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Ip S, Chung M, Trikalinos T, et al. Screening for Bilirubin Encephalopathy [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Oct. (Evidence Syntheses, No. 72.)

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Screening for Bilirubin Encephalopathy [Internet].

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1Introduction

Scope and Purpose

Some degree of jaundice or hyperbilirubinemia occurs in most newborns. Severe neonatal hyperbilirubinemia is associated with kernicterus, a rare condition characterized by athetoid spasticity, gaze and visual abnormalities, and sensori-neural hearing loss in survivors. It may also be associated with mental retardation. A 2003 review concluded that kernicterus has a mortality of at least 10% and a morbidity of at least 70%.1 The true incidence of kernicterus is unknown because it is not a mandatory reportable disease. However, a 2001 Joint Commission Sentinel Event Alert stated that cases of kernicterus have continued to be reported in recent years.2 Efforts have been made by clinicians and investigators to eliminate this rare disease by instituting system-level measures to screen for hyperbilirubinemia and prevent the occurrence of kernicterus.3–5 Most notable among these is a set of clinical practice guideline concerning the management of hyperbilirubinemia in infants of at least 35 weeks gestation published by the American Academy of Pediatrics (AAP) in 2004.3 The 2004 guideline emphasizes the attention to risk factors associated with hyperbilirubinemia, close followup of at-risk infants, and the use of phototherapy and exchange transfusion to decrease the level of hyperbilirubinemia as appropriate.

Tufts-New England Medical Center Evidence-based Practice Center (Tufts-NEMC EPC) completed a review in 2003 examining the effects of bilirubin on neurodevelopmental outcomes in infants of at least 34 weeks gestation.1 The report also examined the efficacy of phototherapy, the accuracy of transcutaneous bilirubin (TcB), and the various strategies for predicting hyperbilirubinemia. The Center on Primary Care, Prevention and Clinical Partnerships at the Agency for Healthcare Quality and Research (AHRQ), on behalf of the US Preventive Services Task Force (USPSTF), has now requested an update evidence report on the effectiveness of various screening strategies to prevent the development of kernicterus. This topic has not been previously considered by the USPSTF.

In the literature, the term “kernicterus” has been used interchangeably with both the acute and chronic findings of bilirubin encephalopathy. To avoid confusion as has been advocated by the AAP Subcommittee on Hyperbilirubinemia,3 we use the terms acute and chronic bilirubin encephalopathy in this report. The term “kernicterus” is reserved for the chronic form of bilirubin encephalopathy.

This review examines the effectiveness of screening for hyperbilirubinemia to reduce the incidence of acute or chronic bilirubin encephalopathy. It also examines the benefits and harms of phototherapy. Populations of interests are healthy term infants, pre-term infants of at least 35 weeks gestation, and their mothers. Examples of screenings are system approach measures based on risk factors assessment, universal screening for bilirubin level (either serum or transcutaneous), or combinations of both. Outcomes of interest are the rates of acute or chronic bilirubin encephalopathy (if data are available), or surrogate measures (e.g., bilirubin level ≥ 20, 25 mg/dL); and any health outcomes or adverse events related to phototherapy.

To expand on the background behind the present review, the following is a brief summary of the 2003 evidence review.1

Brief Summary of the 2003 Evidence Review

Relationship between peak bilirubin levels and/or duration of hyperbilirubinemia and neurodevelopmental outcome:

  • A summary of 28 reports of 123 cases of kernicterus in infants of at least 34 weeks gestation that spanned over 30 years affirms the role of elevated bilirubin level in kernicterus. The disease, although infrequent, has significant mortality (at least 10 percent) and long-term morbidity (at least 70 percent). It is important to note that a significant amount of demographic information was missing in these case reports. Thirty-five infants of at least 34 weeks gestation with idiopathic hyperbilirubinemia developed kernicterus with a total serum bilirubin level (TSB) ranging from 22.5 mg/dL to 54 mg/dL. Eighty-eight infants with hyperbilirubinemia and other co-morbid factors (like sepsis and hemolysis) developed kernicterus with TSB ranging from 4 mg/dL to 51 mg/dL.
  • The Collaborative Perinatal Project (CPP), with 54,795 live births between 1959 and 1966 from 12 centers in United States has, by far, the largest database for the study of hyperbilirubinemia. Newman and Klebanoff focused only on black and white infants with birth weight ≥ 2,500 grams, and performed a comprehensive analysis of 33,272 subjects on their 7-year-outcomes. All causes of jaundice were included in the analysis. The authors found no consistent association between peak bilirubin level and IQ. Rate of sensorineural hearing loss was not related to bilirubin level. Only the frequency of abnormal or suspicious neurologic examination result was associated with bilirubin.
  • Six high quality studies (not counting the CPP) showed significant relationship between abnormalities in brainstem auditory evoked potentials and high bilirubin levels. The majority reported resolution with treatment. Three studies reported hearing impairment associated with elevated bilirubin (>16 mg/dL to > 20 mg/dL).
  • Excluding CPP, of the eight studies reporting intelligence outcomes in subjects with hyperbilirubinemia, four were considered high quality. These four studies reported no association between IQ and bilirubin level with followup ranging from 6.5 years to 17 years.
  • Again, excluding CPP and the studies looking at IQ, of the nine studies primarily looking at behavioral and neurodevelopmental outcomes in patients, only three studies were of high methodologic quality. One showed a correlation between bilirubin level and decreased scores on newborn behavioral measurements. One found no difference in prevalence of central nervous system abnormalities at age 4 years when bilirubin was below 20 mg/dl, but infants with bilirubin above 20 mg/dl had a higher prevalence of central nervous system abnormalities. Another study that followed infants with bilirubin greater than 16 mg/dl found no relationship between bilirubin and neuro-visual-motor testing at 61 to 82 months of age.
  • Given the overall diverse conclusions, except in cases of chronic bilirubin encephalopathy, we concluded that the use of a single total serum bilirubin level (within the range described in the studies) to predict long-term behavioral or neurodevelopmental outcomes was inadequate and could lead to conflicting results.

Accuracy of various strategies for predicting hyperbilirubinemia:

  • Based on the results from a single study, pre-discharge hour-specific bilirubin percentiles yielded very good accuracy for predicting clinically significant neonatal hyperbilirubinemia in the first week of life, as determined by an analysis of the receiver operating characteristic (ROC) curve, with an area-under-the-curve (AUC) of 0.93. There was no study that directly compared one strategy with another.

Efficacy of phototherapy in reducing the peak bilirubin levels and effects on visual and neurodevelopmental outcomes:

  • Regardless of different protocols of phototherapy, the Number-Needed-to-Treat (NNT) for prevention of serum bilirubin level exceeding 20 mg/dL ranged from six to 10 in infants of at least 34 weeks gestation. This implies that one needs to treat six to 10 jaundiced neonates with TSB ≥ 15 mg/dL by phototherapy in order to prevent the TSB in one infant from rising above 20 mg/dL. Phototherapy combined with cessation of breastfeeding and substitution with formula was the most efficient treatment protocol for infants of at least 34 weeks gestation with jaundice.
  • Eight studies examined the effect of bilirubin reduction on brainstem auditory evoked response (BAER). All consistently showed treatments for neonatal hyperbilirubinemia significantly improved abnormal BAER’s in both healthy jaundiced infants and jaundiced infants with hemolytic disease.
  • Three studies evaluated the effect of phototherapy on visual outcomes. All showed no short- or long-term (up to 36 months) effect on vision as a result of phototherapy when infants’ eyes were properly protected during treatment.
  • There was no evidence to suggest that phototherapy for neonatal hyperbilirubinemia has any long-term neurodevelopmental adverse effect in either healthy jaundiced infants or infants with hemolytic disease.

Accuracy of transcutaneous bilirubin measurements:

  • The Minolta Airshields Jaundice Meter™, the Ingram Icterometer, and the SpectRx BiliCheck showed a linear correlation to TSB and could be useful as screening devices to detect clinically significant jaundice and decrease the need for determinations of TSB.
  • The Minolta Airshields Jaundice Meter™ appeared to perform less well in black infants as compared to white infants, performed best when measurements were made at the sternum, and performed less well when infants had been exposed to phototherapy. This instrument required daily calibrations and each institution must develop its own correlation curves of TcB to TSB. As a screening test, it did not perform consistently across studies as evidenced by the summary ROC curves. The Ingram Icterometer has the added limitation of lacking objectivity of the other methods as it is dependent on observer visualization of depth of yellow color of the skin.
  • BiliCheck™ and Colormate III devices that utilize reflectance data from multiple wavelengths appeared to be a significant improvement over the Ingram Icterometer and the Minolta AirShields bilirubinometer. This could be due to these devices’ ability to determine correction factors for the effect of melanin and hemoglobin.

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