Peak Total Serum Bilirubin Levels Research Articles

Impact of Umbilical Cord Milking on Hematological Parameters in Preterm Neonates With Placental Insufficiency.

BackgroundData is still lacking about the expediency of umbilical cord milking (UCM) in preterm neonates born to mothers with placental insufficiency (PI).ObjectiveTo study the effect of UCM in preterm neonates who had ante-natal evidence of placental insufficiency on peripheral blood cluster of differentiation 34 (CD34) percentage, hematological indices, and clinical outcomes.MethodsPreterm neonates, <34 weeks' gestation, born to mothers with evidence of placental insufficiency that underwent UCM (PI+UCM group) were compared with historical controls whose umbilical stumps were immediately clamped [PI+ICC (immediate cord clamping) group] in a case-control study. Peripheral blood CD34 percentage as a measure of hematopoietic stem cell transfusion was the primary outcome. Early and late-onset anemia; polycythemia; frequency of packed red blood cells (PRBCs) transfusion during NICU stay; peak total serum bilirubin (TSB); incidence of phototherapy, admission rectal temperature; first 24 h hypothermia and hypoglycemia; episodes of hypotension and need for volume expander boluses and inotropic support during the first 24 h of age; duration of oxygen therapy; bronchopulmonary dysplasia (BPD); severe intra-ventricular hemorrhage (IVH); necrotizing enterocolitis (NEC); culture-proven late-onset sepsis; length of hospital stay; and in-hospital mortality were secondary outcomes.ResultsIn preterm infants with placental insufficiency, umbilical cord milking was associated with greater peripheral blood CD34 percentage, hemoglobin levels initially and at postnatal age of 2 months, alongside significantly shorter duration of oxygen therapy compared with ICC group. Frequency of packed RBCs transfusion during hospital stay was comparable. Neonates in UCM group had a greater peak TSB level during admission with significantly higher need for phototherapy initiation compared with ICC. Logistic regression, adjusted for gestational age, revealed that UCM resulted in greater CD34 percentage, higher initial hemoglobin level, higher peak serum bilirubin, significant increase of phototherapy initiation, and higher hemoglobin level at 2 months.ConclusionsUCM in preterm neonates born to mothers with placental insufficiency was feasible and resulted in greater CD34 percentage, higher initial hemoglobin level, higher peak serum bilirubin, significant increase of phototherapy initiation, and higher hemoglobin level at 2 months.

Use of Complete Blood Cell Count Components to Screen for Hereditary Spherocytosis in Neonates.

The neonatal hereditary spherocytosis (HS) index, defined as the mean corpuscular hemoglobin concentration divided by the mean corpuscular volume, has been proposed as a screening tool for HS in neonates. In a population of mostly white infants, an HS Index >0.36 was 97% sensitive and >99% specific. We evaluated the utility of the HS Index among a more racially and ethnically diverse population and determined if its discrimination varies with total serum bilirubin (TSB) levels. Infants born at ≥35 weeks' gestation at 15 Kaiser Permanente Northern California hospitals from 1995 to 2015 were eligible (N = 670 272). Erythrocyte indices from the first complete blood count drawn at ≤7 days and TSB levels drawn at ≤30 days were obtained. Diagnoses of HS were confirmed via chart review. HS was confirmed in 79 infants, 1.2 per 10 000. HS was more common among infants of white and "other" race or ethnicity and among those with higher peak TSB levels. The area under the receiver operating characteristic curve for the HS Index was 0.84 (95% confidence interval 0.78-0.90). Likelihood ratios ranged from 10.1 for an HS Index ≥0.380 to 0.1 for an HS Index <0.310. Dichotomized at 0.36, the HS Index was 56% sensitive and 93% specific. Discrimination of the HS Index appeared best among infants with TSB levels <10 mg/dL. The HS Index, when obtained from a CBC drawn within the first week after birth, had only modest ability to alter the probability of HS.

Early Neurodevelopmental Outcome of Neonates with Gestation 35 Weeks or More with Serum Bilirubin in Exchange Range Without Encephalopathy: A Prospective Observational Study.

To describe early neurodevelopment outcomes of neonates with severe hyperbilirubinemia without acute bilirubin encephalopathy (ABE). Neonates born at gestation ≥35 weeks, admitted to NICU with total serum bilirubin (TSB) in exchange range with no features of ABE, were followed up until the age of 6 months. Infants were assessed for impaired hearing and neurodevelopment at 3 months and 6 months of age. A total of 59 neonates were enrolled in the study. At 3 months of age, 7.6 percent of neonates were found to have hypotonia and motor delay, whereas 42.3 percent had abnormal brainstem evoked response audiometery. At 6 months, 6.4 percent of neonates were found to have persistent neurodevelopmental impairment. Severe hyperbilirubinemia is associated with impaired neurodevelopment and hearing even in infants without ABE. Peak TSB level strongly correlates with abnormal outcomes.

Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants

Cycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g). To identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants. This dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018. Two cycled PT regimens (≥15 min/h and ≥30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT). Mean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power. Consent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, -39; 95% CI, -45 to -32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, -0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of -4.5% (95% CI, -10.9 to 2.0). Morbidities did not differ between groups. Cycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants. ClinicalTrials.gov Identifier: NCT01944696.

The relationship between hyperbilirubinemia and the promoter region and first exon of UGT1A1 gene polymorphisms in Vietnamese newborns.

To investigate the relationship between unexplained indirect hyperbilirubinemia of Vietnamese newborns and the polymorphism of the promoter TATA box and exon 1 of bilirubin uridine diphosphate glucuronosyltransferase (UGT1A1) gene. A total of 149 neonates were divided into the hyperbilirubinemia group (n = 99) and control group (n = 50). The gene polymorphisms of UGT1A1 gene in the two groups were detected by PCR and direct sequencing, which revealed the relationship between UGT1A1 polymorphism with neonatal hyperbilirubinemia of neonates. The types of UGT1A1 polymorphism in the hyperbilirubinemia group and the peak total serum bilirubin (PSB) levels with different genotypes were observed. (1) (TA)7 insertion mutation, 211G>A, 189C>T, 190G>A, 378C>T and 686C>A were detected. (2) The allele frequency of 211G>A allele mutation was significantly different between the two groups (p < 0.05). (3) Logistic regression analysis showed that homozygosity and heterozygosity of 211G>A were both significantly associated with neonatal hyperbilirubinemia. (4) In the hyperbilirubinemia group, the peak total serum bilirubin level of 211G>A homozygous neonates was higher than that of the wild-type neonates (p < 0.05). We noted that there was an association between neonates with unexplained indirect hyperbilirubinemia in Vietnam and the polymorphism of UGT1A1c.211G>A. In addition, the homozygous 211G>A polymorphism was related to the degree of hyperbilirubinemia. Our article provided data on UGT1A1 polymorphism distribution in the Vietnamese population, which have not been reported yet. Our findings revealed that mutations in UGT1A1 gene are risk factors for unexplained hyperbilirubinemia in Vietnamese neonates. Our article will strengthen the cognition of neonatal jaundice at the genetic level in the pediatric field in Vietnam.

Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity

Research Article| January 01 2018 Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity AAP Grand Rounds (2018) 39 (1): 4. https://doi.org/10.1542/gr.39-1-4 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Neonatal Hyperbilirubinemia and Chronic Auditory Toxicity. AAP Grand Rounds January 2018; 39 (1): 4. https://doi.org/10.1542/gr.39-1-4 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: neonatal jaundice, toxic effect, hyperbilirubinemia Source: Amin SB, Saluja S, Saili A, et al. Chronic auditory toxicity in late preterm and term infants with significant hyperbilirubinemia. Pediatrics. 2017; 140(4): e20164009; doi: https://doi.org/10.1542/peds.2016-4009Google Scholar Investigators from multiple institutions in the United States and India conducted a prospective study to assess the association of chronic auditory toxicity and total serum bilirubin (TSB), unbound bilirubin (UB), and bilirubin albumin molar ratio (BAMR) in infants with significant neonatal hyperbilirubinemia. Study participants were infants born at ≥34 weeks’ gestation who were admitted to one of two NICUs in India with TSB levels ≥20 mg/dL or with TSB levels above the recommended threshold for exchange transfusion. In addition to TSB, both albumin levels (used to compute BAMR) and UB were measured. When study participants were 2–3 months old, they had auditory brainstem response and otoacoustic emission testing performed, along with tympanometry to detect auditory neuropathy spectrum disorder (ANSD). When the infants were 9–12 months old, they had formal auditory testing to detect sensorineural hearing loss (SNHL). Infants with either ANSD or SNHL with normal tympanometry were classified as having chronic auditory toxicity (CAT). After correcting for risk factors for bilirubin neurotoxicity (eg, perinatal asphyxia, sepsis, hypoxia, acidosis, hypoalbuminemia, and hemolysis), the association between TSB, BAMR, and UB and CAT were assessed using regression analysis. In addition, covariate-adjusted receiver operating characteristic curves were constructed using each of these markers as a predictor of CAT; the area under the curve (AUC) for each was compared. A total of 100 infants were enrolled in the study, and auditory testing was completed in 93. Overall, 12 infants (13%) were classified as having CAT, including 3 with ANSD, 4 with SNHL, and 5 with both; 4 children had profound SNHL (threshold >70 dB). Clinical characteristics were similar in infants with and without CAT. Mean peak TSB levels were 29.0 mg/dL among those with CAT and 23.6 mg/dL in infants without CAT (P = .14 after adjusting for covariates). Similarly, there was no statistically significant association between BAMR and CAT. However, UB levels were significantly higher in infants with CAT than in those without CAT (P = .001, adjusted odds ratio 2.41; 95% CI 1.43–4.07). The AUC for UB as a predictor of CAT was significantly higher than for TSB and BAMR (0.866, 0.775, and 0.724, respectively, P = .03). Among 63 study infants with a peak TSB <25 mg/dL, 5 (8%) were diagnosed with CAT. UB, but not TSB or BAMR, was significantly associated with CAT in this group of infants. The authors conclude that unconjugated bilirubin (ie, UB) is associated with CAT among infants born at ≥34 weeks’ gestation with significant hyperbilirubinemia. Dr Mintzer has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Based on AAP guidelines, routine screening of bilirubin levels has become standard practice for the prevention of acute bilirubin encephalopathy among all newborn infants.1... You do not currently have access to this content.

The Effects of Placental Transfusion on Placental Residual Blood Volume and 24 to 48‐hour Hemoglobin and Serum Bilirubin in Term Newborns: A Randomized Controlled Trial

PurposeTo determine if newborns who receive a full placental transfusion at birth differ in placental residual blood volume (PRBV) and 24 to 48‐hour hemoglobin (Hb) and total serum bilirubin (TSB) levels compared to newborns who receive no placental transfusion.Research QuestionWill newborns who receive a full placental transfusion have less PRBV, a higher 24 to 48‐hour Hb, and no difference in peak TSB compared to newborns who receive no placental transfusion?SignificanceThe usual maternity care practice in the United States is to immediately clamp the umbilical cord (immediate cord clamping [ICC]) at the time of birth. When ICC occurs, 20% to 40% of the fetal‐placental blood volume (containing iron‐rich red blood cells) is left behind in the placenta, potentially leading to lower iron stores in infancy.MethodsA prospective randomized controlled trial was conducted. Seventy‐three healthy term pregnant women with singleton fetuses were enrolled. At birth, they were randomized to either ICC (&lt;20 seconds; n = 36) or delayed cord clamping (DCC) (≥5 minutes; n = 37) and then placed skin‐to‐skin. The primary endpoints were PRBV in mL/kg, Hb (g/dL), and peak TSB at 24 to 48 hours of age. Primary analyses were conducted by intention‐to‐treat and secondary analyses by actual treatment.ResultsMaternal and newborn demographics were not significantly different between groups. Mean (standard deviation [SD]) cord clamping time was 303 (121) seconds (DCC) versus 10 (6) (ICC) seconds (P = .001). Eleven newborns received cord milking as a proxy for DCC at the time of cesarean birth or when resuscitation measures were indicated. There were 9 protocol violations. Newborns randomized to DCC left behind less PRBV (20.0 vs 30.8 mL/kg, P &lt; .001). At 24 to 48 hours of age, newborns exposed to DCC had significantly higher Hb levels (19.5 vs 17.7 g/dL, P = .002) without a difference in peak TSB levels (DCC = 8.5 vs ICC = 9.0 mg/dL, P = .45) compared to infants with ICC. Two newborns in each group had phototherapy.DiscussionNewborns with ICC left behind more PRBV and had lower Hb levels at 24 to 48 hours. There was no difference between the groups on peak TSB levels or other indicators of hyperbilirubinemia. The results support the early hematological advantage of DCC while demonstrating no association with an increase in hyperbilirubinemia.

Report about term infants with severe hyperbilirubinemia undergoing exchange transfusion in Southwestern China during an 11-year period, from 2001 to 2011.

ObjectivesThis study was intended to explore the etiology and risk factors of severe neonatal hyperbilirubinemia and to analyze the adverse events associated with ECT (Exchange Transfusion), as well as to identify the factors related to the poor prognosis.MethodsAll of the full-term neonates who had undergone ECT for hyperbilirubinemia at Children’s Hospital of Chongqing Medical University from January 2001 to December 2011 were enrolled in this study. General demographic characteristics, comorbidities, pre- and post-exchange TSB(Total Serum Bilirubin) levels, duration and frequency of ECT, and clinical outcomes were recorded and analyzed anonymously.ResultsOf 614 total infants, 368 patients (59.9%) with ABO incompatibility were identified, of whom 197 (53.5%) developed acute bilirubin encephalopathy (ABE) and 16 (4.3%) suffered a poor prognosis. The etiology was unidentified in 103 patients (16.8%), of whom 62 (60.1%) developed ABE and 9 (8.7%) had a poor prognosis. Identified adverse events secondary to ECT included thrombocytopenia (54.6%), hyperglycemia (42.8%), apnea (3.3%) and necrotizing enterocolitis (NEC) (1.3%). No ECT-related mortality was documented in this study.ConclusionsThe etiology, peak TSB level before ECT, and time of ECT had a significant impact on the outcome of severe neonatal hyperbilirubinemia. ABO incompatibility was the most common cause of extreme neonatal hyperbilirubinemia. Pathological weight loss could be involved in the development of extreme hyperbilirubinemia with an unidentified cause.

A Randomized Controlled Trial of Glycerin Suppositories During Phototherapy in Premature Neonates

ObjectiveTo determine if glycerin suppositories were effective in reducing total duration of phototherapy in premature neonates. We hypothesized that glycerin suppositories would have no effect on phototherapy duration or total serum bilirubin levels. DesignProspective randomized controlled double-blinded trial. SettingLevel IV NICU. ParticipantsNeonates born between 30 weeks, 0 days and 34 weeks, 6 days gestational age who developed physiologic hyperbilirubinemia needing phototherapy. MethodsNeonates were randomized to the no-suppository group or to the suppository group. Neonates were randomized to receive glycerin suppositories every 8 hours while under phototherapy or to a sham group. The primary outcome was total hours of phototherapy. Secondary outcomes included peak total serum bilirubin levels, time from start to discontinuation of phototherapy, rate of decline in bilirubin levels, repeat episodes of phototherapy, and number of stools while the neonates received phototherapy. ResultsA total of 39 neonates were assigned to the no-suppository group and 40 to the suppository group. Withholding suppositories was not inferior to providing suppositories. The total hours of phototherapy were not longer (i.e., noninferior) among neonates not provided suppositories (61 ± 53 hours) than among those given suppositories (72 ± 49 hours). There were no differences in peak bilirubin levels, rate of bilirubin decline, or repeat episodes of phototherapy. ConclusionRoutine use of glycerin suppositories among preterm neonates who receive phototherapy does not affect bilirubin levels or phototherapy duration.

Bilirubin-Induced Neurological Dysfunction: A Clinico-Radiological-Neurophysiological Correlation in 30 Consecutive Children.

The clinical expression of bilirubin-induced neurological dysfunction varies according to severity and location of the disease. Definitions have been proposed to describe different bilirubin-induced neurological dysfunction subtypes. Our objective was to describe the severity and clinico-radiological-neurophysiological correlation in 30 consecutive children with bilirubin-induced neurological dysfunction seen over a period of 5 years. Thirty children exposed to acute neonatal bilirubin encephalopathy were included in the study. The mean peak total serum bilirubin level was 625 μmol/L (range 480-900 μmol/L). Acoustic brainstem responses were abnormal in 73% (n = 22). Pallidal hyperintensity was observed on magnetic resonance imaging in 20 children. Peak total serum bilirubin levels correlated with motor severity (P = .03). Children with severe motor impairment were likely to manifest severe auditory neuropathy (P < .01). We found that in a resource-constrained setting, classical kernicterus was the most common bilirubin-induced neurological dysfunction subtype, and the majority of children had abnormal acoustic brainstem responses and magnetic resonance imaging.

Early Neonatal Bilirubin, Hematocrit, and Glucose-6-Phosphate Dehydrogenase Status

To document the patterns of bilirubin and hematocrit values among glucose-6-phosphate dehydrogenase (G6PD)-deficient and G6PD-normal Nigerian neonates in the first week of life, in the absence of exposure to known icterogenic agents. The G6PD status of consecutive term and near-term neonates was determined, and their bilirubin levels and hematocrits were monitored during the first week of life. Infants were stratified into G6PD deficient, intermediate, and normal on the basis of the modified Beutler's fluorescent spot test. Means of total serum bilirubin (TSB) and hematocrits of the 3 groups of infants were compared. The 644 neonates studied comprised 353 (54.8%) boys and 291 (45.2%) girls and 540 (83.9%) term and 104 (16.1%) near-term infants. They consisted of 129 (20.0%) G6PD-deficient, 69 (10.7%) G6PD-intermediate, and 446 (69.3%) G6PD-normal neonates. The G6PD-deficient and G6PD-intermediate infants had higher mean TSB than their G6PD-normal counterparts at birth and throughout the first week of life (P < .001). Mean peak TSB levels were 14.1 (9.48), 10.2 (3.8), and 6.9 (3.3) mg/dL for G6PD-deficient, G6PD-intermediate, and G6PD-normal neonates, respectively. Peak TSB was attained on approximately day 4 in all 3 groups, and trends in TSB were similar. Mean hematocrits at birth were similar in the 3 G6PD groups. However, G6PD-deficient and -intermediate infants had higher declines in hematocrit, bilirubin levels, and need for phototherapy than G6PD-normal infants (P < .001). The G6PD-deficient and G6PD-intermediate neonates had a higher risk of neonatal hyperbilirubinemia and would therefore need greater monitoring in the first week of life, even without exposure to known icterogenic agents.

Evaluation of Treatment Thresholds for Unconjugated Hyperbilirubinemia in Preterm Infants: Effects on Serum Bilirubin and on Hearing Loss?

BackgroundSevere unconjugated hyperbilirubinemia may cause deafness. In the Netherlands, 25% lower total serum bilirubin (TSB) treatment thresholds were recently implemented for preterm infants.ObjectiveTo determine the rate of hearing loss in jaundiced preterms treated at high or at low TSB thresholds.Design/MethodsIn this retrospective study conducted at two neonatal intensive care units in the Netherlands, we included preterms (gestational age <32 weeks) treated for unconjugated hyperbilirubinemia at high or low TSB thresholds. Infants with major congenital malformations, syndromes, chromosomal abnormalities or toxoplasmosis, rubella, cytomegalovirus, herpes, syphilis, and human immunodeficiency infections were excluded. We analyzed clinical characteristics and TSB levels during the first ten postnatal days. After two failed automated Auditory Brainstem Response (ABR) tests we used the results of the diagnostic ABR examination to define normal, unilateral, and bilateral hearing loss (>35 dB).ResultsThere were 479 patients in the high and 144 in the low threshold group. Both groups had similar gestational ages (29.5 weeks) and birth weights (1300 g). Mean and mean peak TSB levels were significantly lower after the implementation of the novel thresholds: 152±43 µmol/L and 212±52 µmol/L versus 131±37 µmol/L and 188±46 µmol/L for the high versus low thresholds, respectively (P<0.001). The incidence of hearing loss was 2.7% (13/479) in the high and 0.7% (1/144) in the low TSB threshold group (NNT = 50, 95% CI, 25–3302).ConclusionsImplementation of lower treatment thresholds resulted in reduced mean and peak TSB levels. The incidence of hearing impairment in preterms with a gestational age <32 weeks treated at low TSB thresholds was substantially lower compared to preterms treated at high TSB thresholds. Further research with larger sample sizes and power is needed to determine if this effect is statistically significant.

Clinical Characteristics of G6PD Deficiency in Infants With Marked Hyperbilirubinemia

This study analyzes the clinical features of glucose-6-phosphate dehydrogenase (G6PD) deficiency in infants with marked hyperbilirubinemia. We retrospectively assessed a cohort of 413 infants with peak total serum bilirubin (TSB) level >or=20 mg/dL from 1995 to 2007. The prevalence of G6PD deficiency was proportional to the level of peak TSB: 21.1% (81/383) in 20 mg/dL to 29.9 mg/dL, 45.5% (10/22) in 30 mg/dL to 39.9 mg/dL, and 100% (8/8) in >or=40 mg/dL. Male sex was more common in G6PD deficiency (75.8%). When compared with G6PD-normal infants, those with G6PD deficiency tended to have extreme hyperbilirubinemia (peak TSB level >or=25 mg/dL) and hemoglobin value<13 g/dL (P<0.001). Furthermore, mortality rate was significantly higher in G6PD-deficient infants (3.0%) than in the G6PD-normal counterparts (0.0%). Among 58 of the G6PD-deficient infants who were followed for more than 12 months, 4 developed the classic neurologic manifestations of kernicterus (6.6%). These findings show that G6PD deficiency is an important risk factor of extreme hyperbilirubinemia, death, and kernicterus.

Does Ibuprofen Increase Neonatal Hyperbilirubinemia?

The aim of this study was to investigate whether ibuprofen exposure was associated with increased hyperbilirubinemia in preterm infants. Since 2000, ibuprofen has been administered to all infants at <30 weeks of gestation who are admitted to our unit, to prevent patent ductus arteriosus. We retrospectively compared data for 418 infants subjected to ibuprofen prophylaxis (2000-2007) and 288 infants not exposed to ibuprofen (1993-1999). The ibuprofen group had a significantly higher peak total serum bilirubin level (9.0 +/- 2.5 mg/dL vs 7.3 +/- 3.3 mg/dL), more need for phototherapy (398 infants [95%] vs 254 infants [87.6%]), and a longer phototherapy duration (94.3 +/- 43.6 hours vs 87.2 +/- 38.6 hours). Groups did not differ with respect to gestational age, birth weight, gender ratio, glucose-6-phosphate dehydrogenase deficiency incidence, or hypoalbuminemia (<2.5 g/dL) incidence. Hemolytic isoimmunization was diagnosed with similar incidences (no-ibuprofen group: 7 of 288 infants; ibuprofen group: 8 of 418 infants). The rates of exchange-transfusion also were similar between the groups (no-ibuprofen group: 14 infants [4.8%]; ibuprofen group: 19 infants [4.5%]). Ibuprofen administration was associated with higher peak total serum bilirubin levels, and the more-pronounced hyperbilirubinemia led to longer phototherapy. The potential role of competition between ibuprofen and bilirubin in the hepatic glucuronidation pathway is discussed.

Hyperbilirubinemia and Language Delay in Premature Infants

Our goal was to evaluate whether language delay at 3 years in premature infants is associated with previous exposure to hyperbilirubinemia during the first 2 weeks after birth. We performed a retrospective case-control study of infants admitted to the NICU between January and October 2003. Inclusion criteria included a birth weight of < or =1500 g and follow-up to age 3 years. Exclusion criteria included genetic disorders and hearing loss or recurrent ear infections. Peak total serum bilirubin levels during the first 2 weeks and duration of hyperbilirubinemia (days with total serum bilirubin level at >8 mg/dL) were determined. Infants with language delay and who were receiving speech therapy by 3 years were identified through developmental clinic charts and a tracking program and compared with infants who had normal language development. A total of 125 infants with birth weight of < or =1500 g were admitted to the NICU between January and October 2003. Fifteen infants died, and 110 were discharged from the hospital. A total of 102 (93%) of 110 infants had follow-up to the age of 3 years. Four infants were excluded (1 genetic disorder, 3 delayed hearing loss or recurrent ear infections). Twenty-four infants had a language delay and received speech therapy, whereas 74 infants had normal language development. There was no significant difference in peak total serum bilirubin level and duration of hyperbilirubinemia between the 2 groups. On logistic regression, only bronchopulmonary dysplasia was associated with language delay. Hyperbilirubinemia, defined as peak total serum bilirubin level or duration of elevated bilirubin in days, is not associated with language delay in premature infants. However, this issue deserves investigation, because other measures of bilirubin, such as unbound bilirubin, may be associated with language delay.

Outcomes in a Population of Healthy Term and Near-Term Infants With Serum Bilirubin Levels of ≥325 μmol/L (≥19 mg/dL) Who Were Born in Nova Scotia, Canada, Between 1994 and 2000

The goal was to study the incidence of kernicterus, developmental delay, autism, cerebral palsy, and hearing loss in infants with peak total serum bilirubin levels of >or=325 micromol/L (>or=19 mg/dL), compared with infants with less-severe or no hyperbilirubinemia, in a population of healthy term and late preterm infants. Prospectively gathered, standardized, maternal and neonatal data for infants at >or=35 weeks of gestation who were born between January 1, 1994, and December 31, 2000, were extracted from the Nova Scotia Atlee Perinatal Database. Infants with Rh factor isoimmunization, significant congenital or chromosomal abnormalities, or severe peripartum asphyxia were excluded. Comparisons were made on the basis of peak total serum bilirubin levels. Diagnoses were obtained through data linkage with the Medical Services Insurance Database for office visits and the Canadian Institute for Health Information Database for hospital admissions. The registration file provided information allowing calculation of follow-up times, which were determined for each separate outcome. Follow-up periods ranged from 2 to 9 years, with the end point being the first time the diagnostic code was encountered in either database. Cox proportional-hazards regression analyses were used to examine the relationships between outcomes and total serum bilirubin levels. Of 61238 infants included in the study cohort, 4010 (6.7%) did not have linkage data, which left 56019 infants for analysis. There were no cases of kernicterus and no significant differences in rates of cerebral palsy, deafness, developmental delay, or visual abnormalities between the groups. There were suggestions of associations with attention-deficit disorder in the severe hyperbilirubinemia group and with autism in the combined moderate and severe hyperbilirubinemia group. There was no increase in adverse effects reported previously to be associated with bilirubin toxicity. Associations with developmental delay, attention-deficit disorder, and autism were observed.

What's in a Name? Physiologic and Pathologic Jaundice: The Conundrum of Defining Normal Bilirubin Levels in the Newborn

Because at some point during the first week after birth almost every newborn has a total serum bilirubin (TSB) level that exceeds 1 mg/dL (17 μmol/L), the upper limit of normal for an adult, and ∼2 of every 3 newborns are jaundiced to the clinician's eye, this type of transient bilirubinemia has been called “physiologic jaundice.” When TSB levels exceed a certain value, the infant is often described as having “pathologic jaundice.” I would like to argue that these terms have limited utility and are often used incorrectly, with potentially damaging consequences. They should be abandoned. The physiology of the newborn differs from that of older children and adults in many ways. Newborns breathe 40 to 60 times per minute, and their hearts beat 120 to 160 times per minute. Their hematocrit levels are frequently >60%. In time, all of these values return to normal levels, as does their bilirubin level. However, we don't talk about physiologic tachypnea, tachycardia, or polycythemia, so why pick on jaundice? Some like the term “physiologic jaundice” because it has a reassuring sound for parents and physicians. Presumably, physiologic jaundice should apply to newborns whose TSB levels fall within a certain range, but what is that range? Because very few (if any) newborns have peak TSB levels <2 mg/dL, should an infant with a peak TSB of 1.5 mg/dL be considered abnormal or hypobilirubinemic? Unlike serum sodium levels, the range of normal TSB levels varies widely depending on the racial composition of the population, the incidence of breastfeeding, and other genetic and epidemiologic factors.1 There are also significant variations between different laboratories in their measurements of serum bilirubin.2 Term, healthy, North American, formula-fed infants have mean peak TSB levels between 5 and 6 mg/dL (86 and 103 μmol/L),3,4 whereas Japanese … Address correspondence to M. Jeffrey Maisels, MB, BCh, Department of Pediatrics, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073. E-mail: jmaisels{at}beaumont.edu

Association between peak serum bilirubin and neurodevelopmental outcomes in extremely low birth weight infants.

To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification. The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids (odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI. PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue.

Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization.

To investigate biological and health services predictors of extreme neonatal hyperbilirubinemia in a health maintenance organization. Nested case-control study. Eleven Northern California Kaiser Permanente hospitals. The cohort consisted of 51,387 newborns born at 36 weeks or later weighing 2000 g or more. Cases were newborns with peak total serum bilirubin levels greater than or equal to 428 micromol/L (> or =25 mg/dL) (n = 73). Controls were a random sample of newborns from the cohort with peak bilirubin levels less than 428 micromol/L (<25 mg/dL) (n = 423). Review of medical records and telephone interviews. Early jaundice was most strongly associated with case status (odds ratio [OR] = 7.3). After excluding subjects with early jaundice, the strongest predictors of hyperbilirubinemia were family history of jaundice in a newborn (OR = 6.0), exclusive breastfeeding (OR = 5.7), bruising (OR = 4.0), Asian race (OR = 3.5), cephalhematoma (OR = 3.3), maternal age of 25 years or older (OR = 3.1), and lower gestational age (OR = 0.6/week). These variables identified 61% of newborns as very low risk (about 1/4200). However, the risk in the remaining 39% was still low (1/370). More cases (79%) than controls (59%) had newborn length-of-stay and follow-up consistent with the American Academy of Pediatrics guidelines, but phototherapy use within 8 hours of the time that the guidelines recommend was uncommon in both cases (26%) and controls (33%). There were no apparent cases of kernicterus. Prevention of extreme hyperbilirubinemia may require closer follow-up than is currently recommended by the American Academy of Pediatrics and more use of phototherapy than was observed in this study. To prevent extreme hyperbilirubinemia (> or =428 micromol/L [> or =25 mg/dL]) in 1 newborn, many newborns would need to receive these interventions.

Lack of Identifiable Risk Factors for Kernicterus

In recent years kernicterus at autopsy has been observed in sick premature infants in the absence of markedly elevated levels of serum bilirubin. Potentiating factors have been suggested to explain kernicterus in such a setting. In order to establish which factors are associated with increased risk for kernicterus in these small babies, this retrospective matched control study was undertaken. Thirty-two infants with kernicterus at autopsy were matched for gestational age, birth weight, length of survival, and year of birth to 32 control infants without kernicterus. Multiple historical, clinical, and laboratory factors were compared, including therapy, sepsis, hypothermia, asphyxia as reflected by Apgar score, hematocrit, acidosis, hypercarbia, hypoxia, hypoglycemia, and hyperbilirubinemia. No statistically significant differences between the kernicteric and nonkernicteric infants were demonstrated for any of these factors, including peak total serum bilirubin levels. Multivariant analysis also failed to determine a group of factors associated with increased risk for kernicterus. It was not possible to separate those infants with and without kernicterus at autopsy on the basis of the clinical factors evaluated.