As noted in several other chapters in this book, bilirubin encephalopathy and kernicterus are still occurring throughout the world with population-based estimates of incidence in North America and Europe ranging from 0.5 to 2.4 cases per 100,000 live births1 (Table 9-1). In contrast to the early clinical case descriptions, most of the infants who now develop kernicterus are not those with Rh disease and they often have no documented evidence of hemolytic disease.9 Many are term and late preterm infants who have been discharged from the nursery as “healthy newborns,” yet have returned to a pediatrician’s office, a clinic, or an emergency department with total serum bilirubin (TSB) levels often exceeding 30 mg/dL9—and have gone on to develop the classic neurodevelopmental findings associated with kernicterus.10 There is also a smaller group of infants, more difficult to identify, who suffer an unanticipated precipitous increase in the TSB while still in the hospital or soon after discharge and present with acute bilirubin encephalopathy.9,11,12 Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an important cause of the hyperbilirubinemia in some of these infants.9,12
| Author(s) | Country | Years | Ascertainment Case Definition | No. of Cases | Denominator | Rate |
|---|---|---|---|---|---|---|
| Bjerre and Ebbesen2 | Denmark | 1994–2002 | Registry; voluntary reports; ≥35 weeks gestation; TSB ≥31.1 mg/dL; symptoms of chronic bilirubin encephalopathy | 8 | 576,000 | 1.4/100,000 |
| Bjerre et al.3 | Denmark | 1994–2002 | National laboratory information system linked to medical reports; ≥35 weeks gestation and ≤28 days of age; TSB ≥26.5 mg/dL and advanced phase symptoms of bilirubin encephalopathy | 1 | 249,308a | 0.4/100,000a |
| Manning et al.4 | United Kingdom | 2003–2005 | Voluntary reports; ≥35 weeks gestation and <1 month of age; TSB ≥30 mg/dL; death or postmortem examination or typical sequelae at 12-month follow-up | 7 | 1,500,052 | 0.46/100,000 |
| Sgro et al.5 | Canada | 2002–2004 | Surveillance program; voluntary reports; ≥35 weeks gestation and ≤60 days of age TSB ≥25 mg/dL and/or exchange transfusion and clinically important neurologic abnormalities at final discharge | 13 | 640,000 | 2/100,000 |
| Sgro et al.6 | Canada | 2007–2008 | Surveillance program; voluntary reports; any child up to 6 years old; ≥35 weeks gestation at birth; TSB ≥25 mg/dL or exchange transfusion and two or more signs/symptoms of kernicterus; or abnormal MRI with history of hyperbilirubinemia | 22 | 900,000 | 2.4/100,000 |
| Burke et al.7 | United States | 1988–2005 | Hospital discharge abstracts; ≤30 days of age; ICD-9 for kernicterus and CPT for phototherapy or exchange transfusion | 436 | Not stated | 2.7/100,000 |
| Brooks et al.8 | California | 1988–1997 | State registry for developmental services; ICD-9 for kernicterus | 25 | 5,697,147 | 0.49/100,000 |
The American Academy of Pediatrics (AAP) in 200410 and the Canadian Paediatric Society in 200713 published guidelines on the management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, and similar, consensus-based guidelines have been published recently in Israel, Norway, and the United Kingdom.14–16 The key elements of the AAP guideline are listed in Table 9-2 and, although a recent commentary17 has provided some important modifications to these guidelines, the basic principles still apply.
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Because at some point during the first week almost every newborn has a TSB level that exceeds 1 mg/dL—the upper limit of normal for an adult—and approximately four of five newborns are jaundiced to the clinician’s eye,18 this type of transient bilirubinemia has been called “physiologic jaundice.” When TSB levels exceed the 95th percentile for the infant’s age in hours,19 the infant is often described as having “hyperbilirubinemia” or “pathologic jaundice,” a distinction that is arbitrary and not particularly helpful, as discussed below. Presumably, physiologic jaundice should apply to newborns whose TSB levels fall within a certain range but, as noted in Chapter 6, defining the normal serum bilirubin level in every population is not easy. Furthermore, in many infants in whom the bilirubin level clearly exceeds the 95th or even the 99th percentile, a battery of tests yields no identifiable pathology.20,21 Finally, interpreting bilirubin levels in the newborn provides a unique challenge because these levels change hourly for the first week or more, so that meaningful interpretation of TSB levels can only be made in relationship to the infant’s age in hours.10
Sackett et al.22 discuss the question of how to define the term “normal” and provide six different definitions of this term. The definition depends on why we are asking the question. In term and late preterm newborns, the most practical way of describing normal bilirubin levels is to use hour-specific percentiles,19,23–25 but this cannot be used in more premature infants. If untreated, low birth weight infants have exaggerated and prolonged hyperbilirubinemia and because this occurs in all preterm infants, it might be considered physiologic. But in these infants, TSB levels well within the “physiologic range” are potentially hazardous26,27 and are treated with phototherapy (see Chapter 10). Thus, today, the natural history of bilirubinemia in the very low birth weight infant is never observed and population-based norms cannot be applied to these infants. A TSB level of 10 mg/dL on day 4 in a 750-g neonate requires no investigation to identify a cause for the jaundice. Nevertheless, almost all neonatologists would treat this infant with phototherapy, because it is believed that treatment is much more likely to do good than harm.15,16,28 The TSB level of 10 mg/dL in this infant can be said to exceed a “therapeutic normal” level, defined by Sackett et al. as a “range of test results beyond which therapy does more good than harm.”22
The therapeutic normal level is also sometimes defined as an “operational” level for purposes of intervention.22 The recommendations of the AAP10 for the use of phototherapy and exchange transfusion in term and late preterm newborns are examples of the use of operational levels. The AAP recommends using phototherapy in a well term infant if the TSB level is ˜15 mg/dL at age 48 hours. Although a level of 15 mg/dL poses no imminent threat to the infant’s well-being, at that age it is well above the 95th percentile19 and, if left untreated, might increase to a level that is dangerous to the infant. The suggested intervention, phototherapy, is believed to be safe and effective and, under these circumstances, more likely to do good than harm.
We suggest that the terms physiologic and pathologic jaundice should be abandoned and instead “neonatal bilirubinemia” should be used. If we can agree on the terminology, then we should be able to agree on other descriptors for different TSB levels in term and late preterm infants. Others have suggested descriptors that are appropriate for different degrees of hyperbilirubinemia9 and it would be helpful to develop an approved common terminology so that terms such as “severe hyperbilirubinemia” have the same meaning for all clinicians. In term and late preterm infants, we suggest that hyperbilirubinemia is the appropriate term for a TSB level that exceeds the 95th percentile for the infant’s age in hours in that population.19 After 96 hours, TSB levels >20 mg/dL might be called severe hyperbilirubinemia and those >25 or 30 mg/dL extreme hyperbilirubinemia.
All pregnant women should be tested for ABO and Rh (D) blood type and undergo a serum screen for unusual immune antibodies.10 If such prenatal testing has not been performed, then a direct antibody test (DAT or direct Coombs), blood group, and Rh (D) type on the infant’s cord blood should be done. Identification of Rh-negative mothers is important because they require anti-D gammaglobulin to prevent Rh (D) sensitization. In infants of group O Rh-positive mothers, routine testing for blood type and DAT is optional provided there is appropriate surveillance and risk assessment before discharge and follow-up10 so that significantly jaundiced infants are not missed.
The first of 10 key elements in the AAP guidelines (Table 9-2) notes that clinicians should “promote and support successful breastfeeding,” although exclusive breastfeeding is associated with an increased risk of hyperbilirubinemia30–32 (see Chapter 6). In many, but not all, cases of severe hyperbilirubinemia in breastfed infants, poor caloric intake as a result of less effective breastfeeding (and manifested by increased weight loss) appears to play an important role.20,33–35 Although hypernatremic dehydration associated within inadequate breastfeeding is a well-known phenomenon,36 by itself, dehydration does not provide a plausible mechanism for severe hyperbilirubinemia. It is much more likely that in breastfed, dehydrated infants, it is the caloric deprivation and its effect on the enterohepatic circulation of bilirubin (see Chapter 6) that is primarily responsible for the hyperbilirubinemia.37–39
Currently, the only primary preventive intervention available that can mitigate the development of hyperbilirubinemia in exclusively breastfed infants is to provide appropriate lactation support to ensure that breastfeeding is successful.40,41 A recommended first step is to ask mothers to nurse their infants at least 8–12 times per day for the first several days42 because increasing the frequency of nursing significantly decreases the likelihood of subsequent hyperbilirubinemia.40,41,43 Evidence for adequate intake in the breastfed infant includes four to six wet diapers in 24 hours by day 3 accompanied by changes in stool color.44 By the fourth to fifth day, stools in an infant who is nursing well should have changed from meconium to mustard-colored, seedy stools.44,45
Unsupplemented breastfed infants experience their maximum weight loss by day 3 and, on average, lose 6.1 ± 2.5% (SD) of their birth weight.34,40,46–51 Thus, approximately 5–10% of exclusively breastfed infants lose 10% or more of their birth weight by day 3. The adequacy of milk production and transfer should be evaluated and the infant monitored if the weight loss is greater than 7–10%.44,52
All infants should be monitored clinically for the development of jaundice in the nursery and protocols established for assessing the jaundiced newborn.10 Detection of jaundice is enhanced by blanching the skin with digital pressure, thus revealing the underlying color of the skin and subcutaneous tissue. It is important for this assessment to be done in a well-lit room and preferably in daylight at a window.
The AAP recommends that protocols for assessing jaundice should include the circumstances in which a nurse can order a TSB measurement without a physician’s order.10 The nurse should order a TSB level in any infant who appears jaundiced before age 24 hours.53 If routine transcutaneous bilirubin (TcB) monitoring is used, the policy should indicate the TcB level (in relation to the infant’s age in hours) that calls for a TSB measurement. Examples include requiring a TSB if the TcB exceeds the 95th percentile on a TcB nomogram25 or the 75th percentile on the Bhutani nomogram19 (Figure 9-1).
Figure 9-1.
Nomogram for designation of risk in 2840 well newborns at ≥36 weeks gestational age with birth weight of ≥2000 g or ≥35 weeks gestational age and birth weight of ≥2500 g based on the hour-specific serum bilirubin values. The serum bilirubin level was obtained before discharge and the zone in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile. Note that because of sampling bias,109 this nomogram should not be used to represent the natural history of neonatal hyperbilirubinemia. (Reproduced from 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;103:6–14, with permission. Copyright 1999 by the American Academy of Pediatrics.)
For reasons that are, as yet, unexplained, dermal icterus is usually seen first in the face and then progresses in a caudal manner to the trunk and extremities so that, for a given bilirubin level, the skin of the face will appear more yellow than that of the foot.54 Although the cephalocaudal progression of jaundice has been confirmed repeatedly with visual assessment as well as by transcutaneous bilirubinometry,54–61 there is considerable overlap in the ranges of TSB levels corresponding to each of the dermal zones.54 Nevertheless, several studies suggest that more than 95% of newborns with TSB levels of ≥12 mg/dL will have jaundice below the level of the nipples, although this is also seen in many infants with lower TSB levels.55,57,62
On the other hand, an infant might have a TSB of 8 or 9 mg/dL at age 24 hours, a value that is above the 95th percentile19 (Figure 9-1), yet show no sign of jaundice,63 producing a false sense of security when further evaluation and early follow-up are required (see sections “Risk Assessment” and “Follow-Up”). Estimates of TSB levels (from physical examination by observers who have had various levels of training) and measured TSB levels have produced correlation coefficients of 0.4–0.7, but these studies have included mostly newborns with TSB levels of 12–15 mg/dL or less and have not directly addressed how frequently TSB levels high enough to warrant treatment at older ages would be missed.18,55,62,64,65 Darker skin pigmentation also makes visual assessment of jaundice more difficult.62,66
Before infants are discharged from the hospital, the TSB levels that require additional investigation, initiation of phototherapy, or closer follow-up are quite low10 and visual estimation at these TSB levels is not sufficiently accurate to allow these decisions to be made with confidence. Certainly, any newborn who appears jaundiced in the first 24 hours should have a TSB measured,10,53 and a recent consensus-based commentary recommends measurement of TcB or TSB in all infants prior to discharge.17 Some experts, and the recently published NICE guideline,16 recommend measurement of a TcB or TSB level in all jaundiced infants regardless of age but, in older infants with mild jaundice, we believe there is room for clinical judgment.
When light is transmitted to the skin, the yellowness of the reflected light can be measured to provide an objective measurement of skin color, and these principles have been applied to predict TSB levels from skin reflectance67,68 using easily portable transcutaneous bilirubinometers.69–71 Currently available devices marketed in the United States include the Draeger JM-103 (Draeger Medical, Hatboro, PA)69 and the BiliChek (Philips Children’s Medical Ventures, Monroeville, PA).70,71 Although these instruments use different algorithms and measurement techniques, the operating principles are similar. The details of how these bilirubinometers work have been described in Chapter 3 and we will deal here with a few clinically relevant issues.
TcB measurements have been evaluated in hospital nurseries18,25,72 and outpatient settings.73,74 They have the advantage of providing instantaneous information as well as reducing the likelihood that a clinically significant TSB will be missed.75 TcB measurements correlate quite closely with TSB measurements and are generally within 2–3 mg/dL of the TSB,71,76,77 although they are not a substitute for TSB values. The TcB is a measurement of the yellow color of the blanched skin and subcutaneous tissues, not the serum bilirubin, and should be used as a screening tool to help determine whether the TSB should be measured. TcB measurements can significantly reduce the number of TSB measurements needed in both the term nursery and the NICU.78–80 They help to estimate the risk of subsequent hyperbilirubinemia18,30 and they are invaluable in the outpatient setting.73,74 Because they are noninvasive, TcB measurements can be repeated several times during the birth hospitalization and provide useful information about the rate of rise of the bilirubin. When plotted on a nomogram (Figure 9-1), TcB levels that are crossing percentiles indicate the need for additional observation and evaluation.
Large studies of both the BiliChek and the JM-103 have shown good correlation between TcB and TSB measurements in diverse populations.25,69,71,81,82 The JM-103 tends to overestimate TSB measurements in darkly pigmented infants. As TcB measurements are used as a screening tool, this does not increase the risk of missing an elevated TSB, but will increase the number of unnecessary TSB measurements. The effect of skin tone on the performance of the JM-103 has been studied by Wainer et al.83 The highest precision and lowest bias were observed for medium skin toned infants. There was a tendency to underread the TSB in the lighter skin tone group and to overread it in the darker skin tone group. Nevertheless, the JM-103 performed well as a screening device in all skin tone groups.83
Although some studies have suggested that TcB measurements in infants <1000 g or 28 weeks of gestation are less reliable,84 others have not found this to be the case.80,85,86 Several studies have demonstrated the utility of TcB measurements in both LBW and ELBW infants in the NICU.77,80,84–88 In all of these studies, screening infants with TcB measurements using different cutoff values identified with appropriate accuracy infants who required a TSB measurement or phototherapy.
TcB measurements are less accurate and tend to underestimate the TSB at higher TSB levels.72,80,89–91 Thus, as the TSB increases, the number of false-negative TcBs also increases.30,83 If appropriate cutoff values are used, however, TcB measurements still work well as a screening device even at TSB levels of >15 mg/dL.74,83
Because variation among instruments can occur, the accuracy of the TcB instrument should be compared with laboratory TSB values before it can be relied upon as a screening tool. A TSB level should always be obtained when therapeutic intervention is being considered. Because the TcB tends to underestimate the TSB at higher TSB levels,75 investigators have adopted various techniques to avoid missing a high TSB level (i.e., a false-negative TSB measurement). These techniques include measuring the TSB if:
- The TcB value is at 70% of the TSB level recommended for the use of phototherapy.80
- The TcB value is above the high-intermediate risk line on the Bhutani nomogram (Figure 9-1)19 or the 95th percentile on a TcB nomogram.25 In one study, if the TcB was <75th percentile on the Bhutani nomogram, 0 of 349 infants had a TSB level above the 95th percentile (a negative predictive value of 100%).71,92
- At follow-up after discharge, the TcB value is >13 mg/dL.73,74 In two outpatient studies, no infant who had a TcB value ≤13 mg/dL had a TSB value of >17 mg/dL.73,74
TcB measurements are very helpful in the outpatient setting,73,74 but the price of these instruments has deterred practicing physicians from purchasing them. Ultimately, one might anticipate that TcB measurements will become as indispensable in the care of the jaundiced newborn as pulse oximetry is in assessing oxygen saturation in the newborn infant, or the asthmatic child.
Because phototherapy bleaches the skin, both visual assessments of jaundice and TcB measurements in infants undergoing phototherapy are not reliable. If an area of the skin is covered during phototherapy, however, TcB measurements in that area can be used to monitor the response to phototherapy.93,94
Instructions for the use of the BiliChek and JM-103 recommend obtaining TcB measurements from the forehead or the sternum. When JM-103 measurements from the forehead and sternum were compared with TSB measurements in 475 infants, the Pearson correlation coefficients were higher for the sternum (0.953) than those for the forehead (0.914).80 Because the forehead is exposed to ambient light, both in the nursery and following discharge, while the sternum is almost always covered, measurements from the sternum are probably a better choice. In a study of 31 infants comparing outpatient BiliChek measurements from the brow and sternum, brow readings were 20% lower than TSB values, but chest readings were only 5% lower.95
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