1. Neonatal Jaundice and Hematology
Raegan Wetzel, M.D.
Oct 5, 2010

2. Causes of Anemia Accelerated Loss Accelerated Destruction
Hemorrhage, Twin-twin transfusion, early umbilical cord clamping, fetal-maternal transfusion
Accelerated Destruction
Immune hemolytic anemia, hemoglobinopathies, enzyme defects, membrane defects, mechanical destruction, infection, vit E deficiency
Diminished Production
Anemia of prematurity, Fanconi/Diamond-Blackfan anemia, parvovirus, iron deficiency
The KB test is the standard method of detecting fetal-maternal hemorrhage (FMH). It takes advantage of the differential resistance of fetal hemoglobin to acid. A standard blood smear is prepared from the mother's blood, and exposed to an acid bath. This removes adult hemoglobin, but not fetal hemoglobin, from the red blood cells. Subsequent staining makes fetal cells (containing fetal hemoglobin) appear rose-pink in color, while adult red blood cells are only seen as 'ghosts'.

3. Case 1
You are called to an emergent C/S for twins now with decelerations. You are unable to get much history from L&D except that they are 33 4/7 weeks, twin A with EFW 1700 g and twin B at 1200 g.
At delivery, Twin A is a female who appears LGA with ruddy appearance. Twin B also female appears smaller with pallor and poor perfusion.
What is the diagnosis ?

4. Twin to Twin Transfusion
Who is at risk and why ?
Monozygotic/monochornic twins
13-33% of twin pregnancies
Donor
Anemia
Recipient
Hyperbili, Hyperviscosity

5. Blood Loss Fetal-placental Cord abnormalities Placental abnormalities
Infant position after delivery
Cord abnormalities
Velamentous insertion, short cords, chord rupture with precipitous delivery or entanglement, nuchal/knot
Placental abnormalities
Abruption or previa
Fetal-maternal
What should you order ?
Kleihauer-Betke
The KB test is the standard method of detecting fetal-maternal hemorrhage (FMH). It takes advantage of the differential resistance of fetal hemoglobin to acid. A standard blood smear is prepared from the mother's blood, and exposed to an acid bath. This removes adult hemoglobin, but not fetal hemoglobin, from the red blood cells. Subsequent staining makes fetal cells (containing fetal hemoglobin) appear rose-pink in color, while adult red blood cells are only seen as 'ghosts'.

6. Case 2
Ex 27 week preemie, now 5 weeks old “feeding and growing” is noted to have poor weight gain, increased A/B’s, and new flow murmur.
Lab results reveal: normocytic normochromic anemia (hct 25%) with normal WBC and platelet indices.
What do you think the diagnosis is ?

7. Anemia of Prematurity Why does it happen ? Blood loss
Shortened RBC lifespan
Preterm days
Inadequate RBC production
Suboptimal erythropoiesis in response to hypoxia
Switch from hepatic to renal O2 sensor not till term

8. Do term infants get anemic ?
YES
Physiologic anemia of infancy happens later in term infants. True or False ?
True
Term:
8-12 weeks, Hemoglobin 9-11 g/dL
Preterm:
3-6 weeks, Hemoglobin 7-9 g/dL
After birth blood O2 increases and therefore tissue O2 delivery increases; down regulating epo
Hgb decreases till O2 demand is greater than O2 delivery capacity, happens at 8-12 wks

9. Transfusion Guidlines

10. Decreased RBC Production
Nutritional
Iron Deficiency
Bone Marrow Suppression
Rubella
Parvovirus
Aplastic/Hypoplastic Anemia
Diamond Blackfan Anemia
Fanconi Anemia

11. Case 3
You are notified by the state lab that a newborn has Hemoglobin Barts. What does this mean ?
Does this relate to Beta or Alpha Thalassemia ?
Bart’s hemoglobin appears in cord blood when there is a deletion of one or more of the 4
alpha goblin genes. The amount of Bart’s hemoglobin reflects the number of genes that
are deleted.
The presence of 1-6% Bart’s hemoglobin indicates the deletion of one or two genes. This
degree of deletion is clinically insignificant to the infant but may be of genetic significance.
The infant may be at risk for having a child with Hydrops Fetalis, if his/her partner carries a
similar deletion. This would be much more likely in an infant of Southeast Asian ancestry.
The presence of approximately 20% Bart’s Hemoglobin indicates the deletion of 3 genes
and the presence of hemoglobin H disease, which is characterized by mild anemia. This
condition would generally be diagnosed during routine pediatric care and does not require
early intervention.
Interpretation

12. Alpha Thalassemia
% Hgb Bart’s = number of alpha globin genes that are deleted
Silent Carrier – 1 abnormal gene
Alpha thal trait – 2 abnormal genes
Hb H disease – 3 abnormal genes
Moderate anemia
Thal Major - 4 abnormal genes
Hydrops fetalis
Transfusion dependent
Hemoglobin Barts consists of four gamma chains. It is moderately insoluble, and therefore accumulates in the red blood cells. Bart’s hemoglobin appears in cord blood when there is a deletion of one or more of the 4
alpha goblin genes. The amount of Bart’s hemoglobin reflects the number of genes that
are deleted.

13. Beta Thalassemia 2 genes of beta-globin production
Silent Carrier: Normal smear and electrophoresis
B-thal trait: Frequently misdiagnosed as iron deficiency anemia, mild anemia
Thal intermedia: Able to maintain Hgb > 7 without transfusion
Thal major: Require regular transfusions
Normal Hgb at birth 2/2 fetal Hgb
4 clinical classifications: based on interaction with alpha globin chains and type of genetic defect
Silent carrier- usually found thru family history of those with more severe disease

14. Case 4
3 day old term female presents to your office for first check up. Mom had prenatal care and decided to have the baby at home with a midwife. Uncomplicated pregnancy and delivery. Mom doesn’t believe in immunizations and didn’t want her baby to get any medicines at birth.
Baby has been having some mild bleeding around her gums with feeding and mom noticed a small amount of blood in the diaper this morning.

15. How could this have been avoided ?
What is her diagnosis ?
Hemorrhagic Disease of the Newborn
How could this have been avoided ?
0.5 to 1 mg IM of vitamin K

16. Hemorrhagic Disease of the Newborn
Why are Newborns deficient in Vit K ?
Placental transfer is poor
Breast milk is a poor source
GI tract is sterile at birth
What lab values are associated ?
Platelet Count
Normal
Fibrinogen PT
prolonged

17. 3 Types of HD of N Early Disease Classic Disease Late-onset
1st 24 hours
Maternal use of anticoagulant/anticonvulsant
Severe bleeding/intracranial hemorrhage
Classic Disease
1-7 days
Cutaneous, GI or circumcision site bleeding
Late-onset
Beyond 1 week
Associated with exclusively breast-fed

18. Case 5
Term male infant noted to be bleeding from the umbilical stump in WBN. Physical exam otherwise unremarkable.
Family history of maternal uncle with frequent nose bleeds.
Labs:
Platelet count : 200
PTT : prolonged
PT : normal
Bleeding time normal
Fibrinogen level : normal
Factor IX and VII : pending

19. Hemophilia A and B X linked disorder
Hemophilia A (factor VIII) : 5x more common
Hemophilia B (factor IX) : milder
Bleeding less common in newborn period
Common bleeding sites ?
Circumcision, umbilical bleeding, subdural > IVH
Contrast with VWD: Newborn bleeding is rare. Auto dom, Prolonged bleeding time. Test: VWF activity, antigen. Most common heritable bleeding disorder

20. How is this different than Von Willebrand’s disease ?
V W is most common heritable bleeding disorder
V W is autosomal dominant
V W will have prolonged bleeding time
What test should you order for diagnosis ?
von Willebrand factor activity (ristocetin cofactor
von Willebrand factor antigen

21. Case 6
Newborn male in WBN noted to be oozing from umbilical stump. Physical exam significant for petechiae. Infant born to a primagravida with no prenatal problems. Maternal CBC is normal.
Laboratory on baby:
Platelet count 20
Normal PT,PTT
Normal fibrinogen

22. What is the pathophysiology ?
What is the diagnosis ?
Neonatal Alloimmune Thrombocytopenia
What is the pathophysiology ?
Placental transfer of maternal antibodies against paternally inherited antigens on fetal platelets.
HPA-1a (78%) and HPA-5b alloantigens
Can the disease occur in the first pregnancy ?
Yes
Antigenic determinants expressed on placental endothelium
Extended window of time for sensitization

23. Blue Berry Muffin Rash
Petechiae

24. Bilirubin Metabolism

25. Case 7
72 hr old infant who was delivered after an uncomplicated 39 WGA appears clinically jaundiced at discharge. Baby is bottle feeding, no family history of jaundice and MBT O+. You get the following lab values:
Total bilirubin 11mg/dl
Direct fraction 0.8 mg/dl
Infant Hct 52%
IBT O+
Does this seem physiologic or pathologic ?
Physiologic

26. Pathologic Vs. Physiologic What’s the difference ?
Elevation is universal and transient
Mechanisms:
Increased RBC destruction
Decreased uptake and conjugation
Ineffective excretion
Pathologic
Jaundice that varies significantly from physiologic expectations in:
Time of appearance
Duration
Pattern of serially determined concentrations
Newborn rbc lifespan days

27. Pathologic Jaundice Occurs in the first ____ hrs of life
Rate of bilirubin rise > ____ mg/dl/day
> 5mg/dl/day
Clinical jaundice > ____ days in duration
> 1 week duration
Direct bilirubin > _____
> 2mg/dl or > 15% of total

28. Natural History Term Infant Preterm Infant Peak day Peak Level
3-5
Peak Level
8-13 mg/dl
Decline day
5-10
Preterm Infant
Peak day
5-7
Peak level
12-15 mg/dl
Decline day
7-15

29. Case 8
Term AGA male born to a 35 yo G3P3 without any prenatal/neonatal complications, presents for 2 week check. Mom is exclusively breastfeeding without any difficulty and infant is gaining weight. He looks a little jaundiced.
Lab results:
H/H and platelet count WNL
Total Bilirubin 19mg/dl
Direct Bilirubin 0.8 mg/dl

30. Breast Milk Jaundice 10-30 % of breast fed infants After first 5 days
Peaks at 2 weeks
Gradual decline over months
Cause ?
Progesterone Metabolite
Fatty acids
Progesterone and fatty acids inhibit conjugation

31. Breastfeeding Failure Jaundice
First few days of life
First time moms
Poor enteral intake → delayed meconium → increased enterohepatic uptake of bilirubin
Prevention:
Lactation consultant
At least 8-12 feeds/day
Avoid supplements

32. Why would these neonates be at risk for hyperbili ?

33. Case 9
2 week old infant here for routine check. Uncomplicated delivery and WBN stay. Vit K given at birth, discharged at 72 hrs, breastfeeding well. Feeding every 3 hrs, stooling 6 x/day and voiding 9x/day. Exam significant for clinical jaundice.
What labs would you order ?
What maternal blood type would you be concerned about ?

34. History from the well baby chart
Labs:
WBC 9 x 10 3/mm3, Hct 26%, Plt 175k/mm3
Retic 7%
Total Bilirubin 19mg/dl, direct 0.6mg/dl
History from the well baby chart
Maternal Blood Type O+
Infant Blood Type A +
DAT +

35. Immune Mediated Hemolytic Disease
Maternal IgG (via placenta) mediated
Maternal Coombs (indirect) +
Hemolysis of fetal cells
Hyperbilirubinemia, anemia
Hydrops Fetalis
Rh Alloimmunization
Rhesus D most common and most severe
28 wks and within 72 hrs of delivery
Severity increases
ABO Incompatibility
Mild to severe
Anti-A
Anti-B
Can occur in 1st pregnancy
Indirect coombs checks for antibodies in mom’s plasma, direct coombs detects antibodies that are bound to red blood cells

36. Case 10
4 day old infant presents to office with jaundice. Term male, uncomplicated delivery to a G1 with blood type B+ Prenatal labs unremarkable. Breast feeding well. Jaundiced yesterday with level of 17, home phototherapy initiated and follow up today with bilirubin of 22.
PE significant for jaundice and palpable spleen.

37. Labs Initial Hct 47, now 28 Reticulocyte count 4%
Infant blood type B+, coombs –
Blood smear
What specific test will be positive ?
Osmotic Fragility Test

38. Hereditary Spherocytosis
Autosomal Dominant
Northern European descent
Anemia
Jaundice
Splenomegaly

39. Other Heritable Hemolytic Diseases
Pyruvate Kinase Deficiency
Inherited as ……..
Auto recessive
G6PD deficiency
Most common in people of what descent ?
Mediterranean, tropical African, and Asian
X linked
PK- diagnosed with decreased PK activity

40. Case 11
7 day old, full term male comes to office with lethargy. Unremarkable prenatal/nursery course. Exclusively breastfeeding. No stool x 2 days and mom has to wake him up for feeds.
Physical exam: lethargic, jaundiced, large head and widely open fontanelles, low tone

41. Congenital Hypothyroidism
Incidence 1:4000
Usually asymptomatic at birth
Conjugating enzyme deficiency lasts weeks to months
L-thyroxine treatment by 2 weeks
Prompt treatment corrects the bilirubin

42. Case 12
Ex 30 week EGA preemie, now 3 weeks old. Delivered for maternal pre-e, otherwise unremarkable pregnancy with negative maternal labs. Now on RA but with frequent feeding intolerance and multiple periods of NPO. Currently on 5 q3 enteral feeds and had been on TPN since birth. Total bili today 11 mg/dl with a direct component of 5.6mg/dl
What are some general causes ?
What labs might help narrow your differential ?

43. Causes of Direct Hyperbilirubinemia
Hepatocellular
Hepatitis
TPN induced
Alpha-1 antitrypsin
Galacotsemia
Cystic Fibrosis
Biliary Tree Abnormalities
Extra-hepatic Biliary Atresia
Paucity of bile ducts
Choledochal cyst
Bile Plug

44. What tests will be helpful ?
Radiology:
Abdominal ultrasound
HIDA scan
Newborn screen:
CF results
GALT enzyme activity
Infant Labs:
Hepatitis panel
ALT,AST, GGT
Urine for reducing substances

45. Management When to start Phototherapy

46. Management When to consider Exchange

47. Why do we treat ? To prevent …… Kernicterus
Which is deposition of unconjugated bilirubin in the ………..
Basal Ganglia

48. Phototherapy
Photoisomerizes unconjugated bilirubin into more H2O soluble form
Excreted rapidly by liver and kidney
Does not need glucuronidation

49. Exchange Transfusion Double volume exchange
Replaces 85% of circulating RBC
Two neonatal blood volumes
160ml/kg
Aliquots = 10% of total blood volume
Thromboembolic complications, NEC, arrythmias, hypocalcemia, blood transfusion related complications

50. THANK YOU