1. Interesting Case Conference Transfusion Medicine
WHITNI MILTON, MD
JANUARY 27, 2015

2. Baby Girl H
Born at 37 1/7 WGA by primary low transverse Cesarian section at 22:32 on 1/10/15
At birth her Apgars were 8/9
Her delivery was uncomplicated with routine resuscitation and care
Her initial examination by the pediatric team at birth was only remarkable for “moderate to severe jaundice”

3. Mother’s History 23 year old African American G1Po
Poorly controlled diabetes, hypertension, pre-eclampsia, obesity
Good prenatal care
All routine prenatal infectious disease testing was negative
Sickledex was negative
Blood type A positive with negative antibody screen
Medications – Novolog and Levemir

4. Bilirubin levels
Day hours of life transcutaneuous bilirubin 18.1
STAT serum total bilirubin 18.4 (direct 0.7)
Started phototherapy
40 mins later repeat TB 19.9
IVIG and NS bolus
Immediately before transfer to VUCH – 18.5 (after another dose of IVIG and NS bolus)

6. Immunohematological and Laboratory Testing
Mother
Baby
A +
Anti-B 4+
Antibody screen negative B+
Antibody Screen negative
DAT +

7. BBH Type and Screen

8. Hyperbilirubinemia in the Newborn

10. Bilirubin Metabolism
Bilirubin is a product of the degradation of heme containing molecules including hemoglobin, myoglobin, and cytochromes
Heme oxygenase
Biliverdin reductase

11. Bilirubin Metabolism
Circulating bilirubin is bound to albumin and transported to the liver
Bilirubin is then conjugated with glucuronic acid to make it more water soluble, where it is then excreted into bile
Enzyme is uridine diphosphogluconurate glucuronosyltransferase (UGT1A1)
Conjugated bilirubin in excreted into the digestive tract. It is then broken down in the intestine by bacterial enzymes into urobilin

12. Bilirubin Metabolism in Neonates
Infants do not have significant amounts of bacterial flora in their digestive tract, so there is little production of urobilin from conjugated bilirubin.
In addition, infants have an enzyme called beta-glucuronidase which deconjugates the conjugated bilirubin that has been made. It is then reabsorbed back through the intestinal wall and recycled in the circulation
This process is called enterohepatic circulati0n of bilirubin

13. Physiologic vs Pathologic Jaundice in the Neonate
Most infants will exhibit some level of hyperbilirubinemia for multiple reasons
Increased hematocrit (~60%), fetal rbcs with shorter life span  increased production of bilirubin
Decreased clearance due to immaturity and lower levels of of hepatic enzymes
Enterohepatic circulation

14. Physiologic Neonatal Hyperbilirubinemia
The average peak is 7-9 mg/dL at hours of life
This varies among different ethnicities
This usually resolves within 1-2 weeks after birth

15. Pathologic Neonatal Hyperbilirubinemia
Although some level of hyperbilirubinemia is normal, the following are features of severe and pathologic neonatal hyperbilirubinemia:
Jaundice recognized within the first 24 hours of life
Rate of TB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.
TB greater than the hour-specific 95th percentile (newborn hyperbilirubinemia assessment calculator)

16. Pathologic Neonatal Hyperbilirubinemia
Hyperbilirubinemia with a TB >25-30 mg/dL is associated with an increased risk bilirubin induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood brain barrier and binds to brain tissue.
The term acute bilirubin encephalopathy (ABE) refers to the acute manifestations of BIND
Kernicterus refers to the permanent sequelae of BIND

17. What causes pathologic hyperbilirubinemia in the neonate?
Increased production
Decreased clearance
Increased enterohepatic circulation
Breast Feeding Failure

18. Neonatal Hyperbilirubinemia: Increased Production
Immune mediated hemolysis (ABO/Rh incompatibility)
Inherited red blood cell membrane defects
Hereditary spherocytosis
Erythrocyte enzymatic defects
G6PD deficiency, pyruvate kinase deficiency
Sepsis
Polycythemia
Sequestration (ex. Cephalohematoma)

19. Neonatal Hyperbilirubinemia: Decreased Clearance
Gilbert’s Syndrome
Common, reduced production of UGT
Crigler-Najjar Syndrome, type 1 and type 2
Type 1 – severe, no UGT1a1, AR
Type 2 – low UGT, AR, treat with Phenobarbital
Maternal Diabetes
Congenital Hypothyroidism
Galactosemia

20. BG H Tennessee Newborn Screen

21. Increased Enterohepatic Circulation
Breast milk jaundice
First 3-5 days of life, peaks within 2 weeks
Likely due to substance in human milk that increases intestinal absorption of bilirubin (deconjugates)
Breast feeding jaundice
First week of life
Inadequate lactation causes hypovolemia which leads to hyperbilirubinemia and hypernatremia

22. Management of Neonatal Unconjugated Hyperbilirubinemia
The focus is on preventing bilirubin induced neurologic dysfunction (BIND), acute bilirubin encephalopathy (ABE), and kernicterus
Two key elements are
Prevention of hyperbilirubinemia by identifying at risk infants and initiation of preventative therapeutic measures as needed (universal screening)
Reduction of total bilirubin in patients with severe hyperbilirubinemia

23. What are the treatments for severe neonatal hyperbilirubinemia?
Phototherapy
Exchange Transfusion
Improving the frequency or efficacy of breastfeeding and/or supplementing with formula
IVIG

24. Phototherapy
babyphototherapy.jpg

25. Phototherapy
Phototherapy reduces the risk that total serum or plasma bilirubin (TB) concentration will reach the level at which exchange transfusion is recommended

26. UV light in the blue-green range 460- 490 nm
Primary mechanism of action: phototherapy causes the isomerization of bilirubin to lumirubin which is water soluble and can be excreted without conjugation, not reversible
Adverse effects - transient rashes, looses stools, hyperthermia, “bronze baby syndrome”
UV light in the blue-green range nm

27. Phototherapy Dose is irradiance (microW/cm^2/nm)
Determines efficacy
Depends on light, distance from infant
Administer continuously if TB >20 mg/dL with maximum body surface area exposed
Protect retina with blindfolds
Light bulbs, fiber optic blankets, LED
Sunlight
Must monitor dose and infant during the procedure
Temperature, dehydration, burns
If TB continues to approach threshold for exchange, send blood for type and cross

28. Indications for Phototherapy

30. Phototherapy Discontinuation
If required at birth, stop when TB is at or below the level where therapy was initiated
If gone home and readmitted, mg/dL
Measure 24 hours after discontinuation, rebound phenomenon common (usually lower than value where therapy was initiated)
Close follow up is important

31. Exchange Transfusion
Most effective therapy to remove bilirubin rapidly
Indicated when
Intensive phototherapy can not prevent a continued rise in bilirubin
Infants are displaying signs of bilirubin induced neurologic dysfunction
Especially useful in infants with hyperbilirubinemia due to isoimmune hemolysis because both circulating antibodies and sensitized red blood cells are removed

32. Exchange Transfusion
Does have significant morbidity and mortality associated
Infections, coagulopathy, NEC, electrolyte derangements
Necessity of this procedure is greatly decreased with RhIg and American Academy of Pediatrics Guideline for Identification and treatment of infants at risk for severe hyperbilirubinemia with phototherapy

33. Exchange Transfusion - Indications

34. A retrospective chart review of 107 patients who underwent 141 single- or double-volume exchange transfusions from was performed. Patients were stratified into 2 groups, and , on the basis of changes in clinical practice influenced by American Academy of Pediatrics management guidelines for hyperbilirubinemia.
Improvements in prenatal and postnatal care have led to a sharp decline in the number of exchange transfusions performed. This decline has not led to an increase in complications despite relative inexperience with the procedure.

35. IVIG
Can reduce the need for exchange transfusion in infants with hemolytic disease caused by ABO or Rh incompatibility
Can be administered 0.5 – 1.0 g/kg over 2 hours in infants if TB is rising despite phototherapy or is 2-3 mg/dL within threshold for exchange. Dose can be repeated in 12 hours.

36. What is going on with this baby girl?
Is it ABO incompatibility- usually doesn’t cause that significant of a hemolysis/hyperbilirubinemia
High Anti-B titers? – we don’t have that information
Antibody to minor blood group antigen? Antibody screen negative
Intrinsic RBC defects HS, HE, G6PD deficiency?
Diabetic mother?
The blood smear was reported to demonstrate significant polychromasia, nucleated RBCs, anistocytosis, poikilocytosis and microspherocytes. There was no note of fragmented cells seen, making membrane defects less likely.

38. What happened to the patient?

39. BB H Course at Vanderbilt
She was admitted 1/12/15 and discharged 1/20/15
She was monitored in the NICU and continued on phototherapy until it was discontinued without significant rebound
PCV continued to decrease, reinforcing concern of hemolytic process and she received 1 transfusion of packed red blood cells
Hemolytic anemia stabilized, studies were pending, baby was discharged in stable condition with follow up in Hematology clinic. She was to be seen by her pediatrician twice weekly for labs until Hematology appointment

45. References
Wong, R. (2014). “Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants”, UpToDate. Retrieved from 
Wong, R. (2014). Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn, UpToDate. Retrieved from 
Wong, R. (2014). Treatment of unconjugated hyperbilirubinemia in term and late preterm infants, UpToDate. Retrieved from 
American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297.
Bhutani VK, Committee on Fetus and Newborn, American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128:e1046.
Semin Fetal Neonatal Med Jun;15(3): doi: /j.siny Epub 2009 Nov 25.
Flaherman VJ, Kuzniewicz MW, Escobar GJ, Newman TB. Total serum bilirubin exceeding exchange transfusion thresholds in the setting of universal screening. J Pediatr 2012; 160:796.
Pediatr Blood Cancer Nov;45(6):861-2.Hemolytic disease of the newborn caused by a high titer anti-group B IgG from a group A mother.Wang M, Hays T, Ambruso DR, Silliman CC, Dickey WC.

46. Assessment: While this baby could be experiencing hemolysis secondary to ABOincompatibility, the blood type set-up seen in this patient (mom A+, baby B+)is unlikely to cause such a significant hemolytic disease. The negative antibody screen in both mom and baby rule out the concern of hemolytic disease secondary to minor RBC antigens. We would recommend researching for additional causes of hemolytic disease; the differential diagnosis would include hereditary pyropoikilocytosis (more common to the african american population, however smear does not demonstrate fragmented cells as we would expect in HPP) as well as hereditary spherocytosis / eliptocytosis, G6PD and other instrinsic RBC abnormalities prone to hemolysis. We agree with the plan to continue monitoring this infant. If hemolysis continues to be brisk we could consider simple transfusion (O- blood products would be provided). Exchange transfusion,if desired, should occur with a RBC blood product reconstituted in plasma todecrease the risk of coagulopathy