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Transcutaneous bilirubin measurement in neonates

Figure 1. Phototherapy is provided for infants with high bilirubin levels.
Figure 2. Infant undergoing transcutaneous bilirubin measurement on the sternum.

Neonatal jaundice is common. Though generally benign, hyperbilirubinemia occasionally leads to neurological dysfunction. Many healthcare experts advocate universal screening for neonatal hyperbilirubinemia before hospital discharge. Serum bilirubin measurement is the standard method of assessing bilirubin levels. Transcutaneous bilirubin measurement provides a noninvasive way of approximating serum bilirubin concentrations. At levels up to 15 mg/dL (257 µmol/L), transcutaneous levels correlate well with serum levels, making this method ideal for screening.
by Dr A. C. Wickremasinghe, Dr W. J. Cook and Dr B. S. Karon

Neonatal jaundice is extremely common. Virtually all newborn infants will have a total serum bilirubin level of >1 mg/dL (17.1 µmol/L), which is the upper limit of normal in adults. Up to 60% of infants have clinically evident jaundice in the first week of life. Newborns are affected due to increased bilirubin production, decreased bilirubin clearance and increased enterohepatic circulation. For most infants, this “physiological jaundice” resolves without long-term sequelae.
Rarely, hyperbilirubinemia leads to bilirubin-induced neurological dysfunction, which includes acute bilirubin encephalopathy and its permanent sequelae, kernicterus. Chronic bilirubin encephalopathy can manifest as cerebral palsy, hearing loss, dental enamel dysplasia, upward gaze paralysis and rarely intellectual or other handicaps. The morbidity and mortality rates associated with kernicterus are at least 70% and 10%, respectively.
The National Quality Forum in the United States considers kernicterus to be one of 28 serious preventable adverse events referred to as “never events”. In the United States, the American Academy of Pediatrics recommends that all infants be assessed for risk of significant hyperbilirubinemia before hospital discharge, either through risk factor assessment or bilirubin measurement [1]. The Canadian Paediatric Society recommends that all infants receive total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) measurement between 24 and 72 hours of life [2]. An hour-specific nomogram, published in 1999, is commonly used to determine risk of hyperbilirubinemia [3]. This tool stratifies infants into one of four risk zones based on their serum bilirubin levels; from this, clinicians can base decisions about follow-up. Interlaboratory variability must be considered when interpreting the results.
Early identification of infants at risk for significant hyperbilirubinemia increases the likelihood that noninvasive bilirubin-reducing intervention will be successful. For infants with high bilirubin levels, phototherapy is provided. Phototherapy induces the isomerisation of bilirubin to forms that can be more readily excreted [Figure 1]. It is estimated that 6-10 infants with TSB levels ≥ 15 mg/dL (257 µmol/L) need to be treated to prevent the TSB of one infant from rising to above 20 mg/dL (342 µmol/L) [4]. For those infants for whom phototherapy fails, or who show signs of bilirubin encephalopathy, exchange transfusion is generally performed.

Recently, the recommendation for universal screening for hyperbilirubinemia has been questioned. The United States Preventive Services Task Force concluded that the evidence is insufficient to assess the benefits and harms of screening for hyperbilirubinemia to prevent chronic bilirubin encephalopathy [4]. The clinical impact of this is not yet known.

Visual inspection is often used to assess jaundice. However, studies have shown clinical assessment to be an inaccurate predictor of hyperbilirubinemia, especially in infants with darker skin tones. Additionally, interrater reliability is low, even among experienced health care providers.

Serum bilirubin measurement
Bilirubin measurement has traditionally been performed through blood sampling. Blood for bilirubin measurement can be of capillary (ie: heel lance), venous or arterial origin. Measurements are obtained via a chemical reaction (the Diazo method), direct spectrophotemetry of whole blood (blood gas analysers or bilirubinometers), spectrophotemetry of separated serum or plasma on an automated chemistry system (the Vitros method), or high performance liquid chromatography (HPLC). HPLC, although suffering from fewer interferences than most laboratory methods, is not practical for routine use. The Diazo method is widely used to estimate bilirubin concentrations, but (depending upon manufacturer formulation) may have interferences with hemoglobin and other intracellular compounds; this can be problematic as blood from neonates is often hemolyzed due to the difficulty of neonatal blood collection.

Bilirubin sampling is one of the most common reasons for neonatal venipuncture. Phlebotomy in infants has many downsides, including pain and stress for infants and parents, potential risk of infection, delay in obtaining results and the need for ancillary support, both by phlebotomy staff and the laboratory. Studies comparing heel lancing to venipuncture have shown the former  to be more painful for infants, and heel lancing may rarely be associated with osteomyelitis.

Transcutaneous bilirubin measurement
Transcutaneous bilirubin measurement has recently gained popularity as a noninvasive way to measure bilirubin levels in neonates. Measurements are obtained using multiwavelength spectral reflectance from the skin surface. The meter’s optic head is pressed against the infant’s skin, usually the forehead or chest, generating a light [Figure 2]. The light passes through the infant’s subcutaneous tissue, and the reflected light returns to the spectrophotometer. A number displayed on the device indicates the intensity of the yellow colour of the reflected light.

The benefits of TcB measurement are based on its noninvasiveness: decreased pain, stress, skin injury and potential for infection. Additionally, TcB measurement provides results more quickly than venipuncture and does not require phlebotomy or laboratory support. However, TcB measurements may not be as reliable after phototherapy and may be affected by sunlight exposure. Measurements cannot be made on skin that is bruised, birthmarked or covered with hair.
The relationship between TcB and TSB is linear. Studies evaluating the correlation between TSB and TcB have produced varied results, with some finding TcB to overestimate TSB, and others finding it to underestimate TSB. TcB is generally thought to reasonably approximate TSB for values <15 mg/dL (257 µmol/L) [1]. Additionally, having blood collected in an amber tube, which protects the sample from light, versus a clear tube, may provide a higher correlation between TSB and TcB values [5].

The two transcutaneous bilirubinometers that have been studied most extensively are the Air-Shields Jaundice Meter (Konica Minolta) and the BiliChek (Respironics, Inc). Both are thought to be acceptable for screening [6]. The Jaundice Meter uses two wavelengths (450 nm and 550 nm) to measure bilirubin. The present version, the JM-103, shows better correlation with TSB than did its predecessors. It needs daily calibration, and may not be as accurate in African Americans as in Caucasians [7]. The BiliChek device uses multiple wavelengths over the entire spectrum of visible light for spectral reflectance. It corrects for the effects of melanin, hemoglobin and dermal thickness. One study showed its correlation with HPLC to be stronger than that of standard laboratory measurements [8]. However, it requires that a clean, disposable tip be used with each measurement, adding to its cost.

Of other devices studied, Bilitest BB77 (Bertocchi SRL Elettromedicali) underestimated TSB at values ≥ 12 mg/dL (205 µmol/L), BiliMed (Medick SA) was less accurate than the BiliChek, and the Colormate III (Chromatics Color Sciences International Inc) requires a baseline measurement to be done for each infant and is no longer manufactured [9,10,11]. Icterometers have been used in the past, but are less reliable as they depend on observer visualisation of the yellow colour of the skin.

Quality issues need to be considered when using transcutaneous bilirubinometers. The mean intradevice coefficients of variation were 1.5% for the JM-102 and near 9% for the BiliChek [6]. The interdevice precision for the difference between two readings on the BiliChek was 2.2 mg/dL (37 µmol/L) [6]. In order to obtain accurate results, staff must be trained on the proper use of the devices.

Some advocates of universal screening consider TcB measurement to be the optimal method of screening before hospital discharge. Though there has been concern that implementing universal screening for neonatal hyperbilirubinemia will increase serum blood draws, the evidence does not support this. A study evaluating the effects of universal screening with TcB found no increase in serum blood draws and fewer hospital readmissions (1.8 vs. 4.5%) after initiation of the screening protocol; however, more initial phototherapy (7.7 vs 5.9%) was performed [12]. This study estimated that implementing universal screening with TcB would cause a small but statistically insignificant increase in cost [12].

There is a paucity of studies examining TcB in the outpatient setting. One study showed TcB to systematically underestimate TSB in outpatients [13]. In this population, it is suggested that the chest is a better location for measurement than the forehead, as it is exposed to less light. Further studies are needed to better determine the optimal use of TcB after
hospital discharge.

Transcutaneous bilirubin measurement can be used to screen neonates for hyperbilirubinemia before hospital discharge, as it reasonably approximates low to medium serum bilirubin levels. Its noninvasive nature allows for less discomfort for infants. It is important that transcutaneous bilirubin levels are adjusted to match local laboratory serum values. Further studies should be performed before transcutaneous bilirubin is routinely used in outpatients.  The long-term cost/benefit ratio of universal screening has yet to be elucidated.

1. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks Gestation. Pediatrics 2004; 114(1): 297-316.
2. Canadian Paediatric Society, Fetus and Newborn Committee. Guidelines for Detection, Management and Prevention of Hyperbilirubinemia in Term and Late Preterm Newborn Infants (35 or More Weeks’ Gestation). Paediatr Child Health 2007;12(5):1B-12B.
3. Bhutani VK, Johnson L, Sivieri EM. Predictive Ability of a Predischarge Hour-Specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near-Term Newborns. Pediatrics 1999;103(1):6-14.
4. US Preventive Services Task Force. Screening of Infants for Hyperbilirubinemia to Prevent Chronic Bilirubin Encephalopathy: US Preventive Services Task Force Recommendation Statement. Pediatrics 2009; 124(4): 1172-7.
5. Karon BS, Teske A, Santrach PJ, Cook WJ. Evaluation of the BiliChek Noninvasive Bilirubin Analyzer for Prediction of Serum Bilirubin and Risk of Hyperbilirubinemia. Am J Clin Pathol 2008; 130: 976-982.
6. Wong CM, van Dijk PJ, Laing IA. A Comparison of Transcutaneous Bilirubinometers: SpectRx BiliCheck Versus Minolta AirShields. Arch Dis Child Fetal Neonatal Ed 2002; 87(2): F137-40.
7. Maisels MJ, Ostrea EM Jr, Touch S, Clune SE, Cepeda E et al. Evaluation of a New Transcutaneous Bilirubinometer. Pediatrics 2004;113(6):1628-35.
8. Rubaltelli FF, Gourley GR, Loskamp N, Modi N, Roth-Kleiner M et al. Transcutaneous Bilirubin Measurement: A Multicenter Evaluation of a New Device. Pediatrics 2001;107(6):1264-71.
9. Bertini G, Pratesi S, Cosenza E, Dani C. Transcutaneous Bilirubin Measurement: Evaluation of Bilitest. Neonatology 2008;93(2):101-5.
10. De Luca D, Zecca E, Corsello M, Tiberi E, Semeraro C et al. Attempt to Improve Transcutaneous Bilirubinometry: A Double-Blind Study of Medick BiliMed Versus Respironics BiliCheck. Arch Dis Child Fetal Neonatal Ed 2008;93(2):F135-9.
11. El-Beshbishi SN, Shattuck KE, Mohammad AA, Petersen JR. Hyperbilirubinemia and Transcutaneous Bilirubinometry. Clinical Chemistry 2009; 55 (7): 1280-7.
12. Petersen JR, Okorodudu AO, Mohammad AA, Fernando A, Shattuck KE. Association of Transcutaneous Bilirubin Testing in Hospital with Decreased Readmission Rate for Hyperbilirubinemia. Clinical Chemistry 2005; 51(3): 540-544.
13. Engle WD, Jackson GL, Stehel EK, Sendelbach DM, Manning MD. Evaluation of a Transcutaneous Jaundice Meter Following Hospital Discharge in Term and Near-Term Neonates. Journal of Perinatology 2005; 25(7):486-90.

The authors
Andrea C. Wickremasinghe MD1
Walter J Cook MD1
Brad S Karon MD, PhD2
1Department of Pediatric and Adolescent Medicine, and
2Department of Laboratory Medicine and Pathology
Mayo Clinic,
Rochester, MN 55905, USA


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