Other studies initiated phototherapy by 24 ± 12 hours of age (Brown 1985), 24 hours of age (Hodgman 1970) and at 12 to 36 hours (Morris 2008).

Types of outcome measures

All studies reported outcomes comparing prophylactic (early initiation) use of phototherapy with late initiation or therapeutic use of phototherapy. One of the studies (Brown 1985) also evaluated the efficacy of phototherapy both in preventing and in the treatment of already established hyperbilirubinaemia in infants weighing less than 2000 g and more than 2000 g respectively. However, for the purpose of this review, we extracted only outcome data for participants where phototherapy was evaluated for prevention rather than treatment of hyperbilirubinaemia.

Follow-up

Two of the studies (Jangaard 2007; Morris 2008) reported outcomes at 18 months of age and another study (Brown 1985) reported outcomes up to six years later. The rest of the studies only reported short-term outcomes.

Excluded studies

Reasons for excluding potentially eligible studies (Elliot 1974; Romagnoli 1996; Sanches 2004; Yaseen 2005) are summarised in the table of Characteristics of excluded studies

Risk of bias in included studies

A summary of the assessment of risk of bias based on the criteria outlined in Higgins 2008 is given in Figure 2 and Figure 3. Additionally, a brief descriptive analysis of the studies is provided below. In general, the overall methodological quality of the included studies was acceptable.

Allocation (selection bias)

Allocation of participants to either intervention or control group was reported as random in seven studies (Giunta 1969; Brown 1985; Curtis 1985; Leite 2004; Tripathi 2006; Jangaard 2007; Morris 2008); however, only four of these mentioned the method used for generating the randomisation sequence (Brown 1985; Leite 2004; Jangaard 2007; Morris 2008). The sequence generation was not clear in three studies. Three studies did not mention any random process for allocation (Lucey 1968; Giunta 1969; Elliot 1974). In these studies participants were allocated alternately into the intervention or control group. Only three studies reported their method of allocation sufficiently clearly to determine that allocation was concealed (Brown 1985; Jangaard 2007; Morris 2008).

Blinding (performance bias and detection bias)

Only one study reported blinding of the outcomesassessor for the treatment arm (Morris 2008).

Incomplete outcome data (attrition bias)

For all the studies included in this review, randomised participants were either reported or analysed in the group to which they were allocated irrespective of the outcome.

Selective reporting (reporting bias)

The study protocol was available for only two of the included studies (Brown 1985; Morris 2008) and all the outcomes specified in the protocol were reported in these two studies. Selective outcome reporting could not be assessed for the rest of the included studies.

Other potential sources of bias

Baseline characteristics were similar in all the studies and all the studies were completed as planned. The sources of funding for the various studies were not likely to influence the outcomes. Of all the nine included studies, we had access to only two of the study protocols (Brown 1985; Morris 2008). Thus it is hard to assess whether all prespecified outcomes were reported or not for seven of the studies.

Effects of interventions

We presented results based on outcome measures as outlined in the review protocol. We also reported other outcomes reported in the primary studies that we deemed to be relevant to the review question. We conducted meta-analysis where we considered it to be appropriate.

Prophylactic phototherapy versus control (COMPARISON 1)

Primary outcomes
Incidence of clinical kernicterus

None of the studies provided data on this outcome.

Incidence of pathological kernicterus

None of the studies provided data on this outcome.

Exchange blood transfusion

Three studies (Brown 1985; Tripathi 2006; Morris 2008) reported data on exchange blood transfusion and contributed 2946 participants. The studies used different thresholds for exchange transfusion (a lower threshold was used in the Brown 1985 study, while Morris 2008 and Tripathi 2006 used a higher threshold). Therefore, we created subgroups based on higher or lower thresholds for exchange transfusion. Brown 1985 reported a statistically significant reduction in exchange transfusion (risk ratio (RR) 0.20; 95% confidence interval (CI) 0.13 to 0.31) while Morris 2008 and Tripathi 2006 did not find any significant difference in the rate of exchange transfusion (RR 0.66; 95% CI 0.19 to 2.28). Overall, prophylactic phototherapy was associated with a 78% reduction in the rate of exchange blood transfusion (typical RR 0.22; 95% CI 0.15 to 0.34), though there was moderate statistical heterogeneity (Chi² = 3.27, df = 2 (P = 0.19); I² = 39%) (Figure 4).

Long-term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language or behavioural/school/social interaction/adaptation test
Neurodevelopmental impairment

This was a composite outcome reported by one study (Morris 2008). Neurodevelopmental impairment was assessed at 18 to 22 months of age and was defined to include blindness, severe hearing loss and moderate or severe cerebral palsy. Prophylactic phototherapy reduced the rate of neurodevelopmental impairment (RR 0.85; 95% CI 0.74 to 0.99, risk difference (RD) -0.04; 95% CI -0.09 to -0.00).

Cerebral palsy

Two studies (Brown 1985; Jangaard 2007) reported on this outcome. There was no significant difference in the incidence of cerebral palsy assessed at one year of age (Brown 1985) and at 18 months of age (Jangaard 2007) (typical RR 0.96; 95% CI 0.50 to 1.85) (Figure 5). Jangaard 2007 also reported separately on the rate of cerebral palsy among infants weighing < 1000 g. There was also no significant difference between the two arms in this subgroup (RR 0.29; 95% CI 0.04 to 2.27). Secondary reports emanating from Brown 1985 at six-year follow-up also showed that there was no significant difference in the rate of cerebral palsy between the phototherapy and control group.

Sensorineural hearing loss

One study (Brown 1985) at six-year follow-up reported on sensorineural hearing loss and found no statistically significant difference between the phototherapy group and the control group for infants weighing less than 2000 g (RR 0.31; 95% CI 0.07 to 1.50).

Secondary outcomes
Peak serum bilirubin level during the first seven days of life

Six studies (Lucey 1968; Curtis 1985; Leite 2004; Tripathi 2006; Jangaard 2007; Morris 2008) reported on this outcome and contributed 2319 participants. The mean peak serum bilirubin was significantly lower in the phototherapy group compared to the control group for all infants weighing < 2500 g (mean difference (MD) -2.73; 95% CI -2.89 to -2.57). However, statistical heterogeneity was substantial and highly significant (I² = 91%) (Figure 6). This is possibly due to the differences in population, timing of assessment and methods of measurement of bilirubin. We conducted a subgroup analysis for this outcome by birth weight and age of participants at time of initiation of phototherapy.

Subgroup analyses
1. Birth weight

Two studies (Jangaard 2007; Morris 2008) reported peak serum bilirubin for infants weighting < 1000 g. The peak serum bilirubin was significantly lower in the phototherapy group compared to the control group (MD -2.79; 95% CI -2.96 to -2.62). Four studies (Curtis 1985; Tripathi 2006; Jangaard 2007; Morris 2008) reported on the peak serum bilirubin for infants weighing less than 1500 g and also found a statistically significant difference in the phototherapy and control group (MD -2.69; 95% CI -2.86 to -2.52) (Figure 6). There was moderate statistical heterogeneity (I² = 34%) in the less than 1000 g birth weight group.

2. Age of participants at time of initiation of phototherapy

In five of the studies (Lucey 1968; Curtis 1985; Leite 2004; Tripathi 2006; Jangaard 2007) phototherapy was initiated within 12 hours of birth in the intervention group. Pooling results from these studies shows that the peak serum bilirubin was significantly lower in the phototherapy group compared to the control group (MD -2.06; 95% CI -2.60 to -1.53). Phototherapy was initiated within 12 to 36 hours of birth in one study (Morris 2008). The peak serum bilirubin was significantly lower in the phototherapy group compared to the control group in this study (MD -2.80; 95% CI -2.97 to -2.63). The difference between commencing phototherapy within 12 hours and between 12 and 36 hours of birth was not significantly different.

Serum bilirubin > 10 mg/dl

This outcome was considered post hoc. Three studies (Hodgman 1970; Brown 1985; Leite 2004) reported incidence of serum bilirubin > 10 mg/dl. There was a statistically significantly lower number of neonates with serum bilirubin > 10 mg/dl in the phototherapy group compared to the control group (typical RR 0.27; 95% CI 0.22 to 0.33) with moderate heterogeneity (I² = 51%) (Figure 7).

Serum bilirubin > 15 mg/dl

This outcome was also considered post hoc. Three studies (Giunta 1969; Hodgman 1970; Brown 1985) reported on this outcome. There was a statistically significant reduction in the number of neonates with serum bilirubin > 15 mg/dl in the phototherapy group compared to the control group (typical RR 0.13; 95% CI 0.07 to 0.23).

Duration of phototherapy in hours

Three studies (Curtis 1985; Jangaard 2007; Morris 2008) reported on this outcome. The mean duration of phototherapy was longer in the prophylactic phototherapy group compared to the control group (MD 49.76 hours; 95% CI 46.37 to 53.15 hours).

Fluid intake/requirement in the first week after birth

None of the studies provided data on this outcome.

Incidence of bronze baby syndrome

None of the studies provided data on this outcome.

Incidence of patent ductus arteriosus (PDA) (clinical diagnosis) or PDA requiring treatment with cyclo-oxygenase inhibitor or surgery

One study (Morris 2008) reported the incidence of PDA. There was no statistically significant difference in the incidence of PDA in both groups (RR 0.94; 95% CI 0.85 to 1.03).

Incidence of retinopathy of prematurity

Three studies reported on retinopathy of prematurity (Brown 1985; Jangaard 2007; Morris 2008). There was no statistically significant difference in the incidence of retinopathy of prematurity in the phototherapy group compared to the control group in two of the studies (Jangaard 2007; Morris 2008) (typical RR 0.93; 95% CI 0.77 to 1.13). Secondary reports emanating from the multicentre trial of Brown 1985 at one-year follow-up shows that 11 infants had severe visual and retinal changes, two in the phototherapy group and nine in the control group. One of the infants in the control group had retinopathy of prematurity. However, the causes of the visual impairments were unrelated and could not be attributed to a single cause.

Intraventricular haemorrhage

Two studies (Jangaard 2007; Morris 2008) presented data on the incidence of intraventricular haemorrhage and meta-analysis revealed no statistically significant difference between groups (typical RR 0.94; 95% CI 0.80 to 1.10).

Periventricular leukomalacia [diagnosed by ultrasound or magnetic resonance imaging (MRI)]

None of the studies provided data on this outcome.

Duration of hospital stay (days)

This outcome was reported in two studies (Jangaard 2007; Morris 2008). There was no difference in the duration of hospitalisation between groups (MD -3 days; 95% CI -7 to +1 days).

All-cause mortality (before discharge)

Four studies reported this outcome (Hodgman 1970; Brown 1985; Tripathi 2006; Morris 2008). There was no statistically significant difference in the risk of mortality between groups (typical RR 1.08; 95% CI 0.93 to 1.26). In the group of infants weighing < 1000 g, there was also no statistically significant difference in the rate of mortality between the phototherapy and control group (RR 1.07; 95% CI 0.91 to 1.25) (Figure 8).

GRADE assessment

We assessed the evidence according to GRADE criteria, although this was not stipulated in the protocol. See Summary of findings table 1 for the main comparison. Using the GRADE tool, we evaluated the evidence provided by the studies and rated this for each outcome identified as critical or important.

Discussion

Summary of main results

Nine studies were eligible for this review. Most of the studies compared early initiation of phototherapy (prophylactic phototherapy) with late commencement of phototherapyin preterm low birth weight neonates without any evidence of haemolytic jaundice due to ABO incompatibility. There was reduction in the number of infants who required exchange transfusion; however, there was marked heterogeneity with one study using a lower threshold for exchange transfusion and reporting a significantly higher number of exchange transfusions in the control group. There was also a significant reduction in peak serum bilirubin and a lower number of infants with bilirubin level > 10 mg/dl or 15 mg/dl. Duration of phototherapy was longer in prophylactic phototherapy group by more than two days. There was no statistically significant difference in the rate of cerebral palsy and sensorineural hearing loss. However, one of the studies which reported on neurodevelopmental impairment (a composite outcome including cerebral palsy) found a slightly lower rate of neurodevelopmental impairment in the phototherapy group. Findings from this review also suggest that prophylactic phototherapy does not significantly reduce the rate of all-cause mortality. The low incidence of long-term outcomes such as cerebral palsy could be because clinical considerations required exchange blood transfusion to prevent bilirubin from reaching very high levels. This could explain the lack of significant difference in long-term outcomes between the prophylactic phototherapy and control group. Also, the power of the studies to detect the difference in the categorical outcomes should be considered.

Overall completeness and applicability of evidence

All the studies directly answered the question of whether prophylactic phototherapy can be used to prevent hyperbilirubinaemia and jaundice in preterm and low birth weight infants. Seven of the studies were conducted in high-income settings (USA and Canada) and two of the studies were conducted in low and middle-income settings (India and Brazil). However, there is no reason to believe that the findings are not applicable to other parts of the world. Two of the studies provided data on follow-up of participants beyond the neonatal period up to 18 months, with low incidence of long-term outcomes. At the time of writing up this review, we did not identify and are not aware of any ongoing or planned studies aiming to answer this question. The available evidence is fairly large for short-term outcomes of peak serum bilirubin and number of infants crossing a threshold bilirubin level. However, not enough studies have reported data on long-term outcomes. Reduction of serum bilirubin by approximately 3 mg/dl for an increase in phototherapy duration by two days will need to be judged in the context of the individual setting. Data from the Morris 2008 report revealed that there was no difference in their primary composite outcome of death or neurodevelopmental impairment between two groups (52% versus 55%; risk ratio (RR) 0.94; 95% confidence interval (CI) 0.87 to 1.02; risk difference (RD) -0.03; 95% CI -0.08 to 0.01) and there was a trend towards an increase in mortality in the preplanned subgroup of 751 to 1000 g infants (39% in phototherapy group versus 34% in control group, RR 1.13; 95% CI 0.96 to 1.34) which may offset the benefit gained of reduction in neurodevelopmental disability in extremely low birth weight infants. However, overall, there was no difference in the rate of all-cause mortality between the phototherapy and control group.

Quality of the evidence

The methodological quality varied across the included studies. Most of the studies did not state the method used for sequence generation and most likely these studies are unblinded. In addition, the sample sizes varied across all the studies and most of the studies did not provide any description of the sample size calculation. Two multicentre, large-scale randomised studies had no risk of bias.

We used the GRADE approach for rating quality of evidence to assess the quality of evidence for seven of the outcomes that were considered to be very important. The quality of evidence was moderate for most of the outcomes, suggesting that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Potential biases in the review process

We conducted comprehensive searches of both journal and conference databases to ensure that all relevant published and unpublished studies were identified. We also scanned through the reference lists of all the identified studies to look for any relevant study titles. There were no language or date limits in our search for studies. We repeated the search for studies just before publication to identify any new studies. It is therefore unlikely that our search missed any relevant study. We also reduced potential bias in the conduct of this review by having two of the authors independently scan through the search output, extract data and assess the methodological quality of each study.

In the meta-analysis, we pooled data from different studies even though the studies were slightly different in terms of gestational age of participants, birth weight and wavelength of phototherapy used. However, we did not consider these differences to be a source of bias, but the results of from the meta-analysis can be considered to be less direct.

Our protocol was aimed at very low birth weight infants; however, after reviewing studies available on the topic we modified the population to include preterm and low birth weight infants.

Authors' conclusions

Implications for practice

Based on the available data there is evidence that prophylactic phototherapy prevents a significant rise in unconjugated hyperbilirubinaemia, reduces the need for exchange transfusion and may reduce long-term neurodevelopmental impairment. There was no effect on all-cause mortality, duration of hospital stay or increase in duration of phototherapy. Longer duration of phototherapy could incur additional cost and the benefit needs to be weighed against the cost and complications.

Implications for research

The quality of evidence assessed using the GRADE approach suggests that further research is likely to have an important impact on our confidence in the estimate of effect for most of the outcomes and may change the estimate. Therefore, further well-designed studies are warranted to determine both the short and long-term effects of prophylactic phototherapy, including a cost-effectiveness analysis. Future research should also report data on the side effects of prophylactic phototherapy.

Acknowledgements

  • None noted.

Contributions of authors

CO conceptualised the review. CO and CAN conducted eligibility of the search outputs, data extraction and quality assessment. PS resolved differences when needed. CO entered the data, conducted the analyses and wrote the first draft of the review. CAN and PS provided feedback into the overall results and their interpretation from a clinical perspective.

Declarations of interest

The review authors: Charles Okwundu, Christy A. Okoromah and Prakesh Shah have no financial, personal or academic affiliations which may be construed as a conflict of interest.

Differences between protocol and review

In the protocol, we set out to evaluate the effect of prophylactic phototherapy in preterm very low birth weight infants, however some of the studies we found included low birth weight infants (weighing < 2500 g). In order not to lose valuable information and evidence on the topic, we decided to include these studies. In addition, we reported outcomes from the primary studies that were not prespecified in the protocol which we thought to be useful in helping to answer the question.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Brown 1985

Methods

Randomised controlled trial

Participants

922 preterm infants weighing less than 2000 g at birth. The number of participants in the intervention and control arm were 462 and 460 respectively.

Interventions

Phototherapy started at 24 ± 12 hours of age for the intervention arm and the duration of phototherapy was 96 hours

Outcomes

Mean daily serum bilirubin level, hyperbilirubinaemia, exchange blood transfusion, neurological abnormalities (including cerebral palsy, abnormal movements, seizures) mental development, psychomotor development and death

Notes

The study evaluated the effect of phototherapy for both treatment and prevention of hyperbilirubinaemia in the National Institute of Child Health and Human Development (NICHD) Network Centres. The evaluation of phototherapy for prevention of hyperbilirubinaemia was studied only in infants weighing less than 2000 g. Only data for the < 2000 g have been included in this review. It was a multicentre study.

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

Sequence generation was random. The authors described the use of a table of random numbers.

Allocation concealment (selection bias) Low risk

The authors described the use of sealed envelopes for allocation concealment

Blinding (performance bias and detection bias) High risk

The study was unblinded

Incomplete outcome data (attrition bias) Low risk

Number lost to follow-up was explicitly described and was similar in both the groups. Follow-up rates at 1 and 6 years were 83% and 62% respectively.

Selective reporting (reporting bias) Low risk

There are no suggestions of any selective reporting of outcomes. All the pre-specified outcomes described in the protocol (Bryla 1985) were reported.

Other bias Low risk

There is no other known potential source of bias in the study.

The study was completed as planned.

Curtis 1985

Methods

Randomised controlled trial

Participants

The study participants were 22 preterm infants (birth weight 850 ± 220 g, gestational age 27.3 ± 1.7 weeks, mean ± SD) admitted to the intensive care nurseries of the children's hospital of Philadelphia and the Pennsylvania within the first 12 hours of life. There were 11 participants in each of the study arms.

Interventions

Phototherapy was administered with broad-spectrum (white) light from a type ENH 250 W tungsten lamp in a model 1400 phototherapy unit. In the prophylactic phototherapy group, the phototherapy was started soon after birth and continued for 5 days. In the control group, phototherapy was initiated only when the serum bilirubin concentration reached 5 mg/dl

Outcomes

Peak serum bilirubin, age at peak serum bilirubin, rate of rise of bilirubin and total duration of phototherapy

Notes

Country: USA

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

The method used for sequence generation was not mentioned. However, the authors mention that participants were randomly assigned to either of the 2 groups

Allocation concealment (selection bias) Unclear risk

Insufficient information to permit judgement

Blinding (performance bias and detection bias) Unclear risk

Insufficient information to permit judgement

Incomplete outcome data (attrition bias) Low risk

The number of participants in each group are clearly reported and accounted for

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

There is no other known potential source of bias in the study. The study was completed as planned.

Giunta 1969

Methods

This was a controlled study. Alternate case series of 96 consecutive neonates weighing less than 2500 g at birth.

Participants

The study participants were 96 preterm neonates weighing < 2500 g.

Interventions

The neonates were placed in a brightly lighted nursery (intervention group) exposed or under the usual dim nursery light and fully clothed. In the intervention group, the lights were two fixtures with four 8 ft, 75 watt fluorescent cool white light tubes in each fixture.

Outcomes

Daily mean indirect serum bilirubin and highest indirect serum bilirubin in 6-day period

Notes

Country: USA

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

No random process is described. Participant were allocated alternately

Allocation concealment (selection bias) High risk

Participants were allocated alternately and therefore allocation cannot be concealed

Blinding (performance bias and detection bias) High risk

There was no mention of blinding in the study

Incomplete outcome data (attrition bias) Low risk

The number of participants in each group are clearly reported and accounted for

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

Both groups were similar at baseline and the study was completed as planned

Hodgman 1970

Methods

Randomised controlled trial

Participants

98 premature infants with birth weights between 1250 to 2000 g. The number of participants in the intervention and control arm were 47 and 51 respectively.

Interventions

Continuous phototherapy commenced at 18 to 30 hours for 5 days versus control. 47 infants were exposed to a light cradle over the incubator starting at 18 to 36 hours of age. The light cradles were constructed to fit over the incubators. Each cradle held 10 20-watt cool white, trigger start, fluorescent bulbs giving 450 foot-candles of light intensity at the level of the infant in the incubator.

Outcomes

Daily peak serum bilirubin

Notes

Country: USA

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

The method used for sequence generation was not mentioned. However, authors mention that participants were randomly assigned to either of the 2 groups

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

No information provided, however it was probably unblinded because of the nature of the intervention

Incomplete outcome data (attrition bias) Low risk

The number of participants in each group are clearly reported and accounted for

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

Jangaard 2007

Methods

Randomised controlled trial

Participants

95 preterm infants with birth weights between 500 g and 1500 g. The number of participants in the intervention and control arm were 46 and 49 respectively.

Interventions

Aggressive versus conservative phototherapy. Aggressive phototherapy was commenced by 12 hours of age, while the conservative phototherapy was commenced if serum bilirubin levels exceeded 150 μmol/L.

Outcomes

Primary outcome: peak unconjugated serum bilirubin level. Other short-term outcomes included incidence of attaining peak bilirubin levels in the first 48 hours, total hours of phototherapy, incidence of rebound hyperbilirubinaemia defined as unconjugated serum bilirubin level of 185 μmol/L and per cent weight, intraventricular haemorrhage, retinopathy of prematurity and periventricular leukomalacia were examined. Long-term adverse outcomes included diagnosis of cerebral palsy, motor development index lower than 2 SDs below the mean on the BSID-II, visual impairment or hearing loss, death.

Notes

Country: Canada

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

Randomisation was performed by sealed, opaque envelopes prepared in blocks of 6

Allocation concealment (selection bias) Low risk

The authors describe the use of sealed opaque envelopes for the concealment of allocation

Blinding (performance bias and detection bias) High risk

The study was not blinded

Incomplete outcome data (attrition bias) Low risk

The number of participants in each group are clearly reported and accounted for. Incomplete outcomes addressed and all infants were kept in the assigned group for analysis.

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

There is no other known potential source of bias in the study. The study was completed as planned.

Leite 2004

Methods

Randomised controlled trial

Participants

The participants were 81 preterm neonates (< 37 gestational age), with birth weight less than 2000 g

Interventions

The newborns were divided in 2 groups: the early group, which started phototherapy 12 hours after birth, undergoing treatment for at least 96 hours; and the late group, which received phototherapy whenever the transcutaneous bilirubin reached 8 mg/dl and phototherapy suspended when bilirubin levels fell to 5 mg/dl. The source of phototherapy used was 8 FANEM Mod 007 devices equipped with 7 Philips TL20W/52 fluorescent lamps (special blue), at the wavelength of 400 to 540 nm and with a peak output of 450 nm.

Outcomes

Peak bilirubin concentration, the mean value of daily bilirubin levels, expressed in mg/dl; and length of phototherapy, expressed in hours

Notes

Country: Brazil

The study was carried out at the Center for Women's Health (CAISM) and Hospital Estadual de Sumaré (HES), public tertiary institutions affiliated with Universidade Estadual de Campinas-UNICAMP. The study was approved by the Research Ethics Committee of the School of Medicine of UNICAMP.

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

The authors mention that the patients were placed in 2 groups (randomly drawn out) within the first 12 hours of life

Allocation concealment (selection bias) Unclear risk

The authors did not provide any information on the method used for the concealment of allocation

Blinding (performance bias and detection bias) High risk

The study is unblinded

Incomplete outcome data (attrition bias) Low risk

81 patients were randomised, however, 11 patients were excluded: 10 of them died and 1 had a positive direct Coombs test. The number balanced across the 2 groups.

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

There is no other known potential source of bias in the study. The study was completed as planned. Financial support: FAPESP (www.fapesp.br)

Lucey 1968

Methods

Quasi-randomised trial. Participants were assigned alternately to either prophylactic phototherapy or to the control group.

Participants

A total of 111 infants of less than 2500 g birth weight were included in the study. The numbers of participants in the intervention and control arm were 53 and 58 respectively.

Interventions

Infants in the prophylactic phototherapy group were placed in light from 12 to 144 hours of age. All infants in the light treatment group were placed in isolettes or Gordon Armstrong incubators, equipped with a light chamber, as soon as possible after birth.

Outcomes

Daily serum bilirubin

Notes

Country: USA

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

Alternate assignment of participants

Allocation concealment (selection bias) High risk

There was no concealment of allocation

Blinding (performance bias and detection bias) Unclear risk

No information provide

Incomplete outcome data (attrition bias) Low risk

The numbers of participants in each group are clearly reported and accounted for

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

Both groups were comparable with respect important baseline characteristics such as: birth weight, gestational age, sex, Apgar score, etc.

The study was supported by a N.I.H Grant HD-02015-02

Morris 2008

Methods

Randomised controlled trial

Participants

1974 infants weighing between 501 and 1000 g at 12 to 36 hours of age. The numbers of participants in the intervention and control arm were 990 and 984 respectively.

Exclusion criteria were a terminal condition (defined as a pH < 6.8 or persistent bradycardia with hypoxaemia for > 2 hours), previous phototherapy, a major congenital anomaly, hydrops fetalis or severe haemolytic disease, congenital nonbacterial infection, or a judgement that the parents would be unable or unlikely to return for assessments at 18 to 22 months.

Interventions

For infants in the aggressive phototherapy group, phototherapy was initiated within 12 to 36 hours of age. The target irradiance level of the phototherapy was 15 to 40 μW per square centimetre per nanometer of wavelength.

Outcomes

Primary: death or neurodevelopmental impairment at 18 to 22 months of corrected age. Neurodevelopmental impairment was defined as blindness (no functional vision in either eye), severe hearing loss (hearing loss for which bilateral hearing aids were prescribed), moderate or severe cerebral palsy.

Secondary: patent ductus arteriosus requiring drug or surgical treatment, retinopathy of prematurity, intraventricular haemorrhage (IVH) by grade, peak total serum bilirubin, exchange transfusion, intraventricular haemorrhage

Notes

Country: USA

Multicentre trial conducted in 12 different centres

The study was sponsored by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Details on the study protocol can be found at http://www.clinicaltrials.gov/ct2/show/NCT00114543 External Web Site Policy

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

Participants randomly assigned to a treatment group by means of a centralised computer system

Allocation concealment (selection bias) Low risk

Allocation was done centrally

Blinding (performance bias and detection bias) Low risk

The outcomesassessors (neurologists and neurodevelopmental testers) were blinded

Incomplete outcome data (attrition bias) High risk

Follow-up rate was 89% of known survivors

Selective reporting (reporting bias) Low risk

All outcomes mentioned in the protocol were reported

Other bias Low risk

There is no other known potential source of bias in the study. The study was completed as planned.

Tripathi 2006

Methods

Randomised controlled trial

Participants

A total of 50 preterm neonates weighing < 1250 g born in the hospital during the study were included

Interventions

Phototherapy was administered by using standard phototherapy units. It was started at the time of admission in the prophylactic phototherapy group while in the control group it was started at serum bilirubin of 1% of the body weight in grams (as per the standard protocol of the neonatal word).

Outcomes

Peak serum bilirubin, age at which peak serum bilirubin levels were reached and number of exchange transfusions

Notes

Country: India

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

The method used for sequence generation was not mentioned. However, the authors mention that participants were randomly assigned to either of the 2 groups.

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

The study was unblinded

Incomplete outcome data (attrition bias) Low risk

The numbers of participants in each group are clearly reported and accounted for

Selective reporting (reporting bias) Unclear risk

Study protocol not available and therefore selective outcome reporting could not be assessed

Other bias Low risk

There is no other known potential source of bias in the study. The study was completed as planned.

Footnotes

BSID-II: Bayley Scales of Infant Development (BSID–II)
SD: standard deviation

Characteristics of excluded studies

Elliot 1974

Reason for exclusion

In this study phototherapy was commenced when the serum bilirubin level had reached 10 mg/dl in the prophylactic group and 15 mg/dl in the control group. This was not considered to be prophylactic.

Romagnoli 1996

Reason for exclusion

In this study phototherapy was commenced when serum bilirubin level was > 5 mg/dl in the prophylactic group and 9 mg/dl in the control group

Sanches 2004

Reason for exclusion

The information provided was from a conference proceeding. We did not did not find any published article from the study for full assessment.

Yaseen 2005

Reason for exclusion

The study included neonates with ABO incompatibility and positive Coombs' test

Characteristics of studies awaiting classification

  • None noted.

Characteristics of ongoing studies

  • None noted.
<

Summary of findings table

1 Prophylactic phototherapy for jaundice in preterm or low birth weight infants

Patient or population: preterm or low birth weight infants
Settings: neonatal units
Intervention: prophylactic phototherapy
Control: standard care
Outcomes Illustrative comparative risks* (95% CI) Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed risk Corresponding risk
Control Prophylactic phototherapy
Exchange transfusion Medium-risk population RR 0.22
(0.15 to 0.34)
2946
(3 studies)
⊕⊕⊕⊝
moderate 1
120 per 1000 26 per 1000
(18 to 41)
Cerebral palsy Medium-risk population RR 0.96
(0.5 to 1.85)
756
(2 studies)
⊕⊕⊕⊝
moderate 1
84 per 1000 81 per 1000
(42 to 155)
Peak serum bilirubin The mean peak serum bilirubin (all infants) in the intervention groups was
2.73 lower
(2.89 to 2.57 lower)
2319
(6 studies)
⊕⊕⊝⊝
low 2,3
Serum bilirubin greater than 10 mg/dl Medium-risk population RR 0.27
(0.22 to 0.33)
1090
(3 studies)
⊕⊕⊕⊝
moderate 4
600 per 1000 162 per 1000
(132 to 198)
Retinopathy of prematurity Medium-risk population RR 0.93
(0.77 to 1.13)
1687
(2 studies)
⊕⊕⊕⊕
high
225 per 1000 209 per 1000
(173 to 254)
All-cause mortality Medium-risk population RR 1.08
(0.93 to 1.26)
3044
(4 studies)
⊕⊕⊕⊝
moderate 5
157 per 1000 170 per 1000
(146 to 198)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

Footnotes

1 There was no mention of blinding of the outcome assessors in two of the studies.
2 In one of the studies participants were allocated alternately. The method of randomisation was unclear in two of the studies.
3 There is marked heterogeneity in the estimates of effect across the studies.
4 There was unclear allocation concealment in two of the studies.
5 There was unclear sequence generation and allocation concealment in two of the studies.

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References to studies

Included studies

Brown 1985

Brown AK, Kim MH, Wu PYK, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985;75:393-441.

Keenan WJ, Novak KK, Sutherland JM, Bryla DA, Fetterly KL. Morbidity and mortality associated with exchange transfusion. Pediatrics 1885;75:417-41.

Lipsitz PJ, Gartner LM, Bryla DA. Neonatal and infant mortality in relation to phototherapy. Pediatrics 1985;75:422-41.

Scheidt PC, Bryla DA, Nelson KB, Hirtz DG, Hoffman HJ. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 1990;85(4):445-63.

Wu YK, Joan EH, Kirkpatrick BV, White NB, Bryla A. Metabolic aspects of phototherapy. Pediatrics 1985;75:427-41.

Curtis 1985

Curtis-Cohen M, Stahl GE, Costarino AT, Polin RA. Randomized trial of prophylactic phototherapy in the infant with very low birth weight. Journal of Paediatrics 1985;107:121-4.

Giunta 1969

Giunta F, Rath J. Effect of environmental illumination in prevention of hyperbilirubinemia of prematurity. Pediatrics 1969;44:162-7.

Hodgman 1970

Hodgman JE, Schwartz A. Phototherapy and hyperbilirubinemia of the premature. American Journal of Diseases of Children 1970;119(6):473-7.

Jangaard 2007

Jangaard KA, Vincer MJ, Allen AC. A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500g: short- and long-term outcomes. Paediatrics and Child Health 2007;12(10):853-8.

Leite 2004

Leite MGC, Facchini FP. Evaluation of two guidelines for the management of hyperbilirubinemia in newborn babies weighing less than 2, 000 g. Jornal de Pediatria 2004;80(4):285-90.

Lucey 1968

Lucey J, Ferreiro M, Hewitt J. Prevention of hyperbilirubinemia of prematurity by phototherapy. Pediatrics 1968;41:1047-54.

Morris 2008

Morris BH, William Oh, Tyson JE, Stevenson DK, Phleps DL, O'Shea MT. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. New England Journal of Medicine 2008;359(18):1885-96.

Tripathi 2006

Tripathi S, Saili A. Effect of prophylactic phototherapy on neonatal hyperbilirubinemia of prematures. Indian Journal of Medical Sciences 2006;60(9):385-7.

Excluded studies

Elliot 1974

Elliot E, Monchrieff MW, George WHS. Phototherapy for hyperbilirubinemia in low birth weight infants. Archives of Disease in Childhood 1974;49(60):60-2.

Romagnoli 1996

Romagnoli C, Frezza S, De CMP, Maggio L, Rizzo V, Tortorolo G. Early or late phototherapy in the treatment of extremely preterm infants. Pediatria Oggi Medica e Chirurgica 1996;16(8-9):208-12. [CENTRAL: CN-00172981]

Sanches 2004

Sanches FBS, Almeida FB, Draque CM, Sanudo A, Peres CA, Kopelman BI. Prophylactic versus therapeutic phototherapy in very low birthweight infants. In: Pediatric Research. 2004. [CENTRAL: CN-00614394]

Yaseen 2005

Yaseen H, Khalaf M, Rashid N, Darwich M. Does prophylactic phototherapy prevent hyperbilirubinemia in neonates with ABO incompatibility and positive Coombs' test? Journal of Perinatology 2005;25:590-4.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Almeida 2004

Almeida MF. When should we start phototherapy in preterm newborn infants? Journal de Pediatria 2004;80(4):285-90.

Bratlid 2001

Bratlid D. Criteria for treatment of neonatal jaundice. Journal of Perinatology 2001;21:S88-S92.

Bryla 1985

Bryla DA. Development, design and sample composition. Pediatrics 1985;75(2):387-441.

Gale 2001

Gale R, Seidman DS, Stevenson DK. Hyperbilirubinemia and early discharge. Journal of Perinatology 2001;21(1):40-3.

Hansen 1996

Hansen TW. Therapeutic approaches to neonatal jaundice: an international survey. Clinical Pediatrics 1996;35(6):309-16.

Hansen 2005

Hansen TW. Treatment of neonatal jaundice. Tidsskr Nor Laegeforen 2005;125(5):594-8.

Hegyi 1994

Hegyi T, Goldie E, Hiatt M. The protective role of bilirubin in oxygen radical disease of the preterm infant. Journal of Perinatology 1994;14(4):296-300.

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;362(7414):557-60.

Higgins 2008

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of interventions Version 5.0.0. [updated February 2008]. Chichester: John Wiley & Sons, 2008.

Kumar 1999

Kumar RK. Neonatal jaundice. An update for family physicians. Australian Family Physician 1999;28(7):679-82.

Maisels 1998

Maisels MJ, Kring EA, Klarr J. Comparison of the efficacy of two fiberoptic phototherapy blankets. Pediatric Research 1998;43:183A.

McDonagh 1990

McDonagh AF. Is bilirubin good for you? Clinics in Perinatology 1990;17(2):359-69.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1, 500 gm. Journal of Pediatrics 1978;92(4):529-34.

RevMan 2008

Review Manager (RevMan) [Computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Rubaltelli 1983

Rubaltelli FF, Jori G, Reddi E. Bronze baby syndrome: a new porphyrin related disorder. Pediatric Research 1983;17(5):327-30.

Turkel 1980

Turkel SB, Guttenberg ME, Moynes DR, Hodgman JE. Lack of identifiable risk factors for kernicterus. Pediatrics 1980;66(4):502-6.

Other published versions of this review

  • None noted.

Classification pending references

  • None noted.

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Data and analyses

1 Prophylactic phototherapy versus control

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

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Exchange transfusion 3 2946 Risk Ratio (M-H, Fixed, 95% CI) 0.22 [0.15, 0.34]
1.1.1 Low threshold for exchange transfusion 1 922 Risk Ratio (M-H, Fixed, 95% CI) 0.20 [0.13, 0.31]
1.1.2 High threshold for exchange transfusion 2 2024 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.19, 2.28]
1.2 Neurodevelopmental impairment 1 1804 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.74, 0.99]
1.3 Cerebral palsy 2 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.3.1 All infants (birth weight < 2500 g) 2 756 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.50, 1.85]
1.3.2 Birth weight < 1000 g 1 30 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.04, 2.27]
1.4 Peak serum bilirubin 6 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.4.1 All infants 6 2319 Mean Difference (IV, Fixed, 95% CI) -2.73 [-2.89, -2.57]
1.4.2 Birth weight < 1000 g 2 2011 Mean Difference (IV, Fixed, 95% CI) -2.79 [-2.96, -2.62]
1.4.3 Birth weight < 1500 g 4 2138 Mean Difference (IV, Fixed, 95% CI) -2.69 [-2.86, -2.52]
1.5 Sensorineural hearing loss 1 681 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.07, 1.50]
1.6 Peak serum bilirubin (by time of intervention) 6 2319 Mean Difference (IV, Fixed, 95% CI) -2.73 [-2.89, -2.57]
1.6.1 Onset of phototherapy within 12 hours of birth 5 345 Mean Difference (IV, Fixed, 95% CI) -2.06 [-2.60, -1.53]
1.6.2 Onset of phototherapy within 36 hours of birth 1 1974 Mean Difference (IV, Fixed, 95% CI) -2.80 [-2.97, -2.63]
1.7 Serum bilirubin greater than 10 mg/dl 3 1090 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.22, 0.33]
1.7.1 All infants (birth weight less than 2000 g) 3 1090 Risk Ratio (M-H, Fixed, 95% CI) 0.27 [0.22, 0.33]
1.8 Serum bilirubin greater than 15 mg/dl 3 1116 Risk Ratio (M-H, Fixed, 95% CI) 0.13 [0.07, 0.23]
1.9 Duration of phototherapy (hours) 3 2088 Mean Difference (IV, Fixed, 95% CI) 49.76 [46.37, 53.15]
1.10 Patent ductus arteriosus 1 1974 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.85, 1.03]
1.11 Retinopathy of prematurity 2 1687 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.77, 1.13]
1.12 Intraventricular haemorrhage 2 2011 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.80, 1.10]
1.13 Duration of hospital stay (days) 2 2061 Mean Difference (IV, Fixed, 95% CI) -2.85 [-6.71, 1.01]
1.14 All-cause mortality 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.14.1 All infants (birth weight less than 2500 g) 4 3044 Risk Ratio (M-H, Fixed, 95% CI) 1.08 [0.93, 1.26]
1.14.2 Birth weight less than 1000 g 2 2051 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.91, 1.25]

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Figures

Figure 1

Refer to figure 1 caption below.

Study flow diagram (Figure 1 summary).

Figure 2

Refer to figure 2 caption below.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies (Figure 2 summary).

Figure 3

Refer to figure 3 caption below.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study (Figure 3 summary).

Figure 4 (Analysis 1.1)

Refer to figure 4 caption below.

Forest plot of comparison: 1 Prophylactic phototherapy versus control, outcome: 1.1 Exchange transfusion (Figure 4 summary).

Figure 5 (Analysis 1.3)

Refer to figure 5 caption below.

Forest plot of comparison: 1 Prophylactic phototherapy versus control, outcome: 1.3 Cerebral palsy (Figure 5 summary).

Figure 6 (Analysis 1.4)

Refer to figure 6 caption below.

Forest plot of comparison: 1 Prophylactic phototherapy versus control, outcome: 1.4 Peak serum bilirubin (Figure 6 summary).

Figure 7 (Analysis 1.7)

Refer to figure 7 caption below.

Forest plot of comparison: 1 Prophylactic phototherapy versus control, outcome: 1.7 Serum bilirubin > 10 mg/dl (Figure 7 summary).

Figure 8 (Analysis 1.14)

Refer to figure 8 caption below.

Forest plot of comparison: 1 Prophylactic phototherapy versus control, outcome: 1.14 All-cause mortality (Figure 8 summary).

Sources of support

Internal sources

  • Mount Sinai Hospital, Toronto, Ontario, Canada
  • Stellenbosch University, South Africa

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.

Feedback

  • None noted.

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2012 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.