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

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”

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

Bilirubin levels Day 1 - 23 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)

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

BBH Type and Screen

Hyperbilirubinemia in the Newborn

http://easypediatrics.com/wp-content/uploads/2012/09/hemoglobin-molecule.gif

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

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

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

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

Physiologic Neonatal Hyperbilirubinemia The average peak is 7-9 mg/dL at 48-96 hours of life This varies among different ethnicities This usually resolves within 1-2 weeks after birth

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)

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

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

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)

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

BG H Tennessee Newborn Screen

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

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

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

Phototherapy https://jasminebirth.files.wordpress.com/2013/06 babyphototherapy.jpg

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

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 460- 490 nm http://emedicine.medscape.com/article/1894477-overview

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

Indications for Phototherapy http://heidi-actually.blogspot.com/2012/03/jaundice-and-few-sessions-of.html

Phototherapy Discontinuation If required at birth, stop when TB is at or below the level where therapy was initiated If gone home and readmitted, 12-14 mg/dL Measure 24 hours after discontinuation, rebound phenomenon common (usually lower than value where therapy was initiated) Close follow up is important

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

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

Exchange Transfusion - Indications

A retrospective chart review of 107 patients who underwent 141 single- or double-volume exchange transfusions from 1986-2006 was performed. Patients were stratified into 2 groups, 1986-1995 and 1996-2006, 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.

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.

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.

What happened to the patient?

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

References Wong, R. (2014). “Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants”, UpToDate. Retrieved from http://www.uptodate.com/home/index.html Wong, R. (2014). Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn, UpToDate. Retrieved from http://www.uptodate.com/home/index.html Wong, R. (2014). Treatment of unconjugated hyperbilirubinemia in term and late preterm infants, UpToDate. Retrieved from http://www.uptodate.com/home/index.html 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. 2010 Jun;15(3):176-82. doi: 10.1016/j.siny.2009.11.001. 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. 2005 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.

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