2. Hyperbilirubinemia
• Bilirubin is the product of hemoglobin metabolism
• 2 forms:
Direct=conjugated
Indirect=unconjugated
• Hyperbilirubinemia is usually the result of:
Increased hemoglobin load
Reduced hepatic uptake
Reduced hepatic conjugation
Decreased excretion
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3. Jaundice
• Jaundice is the yellow discoloration of skin, sclera, and
other tissues caused by the deposition of bilirubin
• Observed during the 1st wk after birth in approximately
60% of term infants and 80% of preterm infants
• Cephalocaudal progression, starting on the face and
progressing to the abdomen and then the feet, as serum
levels increase
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4. Jaundice
• Jaundice from deposition of indirect bilirubin in the skin
tends to appear bright yellow or orange
• jaundice of the obstructive type (direct bilirubin) has a
greenish or muddy yellow
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7. Bilirubin metabolism:
• Unconjugated bilirubin binds to albumin on specific
bilirubin binding sites
• Bilirubin dissociates from albumin at the hepatocyte and
becomes bound to a cytoplasmic liver protein Y (ligandin)
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8. Bilirubin metabolism:
10/14/2015 8
• Bilirubin is produced by the catabolism of hemoglobin in
the reticuloendothelial system
• Heme is cleaved by heme oxygenase to form biliverdin
and carbon monoxide
• Biliverdin is converted to bilirubin by biliverdin
reductase
• Bilirubin is indirect=unconjugated=lipid soluble
9. Bilirubin metabolism:
• Indirect bilirubin is then conjugated to glucoronic acid by
UGT( glucuronosyltransferase)
• Billirubin glucoronides
Billirubin monoglucoronide
Billirubin diglucoronide
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10. Bilirubin metabolism:
• Intestinal flora convert BG to urobilinogen
• B.glucoronidase and intestinal bacteria>>deconjugation
• Reabsorption in terminal ileum
• Enterohepatic circulation
10/14/2015 10
11. Bilirubin metabolism
• One gram of hemoglobin produces 35 mg of bilirubin
• 1 g of albumin binds 8.5 mg of bilirubin in a newborn
• Sulfafurazole (sulfisoxazole) can displace bilirubin from
its binding site on albumin
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12. Bilirubin metabolism
• Compared with adults newborns have a twofold to
threefold greater rate of bilirubin production (6 to 10
mg/kg/24 hr versus 3 mg/kg/24 hr)
Increased RBC mass (higher hematocrit)
A shortened erythrocyte life span of 70 to 90 days
compared with the 120-day erythrocyte life span in adults.
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14. • Age at which jaundice developed
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Hx & PE:
15. Hx & PE:
• The prenatal and birth history
Maternal blood group
Delivery complications
Maternal infection, diabetes mellitus, and drug use
Oxytocin during labor is associated with an increased risk of
jaundice
polyhydramnios suggests an intestinal obstruction
Prematurity
Passage of meconium
• Delay in passage of meconium, which contains 1 mg
bilirubin/dL, may contribute to jaundice by enterohepatic
recirculation
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16. Hx & PE:
• Associated symptoms
Vomiting
Hypoactivity
Poor feeding
Failure to thrive
May suggest an inborn error of metabolism
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17. Hx & PE:
• Family history
Jaundice
Anemia
Spleenectomy
Cholecystectomy
May suggests a hereditary hemolytic disorder
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18. Nutritional Hx
• Breast-fed infants tend to have higher and more
prolonged unconjugated bilirubin levels than formula-fed
infants
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20. Risk factors for development of
severe hyperbilirubinemia
Predischarge TSB level in the high-risk zone
Prematurity
Jaundice observed in first 24 hours of life
Known blood group incompatibility or hemolytic disease
Sibling who required phototherapy
Cephalohematoma
Bruising
Poor breastfeeding
East Asian race
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21. Decreased risk
TSB level in the low-risk zone
Gestational age ≥41 wk
Exclusive bottle-feeding
Black race
Discharge from hospital after 72 hr
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22. Jaundice in the neonate
Perform Hx and PE
Obtain total, direct and indirect
bilirubin levels
Predominantly indirect
hyperbilirubinemia
Predominantly direct
hyperbilirubinemia
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23. Predominantly indirect hyperbilirubinemia
Red flags
bilirubin >95th percentile for
age in hours
Onset of jaundice <24 hours of
age
Rapid rise of bilirubin levels
(>.5 mg/dl/hour)
Maternal blood is group O
Rh-negative mother
Risk factors
absent present
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25. Physiologic jaundice
• Common cause of hyperbilirubinemia among newborns.
• It is a diagnosis of exclusion
• Physiologic jaundice is the result of many factors that are
normal physiologic characteristics of newborns
Increased bilirubin production resulting from an increased
RBC mass
Shortened RBC life span
Hepatic immaturity of ligandin and
glucuronosyltransferase
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26. Physiologic jaundice
• The clinical pattern of physiologic jaundice
In term infants includes a peak indirect-reacting bilirubin
level of no more than 12 mg/dl on day 3 of life
In premature infants, the peak is higher (15 mg/dl) and
occurs later (fifth day).
The peak level of indirect bilirubin during physiologic
jaundice may be higher in breast milk–fed infants than in
formula-fed infants (15 to17 mg/dl versus 12 mg/dl).
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27. Physiologic jaundice
• Jaundice is unphysiologic or pathologic if it is:
Clinically evident on the first day of life
If the bilirubin level increases more than 0.5 mg/dl/hr
If the peak bilirubin is greater than 13 mg/dl in term
infants
If the direct bilirubin fraction is greater than 1.5 mg/dl
If hepatospleenomegaly and anemia are present
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29. Breast-feeding jaundice
• Hyperbilirubinemia develops in 13% of breastfed infants
during the 1st wk
• May be a result of decreased milk intake with dehydration
and/or reduced caloric intake
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30. Breast-feeding jaundice
• Frequent breastfeeding (>10/24 hr)
• Rooming-in with night feeding
• And ongoing lactation support
May reduce the incidence of early breastfeeding jaundice
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31. Breast-feeding jaundice
• Even when breastfeeding jaundice develops
breastfeeding should be continued if possible
• It is an option to temporarily interrupt breast-feedings and
substitute formula for a day or two
• In addition, frequent feeding and supplementation with
formula is appropriate if :
The intake seems inadequate
Weight loss is excessive
The infant appears dehydrated
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33. Breast-milk jaundice
• Develops in an estimated 2% of breastfed term infants
after the 7th day
• Maximal concentrations as high as 10-30 mg/dl reached
during the 2nd-3rd wk
• If breastfeeding is continued, the bilirubin gradually
decreases but may persist for 3-10 wk at lower levels
• If nursing is discontinued, the serum bilirubin level falls
rapidly, reaching normal range within a few days.
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34. Breast-milk jaundice
• The etiology is not entirely clear but may be attributed to
the presence of glucuronidase in some breast milk
• Phototherapy may be of benefit
• Although uncommon, kernicterus can occur in patients
with breast milk jaundice
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35. Jaundice in the neonate
Perform Hx and PE
Obtain total, direct and indirect
bilirubin levels
Predominantly indirect
hyperbilirubinemia
Predominantly direct
hyperbilirubinemia
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36. Predominantly indirect hyperbilirubinemia
Red flags
Bilirubin >95th percentile for
age in hours
Onset of jaundice <24 hours of
age
Rapid rise of bilirubin levels
(>.5 mg/dL/hour)
Maternal blood is group O
Rh-positive
risk factors
absent present
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37. Red flags present
Coombs test
CBC with smear
Reticulocyte count
Infant and maternal blood
type
Coombs test
+ve -ve
10/14/2015 37
38. +ve Coombs test
Immune mechanism attacking
own RBC
Isoimmune hemolytic disease:
ABO incompatibility
Rh isoimmunization
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39. • ABO incompatibility has become the most common cause
of neonatal hyperbilirubinemia requiring therapy
• Accounting for approximately 20% of clinically significant
jaundice in the newborn
• Mother >> O normally has anti- A and anti-B antibodies
These antibodies are IgM
• Fetus >>A or B
A antigene / B antigene
10/14/2015 39
ABO incompatibility
40. ABO incompatibility
• Develops only if the mother has IgG antibodies from a
previous exposure to A or B antigens
• By previous transfusions
• By conditions of pregnancy that result in transfer of fetal
erythrocytes into the maternal circulation, such as first-
trimester abortion, ectopic pregnancy, manual extraction
of the placenta
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41. • Many mothers who have blood group O have IgG
antibodies to A and B before pregnancy, the firstborn
infant of A or B blood type may be affected
Some mothers "naturally" have IgG anti-A or IgG anti-B
antibodies
Exposure to A-antigens and B-antigens, which are both
widespread in nature, usually leads to the production of
IgM anti-A and IgM anti-B antibodies but occasionally IgG
antibodies are produced
Blood transfusion
10/14/2015 41
ABO incompatibility
42. • ABO incompatibility with sensitization usually does not
cause fetal disease other than extremely mild anemia.
• Significant anemia and hyperbilirubinemia
10/14/2015 42
ABO incompatibility
43. • In contrast to Rh disease
• ABO hemolytic disease does not become more severe
with subsequent pregnancies
• Hemolysis with ABO incompatibility is less severe than
hemolysis in Rh-sensitized pregnancy
Because the anti-a or anti-b antibody may bind to
nonerythrocytic cells that contain A or B antigen
Because fetal erythrocytes have fewer A or B antigenic
determinants than they have Rh sites
10/14/2015 43
ABO incompatibility
44. +ve Coombs test
Immune mechanism attacking
own RBC
Isoimmune hemolytic disease:
ABO incompatibility
Rh isoimmunization
10/14/2015 44
45. • RH:
• Blood group system made up of a number of antigens(up
to 50)
• The most important are C, c, D ,E, e
• 90% of cases of Rh isoimmunization are due to
antibodies to D antigen
• A person who lacks the D antigen Rh negative
• A person with the D antigen Rh positive
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Rh Isoimmunization
46. Rh Isoimmunization
• An immunologic disorder that occurs in a pregnant, Rh-
negative mother carrying an Rh-positive fetus
• The immunologic system in the mother is stimulated to
produce antibodies to the Rh antigen
• These antibodies will then cross the placenta and destroy
fetal RBCs
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47. Rh Isoimmunization
• Sensitization:
• The development of maternal antibodies against D
antigens on the fetus RBCs
• Sensitization may occur whenever fetal blood enters the
maternal circulation
•
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48. Rh Isoimmunization
• Transplacental hemorrhage
Spontaneous or induced abortions
Ectopic pregnancy
Second- or third trimester vaginal bleeding
After invasive procedures such as amniocentesis or
chorionic villus sampling
After abdominal trauma
After external cephalic version
10/14/2015 48
49. • The fetus of the pregnancy usually suffers no harm
because the maternal antibody titers are low
• The subsequent pregnancies with an Rh-positive fetus
are at significantly higher risk of hemolytic disease of
newborn (HDN ) because the mother has already
developed memory cells that quickly produce anti-D
antibodies
10/14/2015 49
Rh Isoimmunization
50. Rh Isoimmunization
• INCIDENCE:
• The overall risk of immunization for the second
full-term, Rh-positive, ABO-compatible pregnancy
is about 1 in 6 pregnancies
• Risk of isoimmunization>> 16% of Rh-negative pregnant
women & her fetus is Rh-positive
• 84%>> immune non responder
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51. Rh Isoimmunization
• For isoimmunization to happen:
Sufficient amount of fetal blood enters maternal
circulation
Good maternal immunity
ABO compatibility
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52. Rh Isoimmunization
• The protection against immunization in ABO-incompatible
pregnancies is due to the destruction of the ABO-
incompatible cells in the maternal circulation and the
removal of the red blood cell debris by the liver
• The risk for Rh sensitization following an ABO-
incompatible, Rh-positive pregnancy is only about 2%
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53. Rh Isoimmunization
• The initial response to exposure to Rh antigen is the
production of immunoglobulin M (IgM) antibodies for a
short period of time, followed by the production of IgG
antibodies that are capable of crossing the placenta
• If the fetus has the Rh antigen, these antibodies will coat
the fetal red blood cells and cause hemolysis (HDN)
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54. Rh Isoimmunization
• The first affected newborn may show no serious fetal
disease and may manifest hemolytic disease of the
newborn only by the development of anemia and
hyperbilirubinemia.
• Subsequent pregnancies result in an increasing severity
of response because of an earlier onset of hemolysis in
utero
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55. Rh Isoimmunization
• Fetal anemia, heart failure, elevated venous pressure,
portal vein obstruction, and hypoalbuminemia result in
fetal hydrops
Ascites
Pleural effusion
Pericardial effusion
Anasarca
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56. Rh Isoimmunization
• The management of a pregnancy complicated by rh
sensitization depends on:
The severity of hemolysis
Its effects on the fetus
The maturity of the fetus at the time it becomes affected
10/14/2015 56
63. Extravascular blood
• results in increased bilirubin production
• Examples include cephalohematoma, ecchymoses,
occult hemorrhage as well as swallowed maternal blood
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64. Hypothyroidism
• Prolonged indirect hyperbilirubinemia may be the earliest
clinical manifestation of congenital hypothyroidism as well
as hypopituitarism
• These may also cause conjugated hyperbilirubinemia
10/14/2015 64
65. Increased enterohepatic circulation of
bilirubin
• Any condition causing obstruction or delayed passage of
meconium
• E.g., Hirschsprung disease, meconium plug syndrome
will increase enterohepatic circulation of bilirubin
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66. Crigler-Najjar syndrome
• Serious, rare, autosomal recessive
• Permanent deficiency of glucuronosyltransferase
• Results in severe indirect hyperbilirubinemia
• Type II responds to enzyme induction by phenobarbital,
producing an increase in enzyme activity and a reduction
of bilirubin evels
• Type I does not respond to phenobarbital and manifests
as persistent indirect hyperbilirubinemia, often leading to
kernicterus
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67. Gilbert disease
• Is caused by a mutation of the promoter region of
glucuronosyltransferase
• Results in a mild indirect hyperbilirubinemia
• In the presence of another icterogenic factor (hemolysis),
more severe jaundice may develop
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69. Kernicterus (bilirubin
encephalopathy)
• Lipid-soluble, unconjugated, indirect bilirubin fraction is
toxic to the developing central nervous system
• Especially when indirect bilirubin concentrations are high
and exceed the binding capacity of albumin.
• Kernicterus results when indirect bilirubin is deposited in
brain cells and disrupts neuronal metabolism and
function,
• Especially in the basal ganglia
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70. Kernicterus
• The toxic blood level for an individual infant is
unpredictable, but in general, kernicterus typically occurrs
only in infants with a bilirubin >20 mg/dL
10/14/2015 70
71. Kernicterus
• Kernicterus may be noted at bilirubin levels less than 20 mg/dl
in the presence of :
Sepsis
Meningitis
Hemolysis
Asphyxia
Hypoxia
Hypothermia
Hypoglycemia
Bilirubin-displacing drugs (sulfa drugs)
Prematurity
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72. Kernicterus
• The earliest clinical manifestations of kernicterus are :
Lethargy
Hypotonia
Irritability
Poor moro response
poor feeding
A high-pitched cry and emesis also may be present
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74. Kernicterus
• Infants with severe cases of kernicterus die in the
neonatal period.
• Spasticity resolves in surviving infants, who may manifest
later nerve deafness, choreoathetoid cerebral palsy
mental retardation, enamel dysplasia, and discoloration of
teeth as permanent sequelae
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75. Kernicterus
• Kernicterus may be prevented by avoiding excessively
high indirect bilirubin levels
• By avoiding conditions or drugs that may displace
bilirubin from albumin
• Early signs of kernicterus occasionally may be reversed
by immediately instituting an exchange transfusion
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77. Jaundice in the neonate
Perform Hx and PE
Obtain total, direct and indirect
bilirubin levels
Predominantly indirect
hyperbilirubinemia
Predominantly direct
hyperbilirubinemia
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78. 10/14/2015 78
Predominantly direct
hyperbilirubinemia
Sepsis
Idiopathic neonatal hepatitis
Intrauterine infection
Toxoplasmosis
Cytomegalovirus
Rubella
Herpes
Syphilis
Paucity of bile ducts
Disorders of bile acid metabolism
Biliary atresia
Giant cell hepatitis
Choledochal cyst
Cystic fibrosis
Galactosemia
Alpha1-antitrypsin deficiency
Tyrosinemia
79. Direct hyperbilirubinemia
• Is defined as direct bilirubin>20% of total or
Direct bilirubin >2 mg/dl
• Is not neurotoxic to the infant but signifies a serious
underlying disorder involving cholestasis or
hepatocellular injury
10/14/2015 79
80. • Determination of the levels of liver enzymes
• Bacterial and viral cultures
• Metabolic screening tests
• Hepatic ultrasound
• Sweat chloride test
• Liver biopsy
10/14/2015 80
Direct hyperbilirubinemia
81. Congenital infection
• Suggested by intrauterine growth retardation,
microcephaly, and ophthalmologic abnormalities
• Characteristic facies may suggest syndromes associated
with hyperbilirubinemia
• Any of the “TORCH infections” (e.g., Toxoplasmosis,
rubella, cytomegalovirus, herpes virus, syphilis) may
cause growth retardation and cholestasis
10/14/2015 81
82. Idiopathic neonatal hepatitis
• Prolonged conjugated hyperbilirubinemia without an
obvious etiology after known infectious and metabolic and
genetic causes have been excluded
10/14/2015 82
83. 10/14/2015 83
Biliary Atresia
• The jaundice is not evident immediately at birth
• Develops in the first week or two of life
• The reason is that extrahepatic bile ducts are usually
present at birth, but are then destroyed by an idiopathic
inflammatory process
84. • These infants do not initially appear ill
• The liver injury progresses rapidly to cirrhosis;
• Symptoms of portal hypertension
• Splenomegaly
• Ascites
• Muscle wasting, and
• Poor weight gain
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Biliary Atresia
85. • If surgical drainage is not performed successfully early in
the course (ideally by 2 months), progression to liver
failure is inevitable
10/14/2015 85
Biliary Atresia
87. • The treatment of disorders manifested by direct
bilirubinemia is specific for the diseases
• These diseases do not respond to phototherapy or
exchange transfusion
10/14/2015 87
Direct hyperbilirubinemia
89. • Is an effective and safe method for reducing indirect
bilirubin levels, particularly when initiated before serum
bilirubin increases to levels associated with kernicterus
10/14/2015 89
Phototherapy
90. Phototherapy
• In term infants, phototherapy is begun when indirect
bilirubin levels are between 16 and 18 mg/dL
• In premature infants when bilirubin is at lower levels
10/14/2015 90
91. • Blue lights and white lights are effective in reducing
bilirubin levels
• Bilirubin is transformed into isomers that are water
soluble and easily excreted
10/14/2015 91
Phototherapy
92. • Increased insensible water loss, diarrhea, and
dehydration
• Macular-papular red skin rash
• Lethargy
• Masking of cyanosis
• Nasal obstruction by eye pads
• potential for retinal damage
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Phototherapy complications
93. • Usually is reserved for infants with dangerously high
indirect bilirubin levels who are at risk for kernicterus
10/14/2015 93
Exchange transfusion
94. • A level of 20 mg/dl for indirect-reacting bilirubin is the
exchange number for infants with hemolysis who weigh
more than 2000 g
• Asymptomatic infants with physiologic or breast milk
jaundice may not require exchange transfusion, unless
the indirect bilirubin level exceeds 25 mg/dl.
10/14/2015 94
Exchange transfusion
95. • For other infants
• The exchangeable level of indirect bilirubin may be
estimated by calculating 10% of the birth weight in grams:
• The level in an infant weighing 1500 g would be 15 mg/dl.
• Infants weighing less than 1000 g usually do not require
an exchange transfusion until the bilirubin level exceeds
10 mg/dl
10/14/2015 95
Exchange transfusion
96. • The exchange transfusion usually is performed through
an umbilical venous catheter placed in the inferior vena
cava
• The level of serum bilirubin immediately after the
exchange transfusion declines to levels that are about
half of those before the exchange
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Exchange transfusion
97. Exchange transfusion complications
• Related to the blood ( infection,hyperkalemia,
hypocalcemia)
• Related to the catheter (vessel perforation or
hemorrhage)
• Related to the procedure (hypotension or necrotizing
enterocolitis)
10/14/2015 97
98. • Unusual complications include
Thrombocytopenia
Graft Versus Host Disease
10/14/2015 98
Exchange transfusion complications