Subsequent Hyperbilirubinemia Research Articles

Screening and early postnatal management strategies to prevent hazardous hyperbilirubinemia in newborns of 35 or more weeks of gestation

Although kernicterus is a rare condition, it is still being reported in North America and Western Europe in addition to less developed parts of the world. The majority of affected infants are term and late-preterm newborns who have been discharged from the nursery as 'healthy newborns' yet have subsequently developed extreme hyperbilirubinemia and the classic neurodevelopmental findings associated with kernicterus. Published guidelines provide the basic tools for preventing hazardous hyperbilirubinemia and the two most important of these are a systematic assessment, prior to discharge, of each infant, for the risk of severe hyperbilirubinemia, and appropriate follow-up based on the time of discharge and the risk assessment. The most recent recommendations call for a predischarge measurement of the serum or transcutaneous bilirubin in all infants. When combined with the gestational age and other risk factors for hyperbilirubinemia, this provides the best estimate of the risk, or lack of risk, for subsequent hyperbilirubinemia, and determines the timing of follow-up and the need for further evaluation and treatment. The application of these principles to the management of the jaundiced newborn might not eliminate every case of kernicterus, but should contribute to a reduction in its occurrence.

Does Measuring the Changes in TcB Value Offer Better Prediction of Hyperbilirubinemia in Healthy Neonates?

We evaluated the diagnostic value of changes in transcutaneous bilirubin (TcB) levels for prediction of subsequent hyperbilirubinemia in healthy term and late-preterm neonates. Neonates at 35 weeks of gestation were enrolled in a prospective study. Two TcB determinations were performed for all enrolled neonates (N = 358). The first assessment (TcB(1)) was performed at 24 +/- 6 hours of age, followed by a second (TcB(2)) >or=12 hours later. Changes in TcB levels were calculated. TcB values were plotted on an hour-specific serum bilirubin nomogram, and risk zones were recorded. Of the 358 neonates enrolled, 325 neonates (91%) were monitored for hyperbilirubinemia until 5 days of age. The mean ages of TcB(1) and TcB(2) estimations were 23 +/- 4 hours and 42 +/- 4 hours, respectively. A total of 14.9% of neonates (48 of 325 neonates) developed hyperbilirubinemia by 5 days of age. The sensitivity, specificity, and positive and negative likelihood ratios for prediction of subsequent hyperbilirubinemia for TcB(1) (zone >2, >75th percentile) were 80.4%, 58.0%, 1.9, and 0.34; those for TcB(2) (zone >2, >75th percentile) were 82.6%, 79.0%, 4.0, and 0.22; and those for the change in TcB levels (>0.18 mg/dL per hour, >75th percentile) were 82.5%, 82.9%, 4.8, and 0.21, respectively. Gestational age, TcB risk zone, and change in TcB levels were found to be independent predictors of subsequent hyperbilirubinemia. Single TcB measurements at 30 to 48 hours predict hyperbilirubinemia with a reasonably high degree of accuracy. Changes in TcB levels do not offer any added clinical benefit.

Transcutaneous Bilirubin Nomograms

To compare available nomograms in the literature defining trends in bilirubin levels across populations with different risk factor profiles and to study a mathematical bilirubin kinetics model describing the natural course of jaundice and the bilirubin rate of rise needed to cross percentile curves. We searched PubMed for publications between March 1999 and March 2009 that created transcutaneous nomograms. We performed the same search among abstracts presented in the past 2 years at meetings of the Pediatric Academic Societies or the European Society for Paediatric Research. Inclusion criteria were gestational age of at least 35 weeks among study subjects, the use of an electronic transcutaneous bilirubinometer, and creation of a nomogram based on hour-specific bilirubin values. Four articles met the selection criteria. Jaundice risk factors were analyzed, and raw data were analyzed using nonlinear regression to describe trends in bilirubin levels and kinetics. The bilirubin exaggerated rate of rise needed to cross percentile curves was calculated. Significant differences in bilirubin values exist across populations, and there is substantial variability in rates of rise. Hispanic neonates demonstrate higher rates of rise and later plateaus. Bilirubin rates of rise tend to plateau and become null (equilibrium between bilirubin production and elimination) at about 96 hours of life. Rates of rise needed to cross percentile curves decrease over time but are lower (approximately 0.11 mg/dL/h [to convert bilirubin level to micromoles per liter, multiply by 17.104]) in the first 48 hours of life than previously thought. Transcutaneous bilirubin levels plateau and then decrease after about 96 hours of life in healthy neonates, with some differences across populations. A bilirubin rate of rise higher than in the previous period implies that bilirubin production exceeds elimination and indicates high risk for subsequent hyperbilirubinemia in neonates.

Delayed pediatric office follow-up of newborns after birth hospitalization.

Key recommendations of the American Academy of Pediatrics guideline on management of severe hyperbilirubinemia in healthy infants of >or=35 weeks' gestation include predischarge screening for risk of subsequent hyperbilirubinemia, follow-up at 3 to 5 days of age, and lactation support. Little information is available on contemporary compliance with follow-up recommendations. To assess timing and content of the first newborn office visit after birth hospitalization in urban and suburban pediatric practices in Houston, Texas. We reviewed office records for the first visit within 4 weeks of birth during January through July 2006 for apparently healthy newborns with a gestational age of >or=35 weeks or birth weight of >or=2500 g seen within a pediatric provider network. For each pediatrician, we selected every fifth patient up to a total of 6. Of 845 records abstracted, 698 (83%) were eligible for analysis. Infants were seen by 136 pediatricians in 39 practices. They had vaginal (64%) or cesarean (36%) deliveries at 20 local hospitals, of which 17 had routine predischarge bilirubin screening policies. Only 37% of all infants, 44% of vaginally delivered infants, and 41% of exclusively breastfed infants were seen before 6 days of age. Thirty-five percent of the infants were seen after 10 days of age. Among 636 infants seen at <or=15 days, jaundice was noted on examination in 33%; of these, 44% had bilirubin measured. Nine infants had phototherapy documented after birth hospitalization. Among a large group of urban and suburban pediatricians, implementation of the American Academy of Pediatrics recommendation for follow-up was inconsistent, and delayed follow-up was common. Understanding reasons for delayed follow-up and providing guidance for jaundice management may promote a safer first week of life.

Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia

To evaluate predischarge transcutaneous bilirubin (TcB) measurements combined with risk factors as predictors of the risk of a subsequent total serum bilirubin (TSB) >or=17 mg per 100 ml (291 micromol l(-1)). Routine TcB measurements are obtained daily for all infants in our well baby nursery. We performed a nested case-control study comparing all 75 infants who had been readmitted with TSB >or=17 mg per 100 ml (291 micromol l(-1)) between 1 February 2005 and 28 February 2007 with randomly selected controls that had not been readmitted. Between 1 February 2005 and 28 February 2007, 11 456 infants were discharged from the well baby nursery. Seventy-five infants (0.65%) were readmitted at a mean age of 110+/-29.9 h with a TSB>or=17 mg per 100 ml (291 micromol l(-1)). All received phototherapy. Using logistic regression analysis, three variables were statistically significant for predicting cases: the maximum predischarge TcB percentile group (P<0.0001, adjusted odds ratio (AOR), >95th percentile 148; 95% confidence interval (CI) 21 to >999, AOR 76 to 95th percentile 15; 95% CI 3.1 to 70, AOR 50 to 75th percentile 6.1; 95% CI 1.3 to 28 compared with <50th percentile), exclusive breastfeeding (P<0.0001, AOR 11; 95% CI 3.7 to 34) and gestational age (P=0.0057, AOR 35 to 36 6/7 week 21; 95% CI 2.3 to 185, AOR 37 to 37 6/7 week 15; 95% CI 1.9 to 115, AOR 38 to 38 6/7 week 1.8; 95% CI 0.3 to 11, AOR 39 to 39 6/7 week 1.1; 95% CI 0.2 to 7 AOR >or=41 week 0.88; 95% CI 0.1 to 10 compared with 40 to 40 6/7 week infants). These three variables provided the best prediction of a case (c=0.885, area under the receiver operating characteristic curve) and this prediction was significantly better than the use of the clinical risk factors, gestation and exclusive breastfeeding, alone (c=0.770, P<0.001) or the TcB percentile grouping alone (c=0.766, P<0.001). Substituting the TcB rate of rise (c=0.903, P=0.316) or the last measured TcB (c=0.873, P=0.292) for the maximum TcB measurement did not significantly improve the predictors of a case. Combining predischarge TcB levels with two clinical risk factors-gestational age and exclusive breastfeeding-significantly improves the prediction of subsequent hyperbilirubinemia.

False-negative results of pre-discharge neonatal bilirubin screening to predict severe hyperbilirubinemia: a need for caution

Routine bilirubin screening prior to newborn hospital discharge, using an hour-specific bilirubin nomogram, has been advocated to assess risk for subsequent severe hyperbilirubinemia. However, the false-negative rate has never been adequately studied. Our objective was to determine false-negative results of pre-discharge bilirubin screening. After routine pre-discharge, bilirubin screening was in place for over 4 years, we performed a retrospective chart review to identify infants readmitted for total bilirubin levels > 17 mg/dl (>290.7 micromol/l). We documented each infant's pre-discharge bilirubin level, risk-zone assignment by nomogram, the presence or absence of risk factors for severe hyperbilirubinemia, co-morbidities upon readmission, treatment received, and ultimate disposition. Readmitted infants whose pre-discharge bilirubin was in the low-risk (<40th percentile) and low-intermediate (40-75th percentile) risk zones of the nomogram, were considered false-negatives. Of the 6,220 infants discharged from the newborn nursery during the 51-month study period, 28 (0.45%) were readmitted for treatment of serum bilirubin levels > 17 mg/dl (>290.7 micromol/l). All received phototherapy and none required exchange transfusion. Pre-discharge bilirubin values were <40th percentile (low-risk zone) in one infant (3.6%), and between 40-75th percentiles (low-intermediate risk zone) in twelve infants (43%). Risk factors for the development of severe hyperbilirubinemia were present in 27 (96%) readmitted infants. In conclusion, nearly half of readmitted infants had pre-discharge bilirubin values in zones considered at lower risk. The use of pre-discharge bilirubin screening alone to assign future risk for severe hyperbilirubinemia may provide false reassurance. Rigorous research is required to determine the test characteristics of pre-discharge bilirubin screening before widespread acceptance and implementation. Universal early post-discharge follow-up should remain the cornerstone of preventing severe hyperbilirubinemia.

Transcutaneous bilirubin in predicting hyperbilirubinemia in term neonates

To assess the utility of 24 and 48 hours transcutaneous bilirubin (TcB) index for predicting subsequent significant hyperbilirubinemia in healthy term neonates. TcB indices were obtained for healthy, breastfed, term AGA newborns at 24 +/- 2, 48 +/- 2 and subsequently at intervals of 24 hours. Neonates with illness, on treatment and positive Direct Coomb's test were excluded. Serum bilirubin levels were obtained whenever indicated. Neonates having serum bilirubin > or = 17 mg/dL were considered as significant hyperbilirubinemia. The 24 and 48 hour TcB indices, as risk predictors for such hyperbilirubinemia were determined. Study included 461 healthy term neonates. The mean birth weight was 2949 (+/- 390) gm and mean gestation of 38.6 (+/- 1.1) weeks. Eight one (17.6%) had significant hyperbilirubinemia. Of 461, 135 (29.3%) had TcB index. The 24 and 48 hour TcB indices are predictive for subsequent significant hyperbilirubinemia and can guide clinician in early discharge of healthy term newborns.

Cord blood bilirubin level in relation to bilirubin UDP‐glucuronosyltransferase gene missense allele in Chinese neonates

To investigate bilirubin UDP-glucuronosyltransferase (UGT1A1) gene allele in healthy Chinese neonates, their cord bilirubin level and the subsequent hyperbilirubinemia to determine relationships among them. Cord blood of 48 neonates was obtained to determine the exon 1 of UGT1A1 gene, total serum bilirubin, albumin, glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT) and haemoglobin (Hb) concentration. Neonatal jaundice was assessed by measurement of transcutaneous bilirubin (TCB) and serum bilirubin. Neonates were divided into two groups according to mutant or normal allele to compare the variables. Nineteen infants had the nucleotide 211 G-->A allele, 3 had the heterozygous variation (686C-->A, 845 A-->T, 231G-->A). In the 211 A allele group, cord bilirubin was significantly higher than in the 211 G allele group (p = 0.034), but there were no differences in albumin (p = 0.678), GPT (p = 0.460), GOT (p = 0.440) and Hb (p = 0.886). The TCB (at 48, 96 h), the frequency of the hyperbilirubinemia and prolonged jaundice were also significantly higher in the 211 A allele group. The UGT1A1 gene codon G71R allele is a risk factor for neonatal hyperbilirubinemia in the Chinese population. Its effect on bilirubin metabolism may present early on, as well as late in foetal life.

Combining Clinical Risk Factors With Serum Bilirubin Levels to Predict Hyperbilirubinemia in Newborns

(1) To validate a previously reported risk index for predicting total serum bilirubin (TSB) levels of 25 mg/dL (428 micromol/L) or higher; (2) to combine a subset of this index with TSB levels measured at less than 48 hours to predict subsequent TSB levels of 20 mg/dL (342 micromol/L) or higher. Nested case-control study using electronic and paper records (study 1). Retrospective cohort study using electronic records only (study 2). Northern California Kaiser Permanente hospitals. Subjects for both studies were newborns weighing 2000 g or more and of 36 weeks' or more gestation. The validation study included 67 cases born 1997-1998 who developed TSB levels of 25 mg/dL or higher at less than 30 days and 208 randomly selected control subjects. Subjects for study 2 were 5706 newborns who both were discharged from the hospital and had a TSB level measured at less than 48 hours. The risk index performed similarly in the validation group, born in 1997-1998, and the derivation group, born in 1995-1996 (area under the receiver operating characteristic curve = 0.83 vs 0.84). Of the 5706 newborns with TSB levels measured before 48 hours, 270 (4.7%) developed a TSB level of 20 mg/dL or higher. Of these, 254 (94%) had a TSB level at the 75th percentile or higher at less than 48 hours. The risk index improved prediction over the TSB level alone, largely owing to the effect of gestational age. For example, for those with a TSB level at the 95th percentile or higher at less than 48 hours, the risk increased from 9% for newborns born at 40 weeks' or more gestation to 42% for those born at 36 weeks. Clinical risk factors significantly improve prediction of subsequent hyperbilirubinemia compared with early TSB levels alone, especially in those with early TSB levels above the 75th percentile.

Conflict of Interest and Purpose in Bilirubin Screening: In Reply

In Reply .— I thank Dr Lavin for his comments. Perhaps my conclusion was a trifle hyperbolic, but I have no hesitation in standing by the statement that the ability to measure a transcutaneous bilirubin (TcB) level in the office should be very valuable for the practicing physician. When Dr Lavin sees a jaundiced newborn on day 3 or 4 in his office and decides to get a bilirubin level, would he prefer a completely noninvasive, instantaneous measurement of the bilirubin or would he rather perform a heel stick on the infant (or have it done elsewhere) and wait several hours for the results? More important, what does he think the mother (and the infant) would prefer? In our study, data from 40 infants were obtained from a private-practice group, and discussions with these physicians amply confirms that they have found this instrument to be very useful. We have been using TcB measurements in our own outpatient clinic for >6 months, and I can assure Dr Lavin that our residents and attending physicians find it equally useful. In addition to providing instantaneous and important information about the infant's bilirubin level, the use of TcB measurements in both the nursery …

End-tidal carbon monoxide is predictive for neonatal non-hemolytic hyperbilirubinemia.

The aim of the present study was to evaluate the value of an end-tidal carbon monoxide corrected for inhaled carbon monoxide concentration (ETCOc) at the early neonatal period. The value would be useful for predicting subsequent hyperbilirubinemia in non-hemolytic full-term infants. The ETCOc levels were measured every 6 h during the first 72 h of life in healthy, full-term, non-hemolytic, newborn Japanese infants using a breath carbon monoxide analyzer. The ETCOc levels in hyperbilirubinemic infants were compared with those in non-hyperbilirubinemic infants. Hyperbilirubinemia was defined as the level of the peak total serum bilirubin concentration (TBC) greater than or equal to 257 micromol/L (15.0 mg/dL). The ETCOc measurement for predicting subsequent hyperbilirubinemia was evaluated with a receiver-operating characteristic (ROC) curve. Fifty-one infants were enrolled in the study. Seven of the 51 infants developed hyperbilirubinemia. The ETCOc levels in non-hyperbilirubinemic infants were decreased in the first 72 h after birth. However, those in the hyperbilirubinemic infants were not decreased significantly, and were higher than those in non-hyperbilirubinemic infants at 42, 48, 54 and 66 h of age. The ETCOc level at 42 h of age was the most predictive of subsequent hyperbilirubinemia by ROC analysis. At the cut-off level of 1.8 microL/L (p.p.m.), the sensitivity, the specificity, the positive predictive value and negative predictive value were 86, 80, 40 and 97%, respectively. Increased ETCOc level in the early neonatal period is associated with subsequent hyperbilirubinemia, even in infants without hemolytic disease. The ETCOc measurement may be useful as a screening test for predicting hyperbilirubinemia without hemolytic diseases.

Breastfeeding, Diet, and Neonatal Hyperbilirubinemia

After completing this article, readers should be able to: 1. Compare and contrast the incidence of hyperbilirubinemia between breastfed and formula-fed infants throughout the neonatal period and its relationship to early hospital discharge. 2. Describe possible reasons for the occurrence of hyperbilirubinemia in breastfed infants. 3. Compare and contrast the incidence of hyperbilirubinemia related to different infant formulas. Among the many factors related to neonatal hyperbilirubinemia is the composition of an affected infant’s diet. In 1879, Frerichs suggested that “bad nursing” could “exercise a powerful influence” on neonatal hyperbilirubinemia. Much has been learned since this suggestion was made. ### EPIDEMIOLOGY Many investigations have documented that the consumption of human milk is related to neonatal hyperbilirubinemia, including one review of 12 studies involving more than 8,000 infants in the first week of life and controlled for factors such as hemolysis to enable comparison of dietary effects alone. Moderate hyperbilirubinemia (total serum bilirubin [TSB], 205 mcmol/L [12 mg/dL]) was present in 12.9% of the breastfed infants and 4% of the formula-fed infants ( P <0.00001). Severe hyperbilirubinemia (TSB, 256 mcmol/L [15 mg/dL]) was present in 2% of the breastfed infants and 0.3% of the formula-fed infants ( P <0.00001). Breastfed infants have higher serum bilirubin levels on each of the first 5 days of life, and this hyperbilirubinemia can persist for weeks to months. The association between feedings of human milk and neonatal hyperbilirubinemia has been reported in preterm infants fed banked human milk or mixtures of human milk and formula and among various races. More recent studies of otherwise healthy newborns have used noninvasive transcutaneous devices to assess hyperbilirubinemia daily (Figs. 1⇓ and 2⇓ ). These studies agree with earlier conclusions that otherwise healthy infants exclusively fed human milk will have higher levels of hyperbilirubinemia than infants who consume formula. The difference begins to become significant …

Recent Developments in the Management of Neonatal Hyperbilirubinemia

After completing this article, readers should be able to: 1. Describe the morbidity associated with exchange transfusion used to treat neonatal hyperbilirubinemia. 2. Explain how phototherapy affects bilirubin. 3. Describe potential toxicities of phototherapy. 4. Explain the role of carboxyhemoglobin in hemolysis. 5. Delineate the guidelines for administering intravenous immunoglobulin to healthy ABO-incompatible Coombs-positive neonates. 6. Describe the action of protoporphyrins on bilirubin. Recent clinical trends toward early discharge coupled with a new, more relaxed, “kinder, gentler approach” to the treatment of newborn hyperbilirubinemia have thrust concerns about bilirubin-related toxicity once again to the forefront of neonatologists’ consciousness. In recent years we even have witnessed a resurgence of kernicterus, which had been rendered almost nonexistent in the 1970s and 1980s. Although exchange transfusion is the oldest and most effective method of treating hyperbilirubinemia, mortality associated with this therapy has been reported to be between 0.3% and 1.2% in healthy infants and as high as 10% to 25% in sicker preterm infants. Furthermore, potential morbidity related to exchange transfusion remains significant and includes anemia, apnea, bradycardia, hypothermia, sepsis, necrotizing enterocolitis, thromboembolic phenomena, graft versus host disease, transient metabolic abnormalities, and thrombocytopenia. Accordingly, it behooves us to re-evaluate other therapeutic modalities for hyperbilirubinemia that may be equally efficacious but less invasive. Ever since the 1950s, when Sister Ward of Rochford General Hospital in Essex noted that a jaundiced baby’s skin had “faded” in natural sunlight, physicians have been searching for artificial light sources that might be used safely to treat neonatal hyperbilirubinemia. Phototherapy, which has become the standard of care, has had such a dramatic impact that a recent editorial raised the concern that exchange transfusions are becoming extinct and lamented the fact that future generations of house officers may not receive adequate training in this procedure. Under the effects of phototherapy light with maximal irradiance in the …