Perinatal Symposium--2012

Transcription

1 Perinatal Symposium Neonatal Jaundice: When Do the Light Bulbs Go On? Theodore R. Thompson, MD Professor of Pediatrics Division of Neonatology University of Minnesota Medical School I have no financial relationships to disclose. I will not discuss off label use and/or investigational use of drugs in my presentation

2

3 Objectives: Neonatal Jaundice Identify the four reasons that contribute significantly to the occurrence of developmental/physiologic jaundice in newborn infants Outline how to (and NOT to ) initially evaluate the newborn infant who is jaundiced Outline methods/risk factors to help predict the newborn infant who is likely to develop severe hyperbilirubinemia Describe when transcutaneous bilirubin measurements can and can NOT be used as a screening tool Describe how to manage the jaundiced newborn infant including plans for follow up if the infant is being discharged List three factors that contribute significantly to the efficacy of phototherapy

4 Neonatal Hyperbilirubinemia Patient Study #1: BA is a 3100 gram, gestational age male born to a 29 year old, 0+, Gr 1 P0000 female whose pregnancy was uncomplicated. The infant s course in the hospital was unremarkable except for the mother needing help to establish breast feeding. He was noted to be jaundiced at 34 hours of age; total serum bilirubin (TSB) was 8.5mg/dL. He was discharged at 40 hours of age with follow up at 2 days of age when he was noted to be very jaundiced (to his feet). The TSB was 19mg/dL (0.3 directconjugated). His blood type is A+. He is active, pink, alert, with a normal cry and normal tone. What would you do?

5 »GENERAL

6

7 Neonatal Indirect-Unconjugated Hyperbilirubinemia Enhanced production (2.5 times adult)-load: Shortened RBC life span Higher RBC Volume (higher hematocrit) Reduced hepatic cell entry (clearance) of bilirubin (ligandin) Uptake Reduced uridine diphosphate glucuronosyl transferase (UDPGT) activity (1% of adult activity) Conjugation Enhanced enterohepatic circulation increased load Decreased oral intake-decreased intestinal motility High concentration of beta-glucuronidase activity (intestinal mucosa)- resultant hydrolysis of conjugated bilirubin and reabsorption of unconjugated (indirect) bilirubin. Low amounts of bacteria

8 Neonatal Jaundice Physiologic Developmental or Physiologic Jaundice Jaundice Bilirubinemia (Cause of Jaundice in 95% of newborn infants) Defined as occurrence of jaundice in a newborn in whom the bilirubin rate of rise does NOT cross percentile curves and in whom the peak bilirubin level is below the 95 th percentile for age. NOTE: About 60-67% of full term and late preterm newborn infants become jaundiced.

9 Neonatal Hyperbilirubinemia Bilirubin INDIRECT (UNCONJUGATED) Fat Soluble Bound to albumin-non toxic Crosses Blood Brain Barrier, Placenta if UNBOUND to albumin Total Serum Bilirubin = TSB = INDIRECT BILIRUBIN level unless abnormal direct (see below) Direct (conjugated) Water soluble Excreted in stool, urine Does NOT cross Blood Brain Barrier, Placenta >1mg/dL if TSB 5mg/dL-Abnormal >15-20% of TSB if TSB 5mg/dL-Abnormal Do NOT subtract direct level from TSB unless abnormal-rely usually on TSB =Indirect Level

10 Neonatal Hyperbilirubinemia General Bilirubin production in newborn infants: 6-10mg/kg/day (2.5 times higher load than adults) Hemoglobin is the major heme containing protein (1g produces 34mg of bilirubin) Total Serum Bilirubin (TSB): Indirect (unconjugated) Bilirubin bound to albumin (most) plus free, indirect bilirubin (toxic) plus direct (conjugated) bilirubin (usually very low in newborn infants) One gram of albumin binds 8.5mg/dL of indirect (unconjugated) bilirubin somewhat tightly Bilirubin bound to albumin is nontoxic Free, indirect (unconjugated) bilirubin, which is POTENTIALLY TOXIC to the CNS, is very difficult to measure and NOT done in most laboratories. Direct or conjugated bilirubin is non toxic (water soluble) Early discharge (<36-48 hours) often makes neonatal hyperbilirubinemia an OUTPATIENT DISORDER

11 Neonatal Hyperbilirubinemia General (Continued) Usually detect jaundice at bilirubin levels of 5-8mg/dL in newborn infants (2mg/dL in adults), range 2-12 mg/dl Visual estimation of TSB is NOT RELIABLE to determine level At least 60-67% of full-term, late preterm infants develop jaundice by 7 days of age Most common clinical sign in neonatal period-primarily indirect (unconjugated) bilirubin = TSB Indirect (unconjugated) bilirubin will NOT harm most full term infants unless TSB levels at or above mg/dl (extremehazardous) or risk factors exist with TSB levels at or above mg/dl (severe-extreme) TSB: Total Serum Bilirubin

12 Neonatal Hyperbilirubinemia General (Continued) Peak total serum bilirubin (TSB) levels (indirect bilirubin) occur at 3-7 days postnatal age in full term infants Later, higher TSB levels: 4-10 days, often mg/dl or higher in: Preterm infants (including late preterm) infants Exclusively breast fed infants East Asian infants Peak indirect (unconjugated) bilirubin levels (TSB) should be under mg/dl (< mg/dl?) 4-6% of full term infants with TSB >13mg/dL 3% of full term infants with TSB >15mg/dL (95 th percentile, 15-17mg/dL), 1-2% with TSB > 20 mg/dl 10-20% of breast fed infants with TSB levels >13-14 mg/dl

13 Neonatal Hyperbilirubminemia TSB LEVEL-95 th Percentile Developmental or Physiologic Higher, more prolonged in: Premature (includes late preterm) Breast fed infants (exclusive) East Asian Race for Age in Hours mg/dl mg/dl Moderate Hyperbilirubinemia Significant Hyperbilirubinemia Severe Hyperbilirubinemia Extreme Hyperbilirubinemia Hazardous Hyperbilirubinemia Prolonged Jaundice (Indirect)- Breast Milk Jaundice? > mg/dl 17 mg/dl 20 mg/dl 25 mg/dl > 30 mg/dl 3 weeks-3 months

14 RISK FACTORS NEONATAL HYPERBILIRUBINEMIA

15 Important Risk Factors-Significant Hyperbilirubinemia Predischarge TSB* or TcB* level: High-intermediate (>75th) (under 38 weeks or other high risk factors) or High Risk (>95th) (full-term, no risk factors) zone on hour specific nomogram (Bhutani,VK et al Pediatrics, 1999; 103: 6) Lower gestational age or prematurity including late preterm infants (34 0/7-36 6/7 weeks)-two fold increased risk Exclusive breastfeeding (particularly if difficulties with nursing, excessive weight loss(> 7-10%) and/or first time mother with little family support) Jaundice in first 24 hours Early Hospital discharge-less than 24/48 hours of age and/or, excessive weight loss (>7-10%)

16 Treatment Guidelines-Hour Specific Nomogram 16

17 Breastfeeding versus Breast Milk Jaundice Breast feeding* (Nonfeeding) Breast Milk+ Time of Onset 2-4 days 4-7 days Usual time to peak bilirubin 3-6 days 5-15 days Peak TSB >12mg/dL >5-10mg/dL (at 3 wks) occasionally 15-20mg/dL Mean age for TSB <3mg/dL 3 weeks 9-12 weeks Weight Loss 7-10% or greater Gaining weight, vigorous, active Incidence-full term infants 12-20% 10-50% Management E-lytes, more frequent breast feedings with formula supplementation; lactation consultant; phototherapy-tsb levels Observe, stop breast feeding for 2 days; phototherapy?- TSB level? L-aspartic acid? Note: Considerable overlap exists early in the patient s course * May be related to dehydration/weight loss, starvation/poor intake, increased enterohepatic circulation + Interruption of breast feeding for 48 hours results in 50% decline in TSB with a 2-3mg/dL rebound with resumption of breast milk; healthy, vigorous infants Modified from Gourley, GR NeoReviews 2000; 1: e25-e31

18 Risk Factors for Breastfeeding Problems Maternal-need for lactation consultant Medical illness C-section Lack of breast enlargement (prenatal, postnatal) Flat or inverted nipples Previous breast surgery Sore nipples, breast enlargement postnatally Infant-need for lactation consultant Oral cleft, microagnathia Multiples Latch on difficulties Respiratory, cardiac, or neurologic disorders; anomalies Sleepy, lethargic Jaundice

19 Adequacy of Breast Feeding Adequacy of Intake Latching On 4-6 wet diapers per day Weight loss less than 7-10% by day 3, 4 Breast feeding 8-12 times per day 3-4 stools per day Mustard yellow, mushy by day 3, 4 Supplementation if necessary: Formula, NOT glucose water/ water

20 Important Risk Factors-Significant Hyperbilirubinemia (Continued) Isoimmune hemolytic disorder (e.g., ABO or Rh incompatibility, other)-direct Antiglobulin Test (+) (most) Other hemolytic disorder Membrane or structural disorder- (e.g.,spherocytosis) Enzyme deficiency (e.g.,g6pd deficiency, pyruvate kinase) Previous sibling who required phototherapy Cephalohematoma or significant ecchymoses Polycythemia East Asian Race Maisels, MJ et al *TSB/TcB: Total Serum Bilirubin/Transcutaneous Bilirubin Pediatrics 2009; 124: 1193

21 Neonatal Hyperbilirubinemia: ABO Incompatibility MOther s blood type O, BABy A or B PLUS Positive Direct Antiglobulin Test (DAT, Direct Coombs Test) Common B antigen stronger than A antigen of infants born to O mothers 33% of A or B infants born to O mothers have anti A or B antibodies (IgG) attached to RBC (20% of these with significant hyperbilirubinemia) ABO Hemolytic disease may occur with negative Coombs or DAT Jaundice often present first 24 hours, but uncommon reason for readmission Gilbert Syndrome genotype (?) if prolonged jaundice (breast milk?) Rare late anemia (in contrast to Rh isoimmunization) High risk factor-use hour specific nomogram (Bhutani, VK et al Pediatrics 1999: 103:6) + phototherapy/exchange transfusion nomogram Start phototherapy 2-5mg/dL lower than for usual patient

22 Neurotoxicity Risk Factors-- Lowers the Threshold for Treatment of Hyperbilirubinemia Any illness (e.g. RDS) Prematurity including Late Preterm Infants (34 0/7-36 6/7 weeks) Isoimmune hemolytic disease (e.g.,abo incompatability (?), Rh, Other) G6PD deficiency Asphyxia Acidosis Sepsis Serum albumin < 3gm/dL-not routinely measured

23 » EVALUATION-NEONATAL JAUNDICE

24 Neonatal Jaundice General Bilirubin deposits in skin, subcutaneous tissues as total serum bilirubin (TSB) rises At least 60-67% of healthy full term infants appear jaundiced during the first postnatal week Somewhat (?) direct relationship between TSB and intensity of jaundice(?)-cephalocaudal progression: Face to trunk to abdomen to extremities progression Jaundice can be noted with TSB levels <5mg/dL Jaundice NOT always detected with TSB levels of 8-12mg/dL TSB likely below 12mg/dL if no jaundice Transcutaneous bilirubin measurements (TcB)-comparable to TSB levels (may be lower by 2-3 mg/dl) Peak bilirubin levels at 3-7 days of age in full term infants, 4-10 days in breast fed and/or premature infants

25 2 3 1 Neonatal Jaundice Dermal Zone Indirect Bilirubin Mean Range Risk 0 (none) <12mg/dL (likely) Low 1 (face, neck) Low 2 (chest, back) I 3 (abdomen-below I umbilicus to knees) 4 (arms, legs below knees) High 5 (hands and feet) >15-20 High Visual Assessment: Fraught with Hazards! 4 5 From Kramer, LI Am J Dis Child :454 Keren, R et al Arch Dis Child Fetal Neonatal Ed 2009; 94: F317

26 Neonatal Hyperbilirubinemia-Pathologic When to evaluate pathologic jaundice (laboratory tests): Jaundice in first 24 hours (TcB*/TSB*) Excessive production usually-hemolysis TcB/TSB above 75 th percentile (high intermediate or high risk zone) or rapidly rising (i.e. crossing percentiles) on hourly nomogram (Bhutani, VK et al, 1999: 103: 6) Cord TSB > 4-5 mg/dl or TSB > 5 mg/dl at 24 hours TSB crossing lines (of concern) or rising more than mg/dl/hr for 4-8 hours(?) TSB crossing lines (of concern) or increasing more than 5 mg/dl per 24 hours TSB over 13(?),15-17 ml/dl in full term infant *TcB/TSB-Transcutaneous Bilirubin/Total Serum Bilirubin

27 Neonatal Hyperbilirubinemia-Pathologic (Continued) When to evaluate (laboratory tests): Cannot explain jaundice/high TSB by history, physical exam TSB approaching exchange level or not responding to phototherapy Jaundice at or beyond 3 weeks of age or infant is ill (total, direct) Elevated direct (conjugated) bilirubin level At or Above 1 with TSB 5mg/dL At or Above 15-20% of total TSB when TSB is >5mg/dL Dark urine, light colored stools *TcB/TSB-Transcutaneous Bilirubin/Total Serum Bilirubin

28 Initial Evaluation--Neonatal Hyperbilirubinemia LABORATORY TESTS: TSB*-TOTAL: Indirect (uncojugated) plus Direct (conjugated) Repeat TSB in 4-24 hours depending on TSB level, postnatal age, risk factors Blood type, Rh (maternal, infant for both); Direct Antiglobulin or Coombs test (DAT) Save cord blood when maternal blood type is O or Rh(-) CBC, reticulocyte count, smear (?) Consider albumin level, G6PD level for G6PD deficiency (family history, ethnicity) *Total Serum Bilirubin

29 Additional Evaluation of Neonatal Hyperbilirubinemia (Contd) LABORATORY TESTS: Consider bacterial or viral infection (blood, urinary tract infection) if indicated most with both elevated indirect and direct bilirubin levels T 4 /TSH--state screen results for prolonged hyperbilirubinemia (over 2-3 weeks of age) Consider tests for other metabolic disorders (state screen) often with both indirect (unconjugated) and direct (conjugated) hyperbilirubinemia including galactosemia for prolonged jaundice *Total Serum Bilirubin

30 Transcutaneous Bilirubin (TcB) Measurements Instantaneous, non-invasive, safe, reliable, easy, cost effective (fewer TSBs) Measures tissue bilirubin, not TSB--yellow color of blanched skin, subcutaneous tissue Chest (most accurate) Forehead (usual site-ease) Much more accurate than visual estimation of TSB Valid screening test for hyperbilirubinemia with good correlation with Total Serum Bilirubin(TSB)-may underestimate TSB by 2-3mg/dL Compare with TSB measurements (laboratory)-quality control May use for all races and for preterm (at least > 29 weeks), full term infants TcB results NOT reliable under phototherapy (ok if >24 hours off phototherapy? or covered area?), marked hirsutism (e.g. Hispanic), dark skinned? or >15mg/dL Always obtain TSB if to initiate therapy or if TcB >13-15 mg/dl TcB value is at 70% of value to start phototherapy TcB at or above the 75 th percentile on hour specific nomogram (high intermediate or high risk zone)

31 Monitoring with Transcutaneous Bilirubinometry (TcB) (Continued) Screening tool Worry about infant, then obtain TSB? Obtain TSB if TcB at or above 75 th percentile (high intermediate or high risk zone) on hour specific nomogram (Bhutani VK et al. Pediatrics 1999; 103: 6) Factor in age in hours, risk factor(s) Obtain TSB before implementing therapy (TcB at 70-75% of TSB level for phototherapy) Obtain TSB if TcB is > ml/dl in full term or preterm infant Superior to visual estimate and reduces likelihood of missing clinically significant TSB NOTE: TcB: NOT a substitute for TSB measurement, NOT to be used alone TSB/TcB: Total Serum Bilirubin/Transcutaneous bilirubin

32 Transcutaneous Screening for Bilirubinemia (TcB) Transcutaneous Measurements JM-103 (Konica Minolta) Overestimate bilirubin level in dark-skinned infants (?) Bili Check (Respironics) Underestimate bilirubin levels in Hispanic infants (?) Sternum more accurate than forehead (exposure to light in latter) Obtain Total Serum Bilirubin (TSB)-laboratory-: Under phototherapy Total bilirubin 15mg/dL Rapidly rising bilirubin levels (crossing lines)

33 Transcutaneous Bilirubinometry Screening Program and Resource Utilization Significant Reduction: Total serum bilirubin levels (capillary sticks) Phototherapy utilization Age at readmission for therapy Duration of re-hospitalization stay Improved laboratory utilization, patient care, patient convenience, patient safety. Consider Integration with a public health nurse newborn follow-up program From Wainer, Setal Pediatrics 2012; 129: 77-86;

34 Hour Specific Nomogram for Transcutaneous Bilirubin (TcB) Measurements in Healthy Newborns 35 Weeks Gestation

35 Common Causes of Prolonged (3 weeks or longer) or Recurrent, Indirect Hyperbilirubinemia Hemolytic disorders (may develop anemia) Blood group incompatibility-abo (?); Rh, Kell, Duffy, c, C, E RBC membrane abnormality (e.g. spherocytosis) RBC enzymatic defect (e.g. G6PD deficiency) Disorders of hemoglobin synthesis (rare) Extravascular Blood (e.g., cephalohematoma, ecchymoses) Congenital Hypothyroidism (T 4, TSH)-state screen results Galactosemia (state screen results-often has both indirect and direct bilirubin components) Urinary tract infection(may have direct bilirubin component) Pyloric Stenosis Constipation Crigler Najjar syndrome (I, II), Gilbert syndrome Breast Milk Jaundice (role of Gilbert Syndrome?)

36 » MANAGEMENT-NEONATAL HYPERBILIRUBINEMIA

37 Neonatal Hyperbilirubinemia Patient Study #1: BA is a 3100 gram, gestational age male born to a 29 year old, 0+, Gr 1 P0000 female whose pregnancy was uncomplicated. The infant s course in the hospital was unremarkable except for the mother needing help to establish breast feeding. He was noted to be jaundiced at 34 hours of age; total bilirubin (TSB) was 8.5mg/dL. He was discharged at 40 hours of age with follow up at 2 days of age when he was noted to be very jaundiced (to his feet). The TSB was 19mg/dL (0.3 direct-conjugated). His blood type is A+. He is active, pink, alert, with a normal cry and normal tone. What would you do?

38 Neonatal Hyperbilirubinemia Patient Study #1-Management: Hospitalize Start Intensive phototherapy-- special blue overhead lights with Bili-Blanket or double bank(?) irradiance>30-35 microwatts/cm2/nm Breast feeding (frequent) with IV fluids and/or formula supplementation if indicated ( ml/kg/d)-see how feedings progress Monitor TSB every 4-6 hours until declining, intake/output, daily weights CBC with differential/platelet count, reticulocyte count, Direct Coombs test (DAT-positive); consider blood/urine/csf(?) cultures, CRP; albumin, smear?, G6PD? IVIG (0.5-1 gm/kg over 4 hours) for DAT (+) hemolytic disorder (ABO incompatability, Rh)-infusion every 12 hours for 3 doses Exchange transfusion?

39 Mechanism of Phototherapy Maisels MJ, Mcdonagh AF. N Engl J Med 2008; 358:

40 Phototherapy for Neonatal Hyperbilirubinemia Effectively reduces indirect (unconjugated) bilirubin levels and has dramatically reduced need for exchange transfusions; 30-40% decline in 24 hours Pumps bilirubin (converts to structural and configurational photoisomers) from skin- bleaches skin Degradation products more easily excreted in urine, bile Transcutaneous bilirubin (TcB), Visual inspection: NEITHER RELIABLE UNDER PHOTOTHERAPY Total Serum Bilirubin (TSB) Levels-Laboratory Indirect equals total serum bilirubin (TSB) level unless direct over 20% of TSB level >5 mg/dl Note: Direct bilirubin may reduce albumin binding capacity

41 Factors Related to Efficacy of Phototherapy Maisels MJ, Mcdonagh AF. N Engl J Med 2008; 358:

42 Management Under Phototherapy Increase fluid intake (increased insensible loss less with LED lights) Breast feeding--supplementation with formula (NOT water or glucose water) to reduce enterohepatic circulation IV fluid if needed Monitor weight, intake/output Overheating burns if halogen (spotlight) light too close (use manufacturer s recommendation for distance); does NOT occur with LED lights Cover eyes with patches, genitalia with diaper Do NOT always need eye patches with bili-blanket Monitor TSB (NOT TcB) every 4-24 hours depending on TSB level, postnatal age, and risk factors

43 Mangement Under Phototherapy (Continued) Discontinue phototherapy when TSB is below the level phototherapy was initiated (12-14mg/dL) Rebound in TSB may occur (1-5mg/dL) particularly in preterm infants and those with hemolysis Monitor intake/output, weight Monitor for diarrhea, rash Monitor for later melanocytic nevi? Interrupt phototherapy for feeding, parental visits to enhance parent-infant bonding, even when under intensive (reduce disruption) phototherapy if infant isresponding to therapy

44 Guidelines for Phototherapy for Infants 35 weeks Gestation

45 Bili Tool Risk for development of hyperbilirubinemia Age (hours) hours Total Bilirubin Risk Zone Start Phototherapy-yes/no-alerts to risk factors

46 Management of Hyperbilirubinemia in Apparently Healthy Full Term/ Late Preterm Infants TSB Levels: Initiate Phototherapy and Exchange Transfusion Age (hours) Consider PT* PT*, ET o if Intensive PT fails** ET o and PT NOT NORMAL > TSB: Total Serum Bilirubin, mg/dl *PT: Phototherapy; use lower ( Consider PT values) TSB levels for late preterm infants or those with risk factors as hemolysis (e.g.,abo, Rh, G6PD) or rapidly rising bilirubin values. o ET: Exchange Transfusion (>20-25 if one or more risk factors) **Administer IVIG if ABO, Rh or other isomimmune hemolytic disease exists Note: Start phototherapy when TSB levels are 5-8mg/dL below exchange transfusion levels

47 Phototherapy-Hospital, Home Bili Blanket Overhead phototherapy lights? Monitor Total Serum Bilirubin (TSB) levels, intake/output, neurologic exam at least every 24 hours-initial 30-40% decline in TSB in 24 h, most in first 4-6 h Do NOT use home phototherapy in presence of high risk factors (e.g., poor feeding, lethargy, excessive weight loss, isoimmune hemolytic disorder, poor temperature control) Do NOT use home phototherapy if TSB approaching exchange transfusion levels Can NOT use Transcutaneous bilirubinometry (TcB) monitoring if under phototherapy Reduced cost, improved parental satisfaction/bonding.

48 Treatment with Phototherapy Best Practice Recommendations for Phototherapy Equipment Capability Blue/green light spectrum: irradiance spectrum Greater than 30 µw/cm 2 /nm LED bulb preferred Maximize surface area exposure ( e.g., bank plus blanket) 50

49 PREVENTION - SEVERE HYPERBILIRUBINEMIA

50 Patient Study # 2 BH was the 4054 gram, early term infant born to an O+, 24 yo Gr 4 P2103, Hispanic female with insulin dependent diabetes mellitus. She was GBS positive and was treated during labor. The infant had a NSVD with Agpars of 9 and 9. At 2 days of age, the infant s TSB was 13.7 and phototherapy was initiated. At 3 days of age when discharged home, the infant s bilirubin was 16.7 and home phototherapy was utilized and continued. The infant was breast feeding well. The infant was A+, DAT (2+) and had a sibling who required phototherapy. The mother, who spoke English and Spanish fluently, was instructed to have the infant seen the next day in clinic. However, no appointment was available until one week later. During the next 5 days, the infant had frequent spit ups and became more lethargic with decreased intake. Vomiting was more frequent on day 9 of age when the infant was taken to the ER.

51 Patient 2 (Continued) In the ER, the infant s bilirubin was 33 (2 direct) and the infant was admitted to the NICU where the bilirubin was 38 (3 direct). Other liver function tests were normal with an albumin of 4.8. UA had 44 WBC (culture was negative) and CRP was <5. Lethargy, hypertonicity (clenched fists, extension of extremities, opisthotonic posturing) with questionable seizures, poor suck, and depressed Moro were noted. Weight loss was 10% from birth weight. How would you manage this infant? What is the infant s prognosis?

52 Three Phases of Bilirubin Encephalopathy Acute Initial Phase Lethargy, sleepiness Hypotonia Poor suck/feeding Acute-Intermediate Hypertonia--Opisthotonus, retrocollis, arching Fever High pitched cry Poor suck/ feeding Advanced or Chronic-Kernicterus Stupor, Coma, Seizures Athetosis, dystonia, chorea, ballismus, tremor-motor Paresis of vertical gaze (oculomotor nuclei)-sunsetting sign Sensorineural hearing loss (auditory neuropathy) Enamel dysplasia of deciduous teeth Minority with cognitive delay Bright Mind Trapped in an Uncontrollable Body

53 Kernicterus Can occur in healthy infants (including those being breast fed) with extremely elevated TSB levels (>25-30 mg/dl, >20-25 mg/dl if hemolysis or other neurotoxicity high risk factors)-still happens Exclusive breast feeding, early discharge (<36-48 hours), first time mother without family support and/or being late preterm contribute significantly to very increased TSB levels and reports of kernicterus Yellow staining of specific regions of the brain: basal ganglia, hippocampus, various brainstem nuclei, eighth nerve, cerebellum-neuronal necrosis Free, indirect or unconjugated bilirubin enters the brain and attaches to cell membranes More subtle form of neurotoxicity? Hemolytic disease or neurotoxicity risk factor(s): Risk of kernicterus increases with TSB 20-25mg/dL(full term, late preterm) Non hemolytic disease, no risk factor(s): risk of kernicterus increases with TSB 25-30mg/dL(full term) Length of exposure to elevated bilirubin level? Free unconjugated bilirubin level? Preterm infants: lower TSB levels associated with kernicterus Role of Gilbert syndrome

54 Neonatal Hyperbilirubinemia-Bilirubin Encephalopathy* (2008) Major neurotoxicity risk factors Rh Isoimmunization (NOT ABO incompatibility) Sepsis Prematurity No Risk Factors TSB 25mg/dL TSB mg/dl *34-36 weeks Gestational Age Note: Biological factors besides bilirubin level are important in pathogenesis of bilirubin encephalopathy From Gamaleidin, R etal Pediatrics 2011; 128;e925-e931

55 Kernicterus Can NOT associate a specific risk of CNS damage with a particular Total Serum Bilirubin level (TSB) in the full term or late preterm infant Kernicterus has been well described in extremely premature infants at very low TSB levels

56 Prevention of Kernicterus Can likely prevent kernicterus in most healthy, full term infants by ensuring adequate feeding, monitoring of TSB/TcB, education of parents, identifying infants at risk for severe hyperbilirubinemia and timely outpatient follow up within hours of discharge However, kernicterus may occur, despite appropriate monitoring and management, in an infant with prematurity, G6PD deficiency, sepsis, asphyxia, genetic predisposition or other unknown neurotoxicity factors Sentinel event? YES, TSB of 30 mg/dl or higher

57 Predictive Ability of a Pre Discharge Hour-Specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near-Term Newborns Bhutani VK et al. Pediatrics 1999; 103: 6-14

58 Hour-Specific Bilirubin Nomogram

59 Predischarge Risk Zone Bilirubin Level as a Predictor of Significant Hyperbilirubinemia Zone Newborns Newborns who developed (n=2840) TSB level >95 th percentile (%) High Risk (>95 th percentile) 6% 40% High Intermediate (76 th -95 th ) 13% 13% Low Intermediate (40 th -75 th ) 20% 2% Low Risk (<40 th ) 62% 0% Maisels MJ, Newman TB. Pediatrics 1999; 103: 493 Bhutani VK et al. Pediatrics 1999; 103: 6

60 American Academy of Pediatrics Clinical Practice Guideline Subcommittee on Hyperbilirubinemia Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation Pediatrics 2004; 114:

61 Hyperbilirubinemia in the Newborn Infant 35 Weeks Gestation: An Update with Clarification Maisels MJ, et al. Pediatrics 2009; 124:

62 Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia Maisels MJ et al, Journal of Perinatology 2009; 29: Noninvasive Measurements of Bilirubin Maisels MJ Pediatrics 2012; 129, 779

63 Commentary on Hyperbilirubinemia in the Newborn Infant 35 weeks (Pediatrics, October, 2009) Update with clarification of the AAP 2004 hyperbilirubinemia practice guideline Consideration for universal predischarge bilirubin screening using TSB/TcB to assess risk of subsequent hyperbilirubinemia More structured approach to management and follow up Predischarge TSB/TcB (75-95(high intermediate) or >95 th percentile (high risk zone) Gestational age (<38 weeks) Exclusive breast feeding Other risk factors Follow-up guidelines TSB/TcB: Total Serum Bilirubin/Transcutaneous Bilirubin

64 Universal Bilirubin Screening-Predischarge Excellent Idea Plot on hour specific nomogram (Bhutani VK et al. Pediatrics 1999; 103: 6)-high or high intermediate risk zones Need to combine TSB/TcB level with clinical (breast feeding, gestational age) and NEUROTOXICITY risk factors (prematurity, asphyxia, acidosis, illness, lethargy, G6PD deficiency, isoimmune hemolysis (ABO, Rh), sepsis, low albumin <3 gm/l) Identifies need for close follow up within hours of discharge Assign risk zone phototherapy/follow up TSB evaluation Likely reduces risk of severe, extreme, hazardous hyperbilirubinemia Concerns TSB level in high risk zone but no further increase in level or low risk zone with subsequent increase in bilirubin level (false positives, false negatives-rare) Does NOT predict risk of kernicterus; may increase earlier, excessive use of phototherapy, laboratory tests Parental anxiety

65 Screening of Infants for Hyperbilirubinemia to Prevent Chronic Bilirubin Encaphalopathy: US Preventive Services Recommendation Statement US Preventive Services Task Force. Pediatrics 2009; 1124:

66 Universal Bilirubin Screening Predischarge (Continued) US Preventive Services Task Force: Insufficient evidence to recommend screening for hyperbilirubinemia Evidence about benefits and harms of screening to prevent kernicterus (chronic bilirubin encephalopathy) is lacking No evidence screening is associated with improved outcomes or use of hour specific nomogram reduces incidence of kernicterus Insufficient evidence about potential harms and efficacy of phototherapy Screening may lead to earlier, excessive use of phototherapy

67 » SUMMARY

68 Neonatal Hyperbilirubinemia Summary Most common condition affecting newborn infants (60-70% become jaundiced) requiring evaluation and management Represents imbalance between bilirubin production and hepatic/enteric clearance Visual estimation of TSB is fraught with hazard Most frequent reason for re-hospitalization of infants during first 7 to 10 days post birth (particularly if breast fed) Benign transitional phenomenon of no overt clinical impact for great majority of infants, but can be catastrophic very rarely New evidence suggests combining a predischarge, hour specific TSB/TcB level (nomogram) with TWO risk factors, Gestational Age <38 weeks and Exclusive Breast Feeding, improves prediction of significant hyperbilirubinemia ( 17mg/dL)

69 Ten Key Recommendations for Preventing and Managing Neonatal Hyperbilirubinemia Promote and support successful breast feeding Establish nursery protocols for the jaundiced infant including TcB measurements, TSB determinations, and physician contact Interpret TcB/TSB levels by age in HOURS, NOT DAYS Measure TcB/TSB in infants jaundiced 24 hours of age Remember, visual assessment of bilirubin level is NOT reliable, particularly in darkly pigmented infants and/or if under phototherapy Late preterm infants must NOT be treated as full term infants; they are more prone to higher bilirubin levels that remain high longer

70 Ten Key Recommendations for Preventing and Managing Neonatal Hyperbilirubinemia (Continued) Perform a pre discharge assessment (TcB screen?) for risk of severe hyperbilirubinemia Provide information, education to parents on newborn jaundice Provide follow up (24-48 hours) based on time of discharge and the risk assessment Treat with phototherapy or exchange transfusion if indicated Modified from: American Academy of Pediatrics, Clinical Practice Guideline, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks gestation. Pediatrics 2004; 114:297

71 Maroon and Gold Summary Points The two most common risk factors for development of significant hyperbilirubinemia in newborn infants are Prematurity (includes late preterm infants) and Exclusive Breast Feeding. Neurotoxicity factors increase risk of CNS damage: any illness, prematurity (including late preterm), hemolysis (ABO?, Rh),, asphyxia, acidosis, sepsis, low albumin level Visual estimation of neonatal bilirubin levels is NOT reliable Transcutaneous bilirubin levels (TcB) are similar or 2-3 mg/dl lower than Total Serum Bilirubin (TSB) levels and are very useful in following patients in the hospital and clinic setting but can NOT be used if under phototherapy

72 Maroon and Gold Summary Points (Cont d) Measurement of TcB, TSB and plotting on Bhutani s hour specific nomogram (Pediatrics 1999; 103:6) is useful in identifying infants at high risk for developing severe hyperbilirubinemia necessitating phototherapy. Does this prevent kernicterus? Neonates who are discharged before hours and those with high risk factors for hyperbilirubinemia should definitely be seen within hours of discharge for a TcB/TSB particularly if jaundice is present (MD, Public Health Nurse) or if in high risk or high intermediate risk zone on nomogram Jaundice in breast fed babies may be present up to 3 months of age although a direct bilirubin level with a TSB level along with the state screening results for T4/ TSH (hypothyroidism) and galactosemia should be checked in those infants with jaundice persisting beyond 3 weeks of age

73

74 References: General American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks gestation. Clinical Practice Guideline. Pediatrics 2004; 114: (Published correction in Pediatrics 2004; 114:1138). Bili Tool: Hammerman C, Kaplan M. Recent developments in the management of neonatal hyperbilirubinemia. NeoReviews 2000; 1: e19-e24. Kaplan M, Hammerman C. American Academy of Pediatrics guidelines for detecting neonatal hyperbilirubinemia and preventing kernicterus. Arch Dis Child Fetal Neonatal Ed 2005; 90: F448-F449. Keren R, et al. Visual assessment of jaundice in term and late preterm infants. Arch Dis Child Fetal Neonatal Ed. 2009; 94: F312-F322. Maisels MJ. Neonatal jaundice. Pediatrics in Review 2006; 27: Maisels MJ, et al. Hyperbilirubinemia in the newborn infant 35 weeks gestation: An update with clarifications. Pediatrics 2009; 124: Maisels MJ. Neonatal Hyperbilirubinemia. Care of the High Risk Neonate. Ed. Klaus MH, Fanaroff AA. Philadelphia, PA: WB Saunders; 2001,

75 References: General (Continued) Maisels MJ. What s in a name? Physiologic and pathologic jaundice: The conundrum defining normal bilirubin levels in the newborn. Pediatrics 2006; 118: McDonagh AF, Maisels MJ. Bilirubin unbound: Déjà vu all over again? Pediatrics 2006; 117: Moerschel SK, et al. A practical approach to neonatal jaundice. American Family Physician 2008; 77: Newman TB, et al. Infants with bilirubin levels of 30mg/dL or more in a large managed care organization. Pediatrics 2003; 111: Newman TB, et al. Outcomes among newborns with total serum bilirubin levels of 25mg/dL or more. New Engl J Med 2006; 354: Wong RJ, et al. Neonatal Jaundice and Liver Disease. Neonatal-Perinatal Medicine, 8th Edition. Ed. Martin RJ, Fanaroff AA, Walsh MC. St. Louis, MO: Mosby; 2006, Wong RJ, et al. Tin mesoporphyrin for the prevention of severe neonatal hyperbilirubinemia. NeoReviews 2007; 8: e77-e83.

76 References: Breast Feeding de Almeida MFB, Draque CM. Neonatal jaundice and breast feeding. NeoReviews 2007; 8: e282-e288. Gourley GR. Breastfeeding, diet, and neonatal hyperbilirubinemia, NeoReviews 2000; 1: e25-e30. References: Phototherapy Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med 2008; 358: Newman TB, et al. Numbers needed to treat with phototherapy according to the American Academy of Pediatrics guidelines. Pediatrics 2009; 123:

77 References Bilirubin Predischarge Screening- Includes Transcutaneous Bilirubin Measurements Bhutani VK, et al. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in ealthy term and near-term newborns. Pediatrics 1999; 103: 6-14 Burgos, AE et al Screening and follow-up for neonatal hyperbilirubinemia: A review. Clin Pediatrics 2012; 51:7-16 Dalal SS, et al. Does measuring the changes in TcB value offer better prediction of hyperbilirubinemia in healthy neonates? Pediatrics 2009; 124: e851-e857. De Luca D, et al. Transcutaneous bilirubin nomograms. Arch Pediatr Adolesc Med 2009; 163: Fay DL, et al. Bilirubin screening for all newborns: A critique of the hour specific bilirubin nomogram. Pediatrics 2009; 124: Keren R, et al. A comparison of alternative risk-assessment strategies for predicting significant hyperbilirubinemia in term and near-term infants. Pediatrics 2008; 121: e170-e179. Keren R, Bhutani VK. Predischarge risk assessment for severe neonatal hyperbilirubinemia. NeoReviews 2007; 8: e68-e76. Maisels MJ, et al. Hyperbilirubinemia in the newborn infant 35 weeks gestation: An update with clarifications. Pediatrics 2009; 124: Maisels MJ, et al. Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia. J Perinatol 2009; 29:

78 References Bilirubin Predischarge Screening Includes Transcutaneous Bilirubin Measurements (Continued) Newman TB, et al. Combined clinical risk factors with bilirubin levels to predict hyperbilirubinemia in newborns. Arch. Pediatr Adolesc Med 2005; 159: Newman TB, et al. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med 2000; 154: Newman TB. Universal bilirubin screening, guidelines, and evidence. Pediatrics 2009; 124: Sarici SU, et al. Incidence, course, and prediction of hyperbilirubinemia in near-term and term newborns. Pediatrics 2004; 113: Trikalinos T, et al. Systematic Review of screening for bilirubin encephalopathy in neonates. Pediatrics 2009; 124: US Preventive Services Task Force. Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encaphalopathy: US Preventive Services Task Force Recommendation Statement. Pediatrics 2009; 124: Varvarigou A, et al. Transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. Pediatrics 2009; 124:

79 References: Transcutaneous Bilirubinometry Bosschaart, N et al. Limitations and oportuniies of transcutaneous bilirubin measurements. Pediatrics 2012; 129: Fonseca, R et al. Covered skin transcutaneous bilirubin estimation is comparable with serum bilirubin during and after phototherapy.j. Perinatology 2012; 32: Maisels MJ. Transcutaneous bilirubinometry. NeoReviews 2006; 7: e217- e225. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of 35 weeks gestation. Pediatrics 2006; 117: Maisels MG. Noninvasive measurements of bilirubin. 2012; 129: Schmidt ET, et al. Evaluation of transcutaneous bilirubinometry in neonates.j Perinatol 2009;29: Wainer, S et al. Impact of a transcutaneous bilirubinometry program on resource utilization and severe hyperbilirubinemia. Pediatrics 2012; 129: 77-86

80 References: Kernicterus Davidson L, Thilo TH. How to make kernicterus a never event. NeoReviews 2003; 4: e308-e313. Gamaleidin,R et al. Risk factors for neurotoxicityh in newborns with severe neonatal hyperbilirubinemia. Pediatrics 2011; 128: e925-e931 Johnson L, Bhutani VK. Editors Bilirubin Supplement. Need for a safer management of newborn jaundice: A Report from the US Kernicterus Registry. J Perinatol 2009; 29: s1- s67 (Supplement 1 February-Multiple Articles). MMWR. Kerincterus in full term infants-united States, ; 50: Newman TB, et al. Infants with bilirubin levels of 30mg/dL or more in a large managed care organization. Pediatrics 2003; 111: Newman TB, et al. Outcomes among newborns with total serum bilirubin levels of 25mg/dL or more. New Engl J Med 2006; 354: Sentinel Event Alert: Kerincterus threatens healthy babies. Issue 18. April, Shapiro SM, et al. Hyperbilirubinemia and kernicterus. Clin Perinatol 2006; 33: Vandborg, PK et al. Follow-up of neonates with total serum bilirubin levels_> 25 mg/dl: A Danish population-based study. Pediatrics : Watchko JF. Hyperbilirubinemia and bilirubin toxicity in late preterm infants. Clin Perinatol 2006; 33: Watchko JF. Neonatal hyperbilirubinemia-what are the risks? New Engl J Med 2006; 354:

81