Trends of Transcutaneous Bilirubin in Neonates Who Develop Significant Hyperbilirubinemia Lito Mantagou, Sotirios Fouzas, Eleni Skylogianni, Ioannis

Giannakopoulos, Ageliki Karatza and Anastasia Varvarigou Pediatrics; originally published online September 10, 2012; DOI: 10.1542/peds.2012-0732

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Trends of Transcutaneous Bilirubin in Neonates Who Develop Significant Hyperbilirubinemia Lito Mantagou, Sotirios Fouzas, Eleni Skylogianni, Ioannis Giannakopoulos, Ageliki Karatza and Anastasia Varvarigou Pediatrics; originally published online September 10, 2012; DOI: 10.1542/peds.2012-0732
Updated Information & Services Permissions & Licensing including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/early/2012/09/04 /peds.2012-0732 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xh tml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Trends of Transcutaneous Bilirubin in Neonates Who Develop Signicant Hyperbilirubinemia

WHAT S KNOWN ON THIS SUBJECT: Although the natural course of bilirubin levels has been extensively studied in general neonatal populations, there is a paucity of data regarding bilirubin trends in neonates before the development of signicant hyperbilirubinemia. WHAT THIS STUDY ADDS: This study provides data on the natural course of transcutaneous bilirubin before the development of signicant hyperbilirubinemia, and on the effect of different demographic and perinatal risk factors on the rate of bilirubin increase in neonates with borderline bilirubin values.
AUTHORS: Lito Mantagou, MD, Sotirios Fouzas, MD, Eleni Skylogianni, MD, Ioannis Giannakopoulos, MD, Ageliki Karatza, MD, and Anastasia Varvarigou, MD
Department of Pediatrics, University Hospital of Patras, Patras, Greece KEY WORDS hyperbilirubinemia, jaundice, neonates, transcutaneous bilirubin ABBREVIATIONS AAPAmerican Academy of Pediatrics G6PBglucose-6-phosphate dehydrogenase TcBtranscutaneous bilirubin TSBtotal serum bilirubin www.pediatrics.org/cgi/doi/10.1542/peds.2012-0732 doi:10.1542/peds.2012-0732

abstract
OBJECTIVES: To provide data on the natural course of transcutaneous bilirubin (TcB) levels in neonates before the development of signicant hyperbilirubinemia, and to assess the effect of different demographic and perinatal factors on the rate of TcB increase. METHODS: We analyzed 2454 TcB measurements from 419 neonates before the development of signicant hyperbilirubinemia. Mean TcB values and TcB percentiles for designated times were calculated, and the effect of different risk factors on the rate of TcB increase was assessed. TcB percentile curves were plotted for comparison on a population-based TcB nomogram. RESULTS: Blood incompatibilities and glucose-6-phosphate dehydrogenase deciency were associated with higher rates of TcB increase during the rst 36 to 48 postnatal hours, whereas smaller gestational age, increased weight loss, and exclusive breastfeeding had a similar but later effect. Compared with general population norms, a different pattern of TcB increase was noted in neonates who developed signicant hyperbilirubinemia, but with a substantial overlap of TcB values during the rst 24 to 48 postnatal hours. CONCLUSIONS: We provide data on the natural course of TcB levels before the development of signicant hyperbilirubinemia in a white population of term and near-term neonates. Smaller gestational age, blood incompatibilities, glucose-6-phosphate dehydrogenase deciency, increased weight loss, and exclusive breastfeeding signicantly affected the rate of TcB increase in a time-dependent manner. These ndings may assist in assessing the risk for signicant hyperbilirubinemia and planning appropriate follow-up strategies for neonates with borderline bilirubin levels. Pediatrics 2012;130:e898e904

Accepted for publication May 29, 2012 Address correspondence to Sotirios Fouzas, MD, Department of Pediatrics, University Hospital of Patras, Rio, Patras, 265 04, Greece. E-mail: sfouzas@gmail.com PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2012 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose. FUNDING: No external funding.

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In the era of early discharge from nurseries and maternity units, prompt detection of neonates at risk for developing signicant hyperbilirubinemia has become particularly challenging.1 On this premise, hour-specic evaluation and predischarge risk assessment of bilirubin levels according to the 2004 American Academy of Pediatrics (AAP) practice guidelines,2 has proved effective in reducing the incidence of severe jaundice.3,4 In the same guidelines, transcutaneous bilirubin (TcB) was recommended as an alternative to total serum bilirubin (TSB) for screening jaundiced neonates 1 ; and because transcutaneous bilirubinometry minimizes invasive blood sampling and allows for a timeeffective and reasonably accurate estimation of bilirubin levels, the method has become particularly popular among health care professionals involved in neonatal care.5 In recent years, several TcB nomograms have been developed in an attempt to incorporate transcutaneous bilirubinometry into daily clinical practice.613 Using such population-based nomograms, signicant hyperbilirubinemia is usually dened as a TcB value that exceeds the 95th hour-specic percentile.14 However, current evidence suggests that there is an important overlap of TcB values between neonates who will and those who will not develop signicant hyperbilirubinemia, 11,12 an overlap that could, and seems to, limit the predictive ability of percentile-based nomograms, especially during the rst 24 to 48 postnatal hours.11,12,15 In this context, knowledge of the natural course of bilirubin levels in neonates who ultimately develop signi cant hyperbilirubinemia would be extremely useful, as it could allow for the earlier identication and appropriate follow-up of these infants. Data on TcB trends in neonates who require
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phototherapy are sparse,11,12 however, because these neonates were either excluded or not separately analyzed in most relevant studies.610,13 The aim of the current study was to provide data on the natural course of TcB values in term and near-term neonates before the development of signicant hyperbilirubinemia. We also sought to examine the effect of different demographic and perinatal factors on bilirubin increment rate, and to assess the pattern of TcB increase in these neonates in comparison with general population norms.

METHODS
Study Population This prospective cohort study was performed at the well-infant nursery of the University Hospital of Patras (Patras, Greece) from September 2006 to August 2011. All neonates with gestational age $35 weeks and birth weight $2000 g who developed significant hyperbilirubinemia and required phototherapy during their hospital stay or after discharge were eligible to participate in the study. Signicant hyperbilirubinemia was dened as a TSB value that exceeded the hourspecic threshold for phototherapy according to the AAP guidelines.2 Neonates admitted to the NICU and those with hyperbilirubinemia who required intervention within the rst 24 hours were excluded. The study was approved by the local ethics committee, and informed consent was obtained from 1 of the parents. The assignment of any medical intervention (including TSB measurements and decision for phototherapy) was strictly adhered to the guidelines applied in our nursery for the management of neonatal jaundice. Protocol Because our institution applies a discharge policy of $72 hours for healthy

infants delivered vaginally and $96 hours for those having cesarean delivery, additional outpatient follow-up that involves repeat TcB (and if needed TSB) measurements is offered to all jaundiced infants. Neonates who develop signicant hyperbilirubinemia before discharge receive phototherapy in the well-infant nursery. Those who develop signicant hyperbilirubinemia after discharge are admitted to our Pediatric Department. Thus, neonates participating in this study had serial TcB measurements at regular time intervals of 12 6 2 hours until the development of signicant hyperbilirubinemia and initiation of phototherapy. TcB values were recorded on a special ow sheet attached to the medical le of each infant. Only TcB measurements obtained at 12 6 2, 18 6 2, 24 6 4, 36 6 4, 48 6 4, 60 6 4, 72 6 4, 96 6 4, 108 6 6, and 120 6 6 hours were considered in the current study. Measurements obtained after the initiation of phototherapy were excluded. TcB sampling was performed with the BiliCheck bilirubinometer (PhilipsRespironics, Koninklijke Philips Electronics NV, Eindhoven, the Netherlands) by properly trained physicians in adequately illuminated rooms and according to the standard described technique.16 TcB measurements were followed by TSB determinations if the TcB value was $15 mg/dL, or if the TcB value exceeded or was closer than 2 mg/dL to the phototherapy hourspecic threshold recommended by the AAP.2 TSB measurements were performed by direct spectrophotometry (Unistat Bilirubinometer, Richert Inc, Depew, NY). Risk Factors Factors known to be associated with the development of signicant hyperbilirubinemia17 were recorded. Demographic and perinatal data were

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obtained from the medical les. Gestational age estimates were based on the last menstrual period and/or early second trimester ultrasound. The exact time of the initiation of phototherapy was noted. Weight loss % was calculated as (birth weight prephototherapy weight) / birth weight % and was expressed in % loss per 24 hours. All neonates with signicant hyperbilirubinemia were assessed before the initiation of phototherapy for ABO and rhesus incompatibilities, positive Coombs test, and glucose-6-phosphate dehydrogenase (G6PD) deciency. All these parameters (including TcB values) were prospectively recorded in a computerized database. Statistics Mean TcB values and TcB percentiles for each designated time, and the mean TcB increase for 12-hour time intervals up to 96 postnatal hours, were calculated. The rate of TcB increase was determined and expressed in mg/dL/h. The effect of different demographic and perinatal factors on the TcB increase was assessed for each time epoch by multiple regression analysis. TcB percentile curves were created and selected percentile curves were plotted for comparison on an hour-specic TcB nomogram,11 which reects the natural course of TcB levels in white, healthy, term, and near-term neonates, and on

the Bhutani predictive nomogram.18 The data were analyzed by using SPSS version 17.0 (SPSS, Inc, Chicago, IL).

TABLE 1 Characteristics of the Study

Population
n Gender: female Gestational age, wk Prematuritya Birth weight, g Delivery Vaginal Cesarean delivery Feeding Breast Formula Both Weight loss per 24 h, % Blood incompatibilities ABO Rhesus Positive Coombs test G6PD deciency Previous sibling with jaundiceb Bruising or cephalhematoma Intermediate care 419 224 (53.5) 383/7 6 14/7 92 (22.0) 3360 6 470 300 (71.6) 119 (28.4) 188 (44.9) 147 (35.1) 84 (20.0) 1.9 6 1.4 73 (17.4) 43 (10.3) 26 (6.2) 20 (4.8) 47 (11.2) 64 (15.3) 22 (5.3)

RESULTS
During the study period, 7302 neonates were cared for in our well-infant nursery; of these, 450 (6.2%) developed signicant hyperbilirubinemia. Thirty-one infants were excluded from the study (24 owing to signicant hyperbilirubinemia within the rst 24 hours and 7 owing to the inconvenient timing of TcB measurements), resulting in a nal sample of 419 neonates from whom a total of 2454 TcB measurements were recorded and analyzed. Fifty neonates (11.9%) reached phototherapy thresholds between 24 and 48 hours, 145 (34.6%) between 48 and 72 hours, 149 (35.6%) between 72 and 96 hours, 47 (11.2%) between 96 and 120 hours, and 28 infants (6.7%) developed signicant hyperbilirubinemia after 120 postnatal hours. Eighteen neonates (4.3%) were diagnosed with signicant hyperbilirubinemia after hospital discharge and were readmitted. Population demographic and perinatal characteristics are presented in Table 1. Mean TcB values and TcB percentiles at designated times are analyzed in Table 2. The rates of TcB increase for different 12-hour time epochs are presented in Table 3, whereas the rates of TcB

Data are mean 6 SD or number of cases (%). a Gestational age ,37 wk. b Jaundice that required phototherapy.

increase in relation to the presence of different risk factors are presented in Appendix 1. Multiple regression analysis revealed that ABO incompatibilities and G6PD deciency were positively related to the rate of TcB increase during the rst 36 and 48 postnatal hours respectively, whereas rhesus incompatibility affected bilirubin increment rate between 24 and 36 hours. A similar relation was noted between percent weight loss and rate of TcB increase after the 48 postnatal hours, whereas the effect of breastfeeding became signicant after the age of

TABLE 2 Mean TcB Values and TcB Percentiles at Designated Times

Postnatal Age, h 12 6 2 (n = 305) TcB, mg/dL Mean (SD) Percentiles 1st 5th 10th 50th 90th 95th 6.2 (0.9) 4.4 4.5 5.0 6.2 7.5 8.0 18 6 2 (n = 283) 7.4 (1.2) 4.9 5.1 5.8 7.3 9.2 9.6 24 6 4 (n = 405) 8.8 (1.5) 5.9 6.1 6.9 8.9 10.6 11.0 36 6 4 (n = 384) 11.2 (1.7) 7.9 8.1 8.7 11.1 13.1 15.1 48 6 4 (n = 341) 13.1 (1.7) 9.7 10.1 11.1 13.0 15.2 16.0 60 6 4 (n = 268) 14.6 (1.6) 11.3 11.8 13.1 14.6 16.7 17.5 72 6 4 (n = 203) 16.2 (1.2) 13.0 13.5 14.8 16.4 17.5 17.8 84 6 4 (n = 121) 17.0 (1.1) 14.9 15.4 16.0 17.1 18.0 18.6 96 6 4 (n = 75) 17.8 (1.0) 15.8 16.3 17.0 17.8 18.9 19.0 108 6 6 (n = 41) 18.5 (1.0) 16.2 16.8 17.6 18.5 19.4 19.8 120 6 6 (n = 28) 19.1 (1.1) 16.8 17.3 18.2 19.0 19.9 20.9

TcB measurements that were obtained after initiation of phototherapy were not included.

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Male Gender Gestational Age Birth Weight Vaginal Delivery Breastfeeding % Weight Loss ABO Incompatible Rhesus Incompatible Coombs Test + G6PD Deciency

Combined effect (factors are adjusted for each other) on the mean rate of TcB increase assessed by multiple regression analysis and presented by standardized regression coefcients b. Signicant values are indicated with an asterisk. P , .001. c P , .01. d P , .05.

72 hours. Conversely, gestational age was inversely related to the rate of TcB increase after the 48 postnatal hours. The effect of gender, birth weight, mode of delivery, and Coombs test on the TcB increment rate was not signicant (Table 3). In Fig 1, the 5th-, 10th-, and 50thpercentile TcB curves of our population are presented in comparison with the 50th-, 75th-, and 95th-percentile curves of a population-based TcB nomogram for white term and near-term infants. During the rst 24 postnatal hours, the 10th-percentile TcB curve of our cohort coincided with the 75th-percentile curve of the hour-specic TcB nomogram, and exceeded the 95th percentile after the age of 48 hours. Similarly, the 5thpercentile TcB curve of our neonates did not exceed the 75th and 95th percentiles of the nomogram until the age of 36 and 72 hours, respectively. In Fig 2, the 5th- and 10th-percentile TcB curves of our cohort were plotted on the Bhutani predictive nomogram. The 5th-percentile TcB curve of our cohort was constantly within the lowintermediate risk zone of the Bhutani nomogram during the rst 72 postnatal hours, whereas the 10thpercentile curve coincided with the 75th percentile of the nomogram up to the age of 60 hours.

high in neonates who required phototherapy, whereas it decreased in those who did not develop signicant hyperbilirubinemia. An important overlap of TcB values between the 2 groups was also reported.11,12 The results of the current study corroborate these earlier ndings (Fig 1), suggesting that the use of such population-based nomograms for predicting subsequent significant hyperbilirubinemia in neonates should be done with extreme caution, especially during the rst 24 to 48 postnatal hours. There is also a paucity of data in the literature regarding the effect of different demographic or perinatal factors on the rate of bilirubin increase in neonates who develop signicant hyperbilirubinemia. In a nested casecontrol study, Kuzniewicz et al19 assessed the effect of such factors in neonates with high TSB levels (1722.9 mg/dL at age $48 hours), and they found that smaller gestational age, bruising on examination, family history of jaundice, and exclusive breastfeeding were important predictors for severe hyperbilirubinemia. Although this study cannot be compared with ours because of major methodological differences, it revealed that risk factors known to be associated with signicant hyperbilirubinemia in the general population17 may be also applicable in neonates with already increased bilirubin levels. In the current study, neonates with smaller gestational age, blood incompatibilities, G6PD deciency, increased weight loss, and exclusively breastfed, had higher rates of TcB increase. Interestingly, the effect of these factors was time dependent. Blood incompatibilities and G6PD deciency affected the rate of TcB increase earlier (ie, during the rst 3648 hours), whereas smaller gestational age, increased weight loss, and exclusive breastfeeding had a later effect. These ndings, which are in
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Factors and Effecta

TABLE 3 Mean TcB Increment Rates and the Effect of Different Factors on the Rate of TcB Increase

20.018 20.030 20.098 d 0.139* c 0.342* b 0.717* b 0.655*

0.077 20.111 20.105 20.124 20.117 0.310 0.275

0.007 0.013 0.058 0.020 0.104 0.004 0.002

0.059 0.048 0.103 0.105 0.185 d 0.360* c 0.421*

0.039 0.070 0.064 b 0.242* c 0.380* c 0.463* b 0.512*

0.221* d 0.124* 0.068 0.040 0.077 0.112 0.098

0.039 d 0.140* 0.046 0.020 0.044 0.025 0.015

0.096 0.078 0.056 0.041 0.026 0.003 0.001

0.163* d 0.131* d 0.130* 0.078 0.037 0.001 0.001

DISCUSSION
The current study is the rst to focus on the natural history of TcB levels before the development of signicant hyperbilirubinemia in neonates. In 2 previous population-based reports,11,12 we have shown that term and late preterm neonates who required phototherapy presented a quite different pattern of TcB increase compared with their counterparts who did not develop signicant jaundice. After an initial (up to 2436 postnatal hours) TcB increase, which was comparable between the 2 groups, the rate of increase remained

Mean Increment Rate (SD), mg/dL/h Time Intervals, h

1224 2436 3648 4860 6072 7284 8496

0.23 (0.11) 0.22 (0.11) 0.21 (0.10) 0.19 (0.10) 0.19 (0.08) 0.10 (0.04) 0.09 (0.04)

0.084 0.078 0.041 0.058 0.040 0.019 0.038

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FIGURE 1
Graphical comparison between the 5th-, 10th-, and 50th-percentile TcB curves of our study population and the 95th-, 75th-, and 50th-percentile curves of an hour-specic TcB nomogram11 that reects the natural course of TcB levels in white, healthy, term, and near-term neonates. *Percentile curves of the TcB nomogram.11

low-intermediate risk TcB measurements.24 The results of the current study, however, suggest that the 75th-percentile curve of the Bhutani nomogram could not be used as a reliable high-risk cutoff in our population, as 10% of the TcB measurements were within the lowintermediate risk zone during the rst 60 postnatal hours, and thus would be misclassied as low risk (Fig 2). Our ndings corroborate previous concerns regarding false-negative rates of the Bhutani predictive nomogram, 25 especially when TcB measurements are used. 26,27 The ndings of the current study should be considered in the context of its potential limitations. We provide data obtained from a sample of white Greek neonates and from a single center. Therefore, although newgeneration transcutaneous bilirubinometers have been shown not to be affected by skin pigmentation and proved highly effective among heterogeneous populations,16,28 our ndings may not be generalizable beyond our settings. The gold standard used to dene signicant hyperbilirubinemia in this study was the AAP phototherapy thresholds,2 an approach that might be considered questionable.14 However, there is evidence that the implementation of the AAP guidelines for the management of neonatal jaundice was associated with a dramatic decline in the incidence of severe and dangerous hyperbilirubinemia.3,4 We consider, therefore, that this therapeutic14 denition of signicant hyperbilirubinemia is a realistic, safe, and closer to clinical practice approach.

FIGURE 2
Graphical comparison between the 5th- and 10th-percentile TcB curves of our study population and Bhutanis predictive nomogram. HRZ, high-risk zone; HIRZ, high-intermediate risk zone; LIRZ, lowintermediate risk zone; LRZ, low-risk zone; TcB, transcutaneous bilirubin.

accordance with the results of earlier reports,2023 may assist health care professionals in stratifying the risk for extreme hyperbilirubinemia and planning appropriate follow-up strategies for neonates with borderline bilirubin levels. Although the current study was not designed to assess the reliability of predictive nomograms in identifying neonates at risk for signicant hyperbilirubinemia, important ndings emerged when TcB values of our cohort were plotted on the nomogram developed by Bhutani et al.18 This
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nomogram is a popular predictive tool that has been broadly recommended for predischarge risk assessment of subsequent severe hyperbilirubinemia. 2,24 Although the Bhutani nomogram was based on, and designated for, TSB measurements, the demarcator between its high- and lowintermediate risk zone (ie, the 75thpercentile curve of the nomogram) has been proposed as a reasonable cutoff for identifying high-risk TcB values.16 Moreover, a different approach is recommended for highintermediate risk compared with

CONCLUSIONS
The current study provides data on the natural course of TcB levels before the development of signi cant

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hyperbilirubinemia in a white population of term and near-term neonates. Infants with smaller gestational age, blood incompatibilities, G6PD deciency, increased weight loss, and who

were exclusively breastfed, presented higher rates of TcB increase; the effect of these factors, however, was time dependent. These ndings may assist health care professionals involved in

neonatal care in assessing the risk for signicant hyperbilirubinemia and planning appropriate follow-up strategies for neonates with borderline bilirubin levels.

REFERENCES
1. Bhutani VK, Johnson LH, Keren R. Diagnosis and management of hyperbilirubinemia in the term neonate: for a safer rst week. Pediatr Clin North Am. 2004;51(4):843861, vii 2. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297316 3. Mah MP, Clark SL, Akhigbe E, et al. Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening. Pediatrics. 2010;125(5). Available at: www.pediatrics.org/cgi/content/ full/125/5/e1143 4. Kuzniewicz MW, Escobar GJ, Newman TB. Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. Pediatrics. 2009;124(4):1031 1039 5. el-Beshbishi SN, Shattuck KE, Mohammad AA, Petersen JR. Hyperbilirubinemia and transcutaneous bilirubinometry. Clin Chem. 2009;55(7):12801287 6. Sanpavat S, Nuchprayoon I, Smathakanee C, Hansuebsai R. Nomogram for prediction of the risk of neonatal hyperbilirubinemia, using transcutaneous bilirubin. J Med Assoc Thai. 2005;88(9):11871193 7. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the rst 96 hours in a normal newborn population of . or = 35 weeks gestation. Pediatrics. 2006;117(4): 11691173 8. De Luca D, Romagnoli C, Tiberi E, Zuppa AA, Zecca E. Skin bilirubin nomogram for the rst 96 h of life in a European normal healthy newborn population, obtained with multiwavelength transcutaneous bilirubinometry. Acta Paediatr. 2008;97(2):146150 9. Engle WD, Lai S, Ahmad N, Manning MD, Jackson GL. An hour-specic nomogram for transcutaneous bilirubin values in term and late preterm Hispanic neonates. Am J Perinatol. 2009;26(6):425430 10. Mishra S, Chawla D, Agarwal R, Deorari AK, Paul VK. Transcutaneous bilirubin levels in healthy term and late preterm Indian neonates. Indian J Pediatr. 2010;77(1):4550 Fouzas S, Mantagou L, Skylogianni E, Mantagos S, Varvarigou A. Transcutaneous bilirubin levels for the rst 120 postnatal hours in healthy neonates. Pediatrics. 2010; 125(1). Available at: www.pediatrics.org/ cgi/content/full/125/1/e52 Fouzas S, Karatza AA, Skylogianni E, Mantagou L, Varvarigou A. Transcutaneous bilirubin levels in late preterm neonates. J Pediatr. 2010;157(5):762766, e1 Yu ZB, Dong XY, Han SP, et al. Transcutaneous bilirubin nomogram for predicting neonatal hyperbilirubinemia in healthy term and late-preterm Chinese infants. Eur J Pediatr. 2011;170(2):185191 Maisels MJ. What s in a name? Physiologic and pathologic jaundice: the conundrum of de ning normal bilirubin levels in the newborn. Pediatrics . 2006;118(2): 805 807 Romagnoli C, Tiberi E, Barone G, et al. Validation of transcutaneous bilirubin nomogram in identifying neonates not at risk of hyperbilirubinaemia: a prospective, observational, multicenter study. Early Hum Dev. 2012;88(1):5155 Bhutani VK, Gourley GR, Adler S, Kreamer B, Dalin C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics. 2000;106(2). Available at: www.pediatrics.org/cgi/content/full/106/2/e17 Watchko JF. Identication of neonates at risk for hazardous hyperbilirubinemia: emerging clinical insights. Pediatr Clin North Am. 2009; 56(3):671687 Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specic serum bilirubin for subsequent signicant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103(1):614 Kuzniewicz MW, Escobar GJ, Wi S, Liljestrand P, McCulloch C, Newman TB. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr. 2008;153(2):234240 Maisels MJ, Kring E. The contribution of hemolysis to early jaundice in normal newborns. Pediatrics. 2006;118(1):276279 Kaplan M, Algur N, Hammerman C. Onset of jaundice in glucose-6-phosphate dehydrogenase-de cient neonates. Pediatrics . 2001;108(4):956 959 Draque CM, Saudo A, de Araujo Peres C, de Almeida MF. Transcutaneous bilirubin in exclusively breastfed healthy term newborns up to 12 days of life. Pediatrics. 2011; 128(3). Available at: www.pediatrics.org/ cgi/content/full/128/3/e565 Salas AA, Salazar J, Burgoa CV, De-Villegas CA, Quevedo V, Soliz A. Signicant weight loss in breastfed term infants readmitted for hyperbilirubinemia. BMC Pediatr. 2009; 9:82 Maisels MJ, Bhutani VK, Bogen D, Newman TB, Stark AR, Watchko JF. Hyperbilirubinemia in the newborn infant . or =35 weeks gestation: an update with clarications. Pediatrics. 2009;124(4):1193 1198 Slaughter J, Annibale D, Suresh G. Falsenegative results of pre-discharge neonatal bilirubin screening to predict severe hyperbilirubinemia: a need for caution. Eur J Pediatr. 2009;168(12):14611466 Rodrguez-Capote K, Kim K, Paes B, Turner D, Grey V. Clinical implication of the difference between transcutaneous bilirubinometry and total serum bilirubin for the classication of newborns at risk of hyperbilirubinemia. Clin Biochem. 2009;42 (3):176179 Varvarigou A, Fouzas S, Skylogianni E, Mantagou L, Bougioukou D, Mantagos S. Transcutaneous bilirubin nomogram for prediction of signicant neonatal hyperbilirubinemia. Pediatrics . 2009;124(4): 10521059 Grohmann K, Roser M, Rolinski B, et al. Bilirubin measurement for neonates: comparison of 9 frequently used methods. Pediatrics. 2006;117(4):11741183

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APPENDIX 1 Mean Rates of TcB Increase at Different Time Intervals in Relation to Various Risk Factors for Signicant Hyperbilirubinemia
Time Intervals, h (No. of Paired Measurements) 1224 (298) Gender, males/females Prematurity, yes/no Delivery, vaginal/cesarean Feeding, breast/formulad Weight loss, yes/noe ABO incompatibility, yes/no Rhesus incompatibility, yes/no Coombs test, positive/ negative G6PD deciency, yes/no Bruising or cephalhematoma, yes/no Previous sibling with jaundice, yes/no 0.25 / 0.22* 0.24 / 0.23 0.24 / 0.22 0.24 / 0.23 0.24 / 0.23 c 0.29 / 0.22* 0.27 / 0.23 a 0.28 / 0.23* b 0.29 / 0.22* 0.23 / 0.23 0.22 / 0.23
a

2436 (364) 0.23 / 0.21 0.22 / 0.21 a 0.24 / 0.21* 0.22 / 0.22 0.24 / 0.22 b 0.26 / 0.21* b 0.26 / 0.22* 0.25 / 0.21 a 0.28 / 0.22* 0.22 / 0.21 0.22 / 0.22

3648 (326) 0.21 / 0.20 0.21 / 0.21 0.21 / 0.20 0.21 / 0.20 0.24 / 0.21 0.24 / 0.21 0.24 / 0.22 0.23 / 0.21 a 0.27 / 0.21* 0.21 / 0.21 0.23 / 0.21

4860 (229) 0.19 / 0.19 a 0.22 / 0.18* 0.19 / 0.19 0.21 / 0.19 b 0.21 / 0.17* 0.21 / 0.18 0.21 / 0.19 0.20 / 0.19 0.24 / 0.19 0.20 / 0.19 0.21 / 0.19

6072 (195) 0.19 / 0.18 b 0.23 / 0.18* 0.18 / 0.19 a 0.21 / 0.18* b 0.22 / 0.17* 0.20 / 0.19 0.19 / 0.19 0.20 / 0.19 0.25 / 0.19 0.19 / 0.19 0.19 / 0.18

7284 (118) 0.11 / 0.10 c 0.14 / 0.09* 0.10 / 0.10 c 0.13 / 0.08* c 0.14 / 0.07* 0.12 / 0.10 0.10 / 0.10 0.12 / 0.10 NAf 0.11 / 0.10 0.12 / 0.10

8496 (75) 0.08 / 0.09 c 0.13 / 0.09* 0.08 / 0.09 c 0.12 / 0.08* c 0.13 / 0.08* 0.10 / 0.09 0.11 / 0.09 NAf NAf 0.10 / 0.09 0.11 / 0.09

Data are rates of TcB increase in mg/dL/h. Signicant values are indicated with an asterisk. NA, non applicable. a P , .05. b P , .01. c P , .001. d Breastfeeding versus formula or mixed feeding. e Weight loss . 3.3% per 24 h (75th percentile of the study population). f Insufcient number of neonates with the risk factor present.

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MANTAGOU et al