Efficacy of strategies for predicting hyperbilirubinemia NEMC Evidence

Efficacy of strategies for predicting hyperbilirubinemia NEMC Evidence Report Stanley Ip, MD Division of General Pediatrics and Adolescent Medicine The Floating Hospital for Children Tufts-New England Medical Center

Strategies evaluated • Cord Bilirubin (4 studies, n=1105) • Early Serum Bilirubin (4 studies, n=3105) • End-tidal Carbon Monoxide Concentration (2 studies, n=1421) • Predischarge Risk Index (1 study, 73 cases, 423 controls) • Predischarge Risk Zone, determined by hourspecific bilirubin percentile (1 study, n=2840)

Subjects from 12 studies • U. S. , China, Denmark, India , Israel, Japan, Spain • N: 51 to 2840 • Term only, term and preterm • Breast feeding: 4% to 90% • No Rh, but some included ABO incompatibility • Some received phototherapy

Definitions of Hyperbilirubinemia • TSB >11. 7 mg/dl, >15 mg/dl, >17 mg/dl, >25 mg/dl • TSB >16 mg/dl at 36 hours • TSB >10 mg/dl at day 2, >14 mg/dl at day 3 >17 mg/dl at day 4 and 5 • TSB ≥ 95%tile • Clinical jaundice (6. 4 mg/dl to 19. 3 mg/dl)

Cord Bilirubin Study Sensitivity Specificity Carbonell, 2001 (n=585) ≥ 2. 2 mg/dl predicts TSB ≥ 17 mg/dl day 3 to day 4 22% 95% Knudsen, 1992 (n=132) ≥ 2. 05 mg/dl predicts TSB > 11. 7 mg/dl 71% 68% Risemberg, 1977 (n=91, ABO) >4 mg/dl predicts TSB >16 mg/dl at 36 h 92% 100%

Test Performance of Cord Bilirubin Levels Adapted from Knudsen, 1992 1. 46 mg/dl 1. 75 mg/dl 2. 05 mg/dl 2. 34 mg/dl

Early Serum Bilirubin level • Awasthi, 1998 (n=274) TSB (18/24) > 3. 99 mg/dl predicts TSB>15 mg/dl; sensitivity 69%, specificity 66% • Carbonell, 2001 (n=1563) TSB(24) ≥ 6 mg/dl predicts TSB > 17 mg/dl; sensitivity 100%, specificity 45. 7% TSB (48) ≥ 9 mg/dl predicts TSB > 17 mg/dl; sensitivity 100%, specificity 64. 3% • Seidman, 1999 (n=1177) TSB (24) > 5 mg/dl is associated with 36. 5 O. R. of TSB(day 2) >10, (day 3) >14, (days 4&5) >17

Factors associated with Jaundice Multiple Logistic Analysis by Seidman, 1999 Day 1 TSB (per 1 mg/dl) ∆ in TSB from day 1 to 2 Maternal blood type O Maternal age (per year) Full breastfeeding Day 1 TSB > 5 mg/dl 3. 1 (O. R) 2. 4 2. 9 1. 1 0. 4 36. 5

Variables associated with TSB ≥ 25 mg/dl Multiple Logistic Analysis by Newman, 2000 Early jaundice FH of jaundice Exclusive Breastfeed Bruising Asian Race Cephalohematoma Maternal age ≥ 25 Lower gestational age 7. 3 (O. R. ) 6. 0 5. 7 4. 0 3. 5 3. 3 3. 1 0. 6/week

ROC of Predischarge Risk Index Source: Newman TB, 2000 RI=7 RI=10 • RI=7 RI=10 RI=15 RI=20

End-tidal Carbon Monoxide Concentration Okuyama, 2001 (N=51) ETCOc > 1. 8 ppm at 42 hours predicts TSB > 15 mg/dl sensitivity 86%, specificity 80%, PPV 40%, NPV 97%

Predischarge Risk Zone Bhutani, 1999 Infants who fulfilled inclusion criteria = 13, 003 Study subjects with at least 2 TSB’s (pre and post discharge) = 2840

Distribution of TSB values at selected study epochal periods Bhutani, 1999

Hour Specific TSB Bhutani, 1999

Predischarge Risk Zone Bhutani, 1999

Predischarge Risk Zone • ≥ 75%tile predischarge zone predicts to subsequent ≥ 95%tile; sensitivity 90. 5%, specificity 84. 7%, PPV 21. 6%, NPV 99. 5%

Racial distribution of study population Race Bhutani, 1999 41% NVS (prelim), 2001 15% Asian 4% 5% Hispanic 4% 21% White 43% 58% Other 8% 1% African-American

ROC Curves Comparing ETCOc, STB Alone, and Combined ETCOc and STB at 30± 6 hrs Stevenson, 2001

Stevenson, 2001 Study sites Study size TSB ≥ 95%tile (from Bhutani, 1999) Cleveland 353 20 (5. 7%) Hong Kong 1 303 25 (8. 3%) Stanford 194 19 (9. 8%) Hong Kong 2 167 9 (5. 4%) Jerusalem 1 119 9 (7. 6%) Providence 116 10 (8. 6%) Philadelphia 50 8 (16. 0%) Jerusalem 2 37 8 (21. 6%) Kobe 31 12 (38. 7%) Total 1370 120 (8. 8%)

Summary • Not possible to directly compare the accuracy of various strategies • Higher TSB at an early age is associated with hyperbilirubinemia • Hour-specific nomogram method appears promising (AUC 0. 93) but further validation is needed