Screening for Severe Neonatal Hyperbilirubinemia

Vinod K. Bhutani


Pediatr Health. 2009;3(4):369-379. 

In This Article


Purpose of the Test

Clinical recommendations for predictive risk assessment aim to reduce the incidence of severe hyperbilirubinemia and bilirubin encephalopathies while minimizing the risks of unintended harm such as decreased breastfeeding, undue parental anxiety and unnecessary treatment. Clinical tests address the need for recognition of early-onset hyperbilirubinemia that are usually due to hemolytic disorders, such as isoimmunization, extravascular hemolysis (bruises and hematomas) and intravascular hemolysis (such as neonatal red blood cell or enzyme disorders), and predischarge risk assessment for late-onset hyperbilirubinemia.

Nature of the test

Assessment of clinical risks for severe neonatal hyperbilirubinemia[31,32,33] include exclusive and insufficient breast-milk transfer, family history of neonatal jaundice, bruising, cephalhematoma, ethnicity (Asian), maternal age (>25 years), male gender and gestational age less than 38 weeks (summarized in Table 2 ). The contribution of these risk factors to chronic bilirubin encephalopathy in healthy children is not well understood. Current literature identifies that combining clinical risk factors with bilirubin levels can be effective in predicting later significant or severe hyperbilirubinemia.[34,35] The predischarge bilirubin level, expressed as a risk zone on the bilirubin nomogram, when combined with multiple clinical risk factors had similar accuracy for predicting significant hyperbilirubinemia. In a single center study, an infant's gestational age improved the overall predictive accuracy of predischarge bilirubin risk zone.[35]

Visual Assessment of Jaundice. All infants should be routinely monitored for the development of jaundice and nurseries should establish protocols for its assessment at the time when the infant's vital signs are measured at least every 8-12 h. Assessment is best carried out in a well-lit room or, preferably in daylight by a window.

Jaundice can be detected by blanching the skin with digital pressure on the forehead, mid-sternum or the knee/ankle, revealing the underlying color of the skin and subcutaneous tissue.[1,36] It is usually seen first in the face and progresses caudally to the trunk and extremities, however, it can also sometimes appear and fade, similar to a tan. It may be helpful to adjust for intensity of color (yellow or orange) as well as to corroborate the progression of jaundice with a TcB value (Figure 1).[37]

Figure 1.

Modified Kramer scale to assess and plot the progression of newborn jaundice.
This is according to demarcated skin zones and intensity of color (yellow or orange) as correlated to TcB levels.
TcB: Transcutaneous bilirubin.
Adapted from [38].

The absence of jaundice is not an indication of the absence of hyperbilirubinemia. Estimating the degree of hyperbilirubinemia can lead to errors, and the absence or the severity of jaundice is not predictive of subsequent severe hyperbilirubinemia.[36,37,38] Before 72 h of age (prior to discharge), the presence of clinical jaundice (particularly at less than 24 h of age) needs to be corroborated by a bilirubin measurement (TB or TcB). In a recent study, the nurses' predischarge assessment of jaundice extent was only moderately correlated with bilirubin concentration and was similar in black and nonblack infants.[39] The correlation was particularly weak among late preterm infants. Jaundice extent had poor overall accuracy for predicting risk of significant hyperbilirubinemia (c-statistic = 0.65), however, complete absence of jaundice had high sensitivity (95%) and negative predictive value (99%) for ruling out the development of significant hyperbilirubinemia. Currently, clinicians should not solely rely on cephalocaudal jaundice progression to estimate bilirubin levels during the birth hospitalization or to predict subsequent severe neonatal hyperbilirubinemia. However, the complete absence of jaundice (when reliably recognized) may predict that these infants will not develop significant hyperbilirubinemia.

Bilirubin Measurement. The strategies recommended for predischarge assessment are screening by a TB/TcB measurement plotted on an hour-specific nomogram that identifies risk zones and/or assessment of clinical risk factors.[1,12] The nomogram provides a more appropriate understanding of the magnitude of hyperbilirubinemia in the context of postnatal age in hours and the percentile level as defined for healthy infants.[22] TB and TcB are the only currently available clinical tests that can be used to predict the risk of subsequent severe hyperbilirubinemia when these values are plotted on an hour-specific nomogram (Figure 2). When measured concurrent to the routine predischarge metabolic screening in term and near-term newborns and plotted on the nomogram in lieu of using day-specific value the bilirubin value, TB is a powerful and significant screening tool (Figure 3). It defines the high risk and low risk for postdischarge excessive hyperbilirubinemia. The predictive accuracy and the significance of its role as a useful and practical screening are shown below. The clinical significance of these data is not only the identification of a high-risk population, but also that of the low-risk population. The predictive ability of TB has now been validated by several other prospective studies.[12,26] Recent data indicate that at least one major clinical analyzer provided inaccurate bilirubin values for Neonatal Bilirubin Survey specimens administered by the College of American Pathologists. The use of human serum-based survey specimens to calibrate bilirubin testing is likely to reduce system error and yield a substantial improvement in bilirubin measurements.[40]

Figure 2.

An approach for a timed follow-up to repeat jaundice and bilirubin evaluation based on predischarge bilirubin testing by plotting total bilirubin or transcutaneous bilirubin (<15 mg/dl) on an hour-specific bilirubin nomogram.
Data adapted from [16].

Figure 3.

Receiver operating curve (c-statistic = 0.83) for the predictive abilities of the 40th, 75th and the 95th percentile-based risk zones and their false-positive and false-negative rates (%). Its location in the upper left corner is indicative of the usefulness of the risk zones.
Data adapted from [1].

Transcutaneous bilirubin testing is a potentially accurate and noninvasive alternative to TB measurement.[12,41,42,43,44,45] TcB devices are useful screening tools and provide a valid estimate of the TB level, although data are limited. TcB levels can be unreliable during phototherapy or with exposure to sunlight owing to the bleaching effect of light on the skin. Confounding effects of skin melanin content among different races and manufacturing consistency among devices are additional limitations. More recently, the BiliCheck™ device (Phillips-Respironics Inc., Murraysville, PA, USA) and the JM-103™ device (Konica Minolta/Air-Shields® JM-103 Jaundice Meter® from Drager Medical, Telford, PA, USA), have overcome earlier limitations of traditional devices by correcting for skin melanin content. They can provide accurate and reproducible measurements comparable to clinical laboratory tests for serum samples. Measurements in newborns using the new TcB devices are within 2 to 3 mg/dl (34-51 μmol/l) of the TB and useful for TB levels less than 15 mg/dl (257 μmol/l). The accuracy and precision of TcB greater than 15 mg/dl is unverified.

Implications of Testing

Practical decision analysis in the clinical setting is complicated by variability in bilirubin measurements attributed to laboratory and sampling methodologies and uncertainty regarding threshold TB/TcB values that can be regarded as safe. By expressing TB values in terms of risk zones, rather than using an actual TB value, the imprecision of TB measurement is reduced and the low-risk zone is possibly a safe zone for term and healthy neonates.

Use of Hour-specific Bilirubin Nomogram to Guide Follow-up. The primary purpose of the bilirubin nomogram is to provide a simple and accurate method for quantifying the risk that a newborn will develop hyperbilirubinemia, requiring treatment after discharge from the nursery. We recommend that infants in the low-risk zone, particularly those discharged from the hospital before 72 h of life, as well as breastfed infants, be seen by a healthcare provider (office or home visit) on day 4-5 of life to evaluate their nutritional status (hydration, weight loss and the ability to breastfeed) and to observe for obvious jaundice. Table 3 charts a bilirubin care map for designating follow-up for a repeat test based on the predischarge bilirubin risk zone.[12,16]

What does an Abnormal Test Result Mean? The hour-specific bilirubin nomogram serves as a useful clinical guide for management since the patterns of severity in mg/dl are at or above the 95th percentile for age in hours. The high-risk zone defines the threshold for which interventions and recommendations for vigilant follow-up are indicated in the diverse US population. This nomogram was not specifically designed to be used in premature infants less than 35 weeks at gestational age or infants with comorbidities requiring intensive neonatal care. These infants, who are not considered healthy, are at higher risk of developing bilirubin toxicity and of developing kernicterus at lower bilirubin levels. In term or near-term infants, the nomogram is helpful in identifying infants who have early hyperbilirubinemia (those in the high-risk zone or with a rapid rate of rise) and who require further evaluation for a cause of their hyperbilirubinemia. Once it is known that an infant has hemolysis owing to conditions such as ABO, Rhesus or minor blood type incompatibility or G6PD, the nomogram is useful to track the progression and resolution of hyperbilirubinemia.

What does a Normal Test Result Mean? Infants with TB or TcB values at less than 40th percentile for age in hours are designated as a low-risk group. These infants may then be followed less intensively but according to routine recommendations to allow for efficient targeting of services as well as cost. More importantly, the families can be reassured that they are most likely to have a safe experience with newborn jaundice. Late preterm infants who have TB/TcB less than 40th percentile should be followed owing to possible delayed onset of severe hyperbilirubinemia ( Table 3 ).

Predischarge Management. A system-based approach in well baby nurseries can address parental education, clinical recognition of jaundice and predischarge risk assessment with multidisciplinary strategies as listed in Box 2 .

Postdischarge Management Recommendations. A seamless continuation of care to provide the following services:

  • Ensuring the arrangement and compliance for outpatient follow-up appointments;

  • Training of personnel to handle outpatient phone calls for assessment of a symptomatic jaundiced newborn;

  • Rapid emergency room/office intervention plans to transfer a symptomatic neonate to a neonatal intensive care facility;

  • Expeditious and timely intervention with the appropriate and effective bilirubin reduction strategies. If appropriate follow-up cannot be ensured in the presence of elevated risk for developing severe hyperbilirubinemia, it may be necessary to delay discharge either until appropriate follow-up can be ensured or the period of greatest risk has passed.

Accuracy of Screening Tests to Predict Need for Treatment

No studies have directly addressed whether screening with risk factor assessments or bilirubin testing reduces the incidence of chronic bilirubin encephalopathy. Overall, screening by individual or combined use of clinical risk factors, such as TcB or TB measurements, is effective in predicting a subsequent high bilirubin level. Only two risk factors have been consistently identified: exclusive breastfeeding (with poor milk transfer) and younger gestational age. These have yet to be independently validated in diverse populations. There are no current studies that directly address whether infants identified by routine bilirubin testing predicts the need for phototherapy. Descriptive uncontrolled observations suggest that screening is associated with increased diagnoses of hyperbilirubinemia and fewer readmissions for hyperbilirubinemia. Of these, infants with TcB measurements less than the 75th hour-specific percentile in one study and below the 90th hour-specific percentile in another study do not reach TB measurements that necessitate use of phototherapy.[12]


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