Anemia in newborns can be caused by several factors: 1. Physiologic anemia of infancy is normal as hemoglobin levels fall after birth but oxygen delivery remains adequate. 2. Anemia of prematurity is an exaggeration of normal physiologic anemia due to low birth weight and iron stores. 3. Other causes include blood loss, hemolysis, infections that diminish red blood cell production, and rare genetic disorders. Evaluation of the newborn involves considering the obstetric history for blood loss risks, a physical exam, and laboratory tests like complete blood counts and smears to determine the etiology and guide treatment if needed. Management may involve iron supplementation, transfusions,

1. Anemia
BY: Mekdes Endale

2. HEMATOLOGIC PHYSIOLOGY OF THE NEWBORN
A. Normal development: the physiologic anemia of infancy
• In utero, the fetal aortic oxygen saturation is low at 45%, erythropoietin levels are high,
and RBC production is rapid
• The fetal liver is the major site of erythropoietin production
• After birth, the oxygen saturation is much higher at 95%, and hence, erythropoietin is
undetectable
• RBC production by day 7 is <1/10th the level in utero
• Reticulocyte counts are low, and the hemoglobin level falls

3. cont...
• Although hemoglobin levels fall, oxygen availability to tissues remains good
• The ratio of hemoglobin A to hemoglobin F increases
• the levels of 2,3-diphosphoglycerate (2,3-DPG) are high (2,3-DPG interacts with
hemoglobin A to decrease its affinity for oxygen, thereby enhancing oxygen release to the
tissues)
• As a result, oxygen delivery to the tissues actually increases
• This physiologic “anemia” is not a functional anemia in that oxygen delivery to the tissues is
adequate

4. cont...
• At 8 to 12 weeks, hemoglobin levels reach their nadir
• oxygen delivery to the tissues decreases
• renal erythropoietin production is stimulated, and RBC production increases
• Infants who have received transfusions in the neonatal period have lower nadirs than normal because
of their higher percentage of hemoglobin A
• During this period of active erythropoiesis, iron stores are rapidly utilized
• Iron is available from degraded RBC
• Iron stores are sufficient for 15 to 20 weeks in term infants. After this time, the hemoglobin level
decreases if iron is not supplied

5. cont...
B. Anemia of prematurity is an exaggeration of the normal physiologic anemia
1. RBC mass and iron stores are decreased because of low birth weight; however, hemoglobin
concentrations are similar in preterm and term infants
2. The hemoglobin nadir is reached earlier than in the term infant because of the following:
a. RBC survival is decreased in comparison with that in the term infant.
b. There is a relatively more rapid rate of growth in premature babies than in term infants
c. Many preterm infants have reduced red cell mass and iron stores because of iatrogenic
phlebotomy for laboratory tests
d. Vitamin E deficiency is common in small premature infants, unless the vitamin is supplied
exogenously

6. cont...
3. The hemoglobin nadir in premature babies is lower than in term infants
• because erythropoietin is produced by the term infant at a hemoglobin level of 10 to 11 g/dL
• produced by the premature infant at a hemoglobin level of 7 to 9 g/dL
4. Iron administration before the age of 10 to 14 weeks does not increase the nadir of the
hemoglobin level or diminish its rate of reduction
• However, this iron is stored for later use
5. Once the nadir is reached, RBC production is stimulated, and iron stores are rapidly depleted
because less iron is stored in the premature infant than in the term infant

7. ETIOLOGY OF ANEMIA IN THE NEONATE
• Anemia due to blood loss
• characterized by a normal bilirubin level (unless the hemorrhage is retained)
• If blood loss is recent (e.g., at delivery), the hematocrit (Hct) and reticulocyte count may
be normal, and the infant may be in shock
• The Hct will fall later because of hemodilution
• If the bleeding is chronic, the Hct will be low, the reticulocyte count up, and the baby
normovolemic

8. 1. Obstetric causes of blood loss
• including the following malformations of the placenta and cord:
a. Incision of the placenta at the time of cesarean section
b. Rupture of anomalous vessels (e.g., vasa previa, velamentous insertion of the cord, or
rupture of communicating vessels in a multilobed placenta)
c. Hematoma of the cord caused by varices or aneurysm
d. Rupture of the cord (more common in short cords and in dysmature cords)
e. Abruptio placentae
f. Placenta previa (uncommon to have fetal blood loss)

9. 2. Occult blood loss
a. Fetomaternal bleeding may be chronic or acute
• by Kleihauer–Betke stain of maternal smear for fetal cells
• Chronic fetal-to-maternal transfusion is suggested by a reticulocyte count >10%
• Many conditions may predispose to this type of bleeding
i. Placental malformations—chorioangioma or choriocarcinoma
ii. Obstetric procedures—traumatic amniocentesis, external cephalic version, internal
cephalic version, breech delivery
iii. Spontaneous fetomaternal bleeding

10. cont...Occult blood loss
b. Fetoplacental bleeding
• i. Chorioangioma or choriocarcinoma with placental hematoma
• ii. Cesarean section, with infant held above the placenta
• iii. Tight nuchal cord or occult cord prolapse
c. Twin-to-twin transfusion
d. Twin anemia polycythemia sequence (TAPS),
• an uncommon form of chronic intertwin transfusion between monochorionic twins
characterized by large intertwin hemoglobin differences in the absence of amniotic
fluid discordance

11. 3. Bleeding in the neonatal period
• may be due to the following causes:
a. Intracranial bleeding associated with:
• i. Prematurity
• ii. Traumatic assisted delivery (especially vacuum extraction)
• iii. Underlying coagulation disorder
b. Massive cephalohematoma, subgaleal hemorrhage, or hemorrhagic caput succedaneum
c. Retroperitoneal bleeding
d. Ruptured liver or spleen
e. Adrenal or renal hemorrhage

12. cont...Bleeding in the neonatal period
f. Gastrointestinal bleeding (maternal blood swallowed from delivery or breast should be ruled
out by the Apt test)
i. Necrotizing enterocolitis (NEC)
ii. Nasogastric catheter
g. Bleeding from the umbilicus
i. Slipped ligature or cord clamp
ii. Loss from an indwelling umbilical artery or venous catheter
4. Iatrogenic causes
• Excessive blood loss may result from blood sampling with inadequate replacement

13. Hemolysis
• is manifested by a decreased Hct, an increased reticulocyte count, and an increased bilirubin
level
1. Immune hemolysis
a. Rh incompatibility
b. ABO incompatibility
c. Minor blood group incompatibility (e.g., c, E, Kell, Duffy)
d. Maternal disease (e.g., lupus), autoimmune hemolytic disease (Direct Coomb’s Test
[DCT] will be positive in the mother and newborn) or drugs

14. cont...
2. Hereditary RBC disorders
a. RBC membrane defects such as spherocytosis, elliptocytosis, or stomatocytosis
b. Metabolic defects—glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate-
kinase deficiency, 5′-nucleotidase deficiency, and glucose-phosphate isomerase deficiency
c. Hemoglobinopathies
i. α- and γ-thalassemia syndromes
ii.α- and γ-chain structural abnormalities
3. Acquired hemolysis
a. Infection—bacterial or viral
b. Disseminated intravascular coagulation

15. Diminished RBC production
• is manifested by a decreased Hct, decreased reticulocyte count, and normal bilirubin level
1. Physiologic anemia or anemia of prematurity
2. Diamond–Blackfan syndrome
3. Congenital leukemia (very rare)
4. Infections, especially rubella and parvovirus
5. Osteopetrosis, leading to inadequate erythropoiesis, presents in infancy

16. DIAGNOSTIC APPROACH TO ANEMIA IN THE NEWBORN
The family history should include questions about anemia, jaundice, gallstones, and
splenectomy
The obstetric history should be evaluated for severe abdominal pain (abruptio) or
intrapartum blood loss
The physical examination may reveal an associated abnormality and provide clues to the
origin of the anemia
1. Acute blood loss leads to shock, with cyanosis, poor perfusion, and acidosis.
2. Chronic blood loss produces pallor, but the infant may look well and exhibit only mild
symptoms of respiratory distress or irritability
3. Chronic hemolysis is associated with pallor, jaundice, and hepatosplenomegaly

17. cont...
• Complete blood cell count
• Reticulocyte count (elevated with chronic blood loss and hemolysis, depressed with
infection and production defect)
• Peripheral blood smear, Coomb’s test and bilirubin level
• Apt test on gastrointestinal blood of uncertain origin
• Kleihauer–Betke preparation of the mother’s blood
• A 50-mL loss of fetal blood into the maternal circulation will show up as 1% fetal cells
in the maternal circulation

18. cont...
• Ultrasound of the abdomen and head
• Parental testing—complete blood cell count, smear, and RBC indices are useful screening
studies. Osmotic fragility testing and RBC enzyme levels (e.g., G6PD, pyruvate kinase) may
be helpful in selected cases
• Studies for infection (toxoplasmosis, other, rubella, cytomegalovirus [CMV], and herpes
simplex), if physical examination has stigmata such as hepatosplenomegaly, cataract, rash,
or severe fetal growth restriction (FGR)
• Bone marrow (rarely used except in cases of bone marrow failure from hypoplasia or tumor)

19. THERAPY
A. Transfusion
• must be made in consideration of the infant’s condition and physiologic needs and not based
on hemoglobin/Hct values alone
Infants with significant respiratory disease or congenital heart disease (e.g., large left-to-
right shunt) may need their Hct maintained above 40%
Infants with ABO incompatibility who do not have an exchange transfusion may have
protracted hemolysis and may require a transfusion several weeks after birth
This may be ameliorated with the use of intravenous immunoglobulin (IVIG)
If they do not have enough hemolysis to require treatment with phototherapy, they
will usually not become anemic enough to need a transfusion

20. cont...
• Premature babies may be quite comfortable with hemoglobin levels of 6.5 to 7.0 mg/d
• The level itself is not an indication for transfusion
• Growing premature infants may manifest a need for transfusion by exhibiting poor
weight gain, apnea, tachypnea, or poor feeding
• Sick infants (e.g., with sepsis, pneumonia, or bronchopulmonary dysplasia) may require
increased oxygen-carrying capacities and therefore need transfusion

23. Blood products and methods of transfusion
• Packed RBCs
• generally transfuse 15 to 20 mL/kg
• The blood has to be used within 35 days of donation
• for exchange transfusion it needs to be used within less than 5 days from donation
• Whole blood
• Partial exchange with high Hct-packed RBCs may be required for severely anemic infants
• when routine transfusion of the volume of packed RBCs necessary to correct the anemia
would result in circulatory overload

24. B. Prophylaxis
• Premature infants (preventing or ameliorating the anemia of prematurity)
• Delayed cord clamping
• Iron supplementation in the preterm infant - improves iron stores, and lowers the risk
of iron deficiency anemia after the first 6 months of life

25. Polycythemia

26. Polycythemia
• As the central venous hematocrit rises, there is increased viscosity and decreased blood flow
• Newborns have larger, irregularly shaped red blood cells (RBCs) with different membrane
characteristics than the RBCs of adults
• As viscosity increases, there may be impairment of tissue oxygenation and decreased glucose in
plasma, leading to an increased risk of microthrombus formation
• if this event occur in the cerebral cortex, kidneys, or adrenal glands, significant damage may result
• Hypoxia and acidosis increase viscosity and deformity further
• Poor perfusion associ_x0002_ated with polycythemia may increase the possibility of peripheral
vascular thrombosis

27. DEFINITIONS
Polycythemia
• defined as venous hematocrit of at least 65%
• Hematocrit initially rises after birth from placental transfer of RBCs and then decreases to
baseline by approximately 24 hours
• The mean venous hematocrit of term infants is 53% in cord blood, 60% at 2 hours of age,
57% at 6 hours of age, and 52% at 12 to 18 hours of age
• The incidence of polycythemia is 1% to 5% in term newborns

28. cont...
Hyperviscosity
• The hyperviscosity syndrome is usually seen only in infants with venous hematocrit
above 60%.
• viscosity increases exponentially at a hematocrit of 70% or greater
• Factors affecting blood viscosity include plasma proteins such as
• fibrinogen, local blood flow, and pH
• Blood viscosity is dependent on factors such as the pressure gradient along the
vessel, radius, length, and flow

29. CAUSES OF POLYCYTHEMIA
• three possible settings for polycythemia:
(i) hypervolemia—placental transfusion
(ii) normovolemia placental insufficiency (fetal growth restriction [FGR]); and
(iii) hypovolemia—dehydration

30. Risk fctors
• Placental red cell transfusion
• Umbilical cord stripping/milking achieves transfer of placental blood in a shorter time;
this also increases the hematocrit
• Holding the baby at a level below the mother before the cord is cut increases transfer of
placental blood—the distance below the vaginal introitus promotes gravity-assisted
transfusion
• Twin-to-twin transfusion is an uncommon phenomenon in monochorionic twins; this is
associated with polycythemia in one twin and anemia in the other

31. cont...
• Placental insufficiency (increased fetal erythropoiesis secondary to chronic intrauterine
hypoxia)
1. FGR infants
2. Maternal hypertension syndromes (preeclampsia, renal disease, etc.)
3. Post-term infants
4. Infants born to mothers with chronic hypoxia (heart disease, pulmonary disease)
5. Pregnancy at high altitude
6. Maternal smoking

32. cont...
Other conditions
1. Infants of diabetic mothers (increased erythropoiesis)
2. Some large-for-gestational-age (LGA) babies
3. Infants with congenital adrenal hyperplasia, Beckwith–Wiedemann syndrome, neonatal
thyrotoxicosis, congenital hypothyroidism, trisomy 21, trisomy 13, and trisomy 18
4. Drugs (maternal use of propranolol)
5. Dehydration of an infant causing hemoconcentration
6. Sepsis increases hyperviscosity in the setting of polycythemia (increase in fibrinogen,
reduced RBC deformability).

33. CLINICAL FINDINGS
• Most infants with polycythemia are asymptomatic
Central nervous system (CNS)
Poor feeding, lethargy, hypotonia, apnea, tremors, jitteriness, seizures, and cerebral
venous thrombosis
Cardiorespiratory
Cyanosis, tachypnea, heart murmur, congestive heart failure, cardiomegaly, elevated
pulmonary vascular resistance, and prominent vascular markings on chest x-ray
Renal
Decreased glomerular filtration, decreased sodium excretion, renal vein thrombosis,
hematuria, and proteinuria

34. cont...
Other
Other thrombosis, thrombocytopenia, poor feeding, increased jaundice, persistent
hypoglycemia, hypocalcemia, testicular infarcts, necrotizing enterocolitis (NEC),
priapism, and disseminated intravascular coagulation
All of these symptoms may be associated with polycythemia and hyperviscosity but may
not be caused by it
They are common symptoms in many neonatal disorders

35. DIAGNOSIS
• Peripheral venous hematocrit sample is preferred to measure polycythemia
• Arterial blood sample is not acceptable for hematocrit estimation as it would underestimate
the hematocrit
• capillary sample would overestimate the hematocrit by 5% to 15%
• However, capillary hematocrit can be used for initial screening, which should always be
confirmed with a venous hematocrit if greater than 65%
• Warming the heel (arterializing the capillary) before drawing blood for a capillary
hematocrit determination will give a better correlation with the venous or central hematocrit

36. MANAGEMENT
• Observe closely
• Asymptomatic infants with a peripheral venous hematocrit between 65% and 75% may
be merely observed and one may repeat the hematocrit in 4 to 6 hours
• Fluid management
• In neonates with hematocrit >65% and mild symptoms nd with evidence of dehydration
• increasing the daily maintenance fluids by 10 to 20 mL/kg and re-evaluating after 4
to 6 hours might be a reasonable alternative option

37. cont...
• Partial exchange transfusion
• PET may increase the risk of NEC
• Partial exchange must be performed with crystalloid solutions; they are equally
effective
• The use of colloids is associated with a risk of infections and anaphylaxis
• The following formula can be used to calculate the volume of normal saline for partial
exchange

38. OUTCOMES OF TREATING POLYCYTHEMIA
• Short term benefits of PET
• PET will lower hematocrit, decrease viscosity, and reverse many of the physiologic
abnormalities associated with polycythemia/hyperviscosity but has not been shown to
significantly change the long-term outcome of these infants
• The symptoms associated with polycythemia (hypoglycemia, hyperbilirubinemia,
lethargy, thrombocytopenia) reversed rapidly (within 24 hours)
• PET was done in asymptomatic neonates with hematocrit >70 or symptomatic neonates
with hematocrit >70

39. Bleeding

40. ETIOLOGY
A. Deficient clotting factors
1. Transient deficiencies of the procoagulant vitamin K–dependent factors II, VII, IX, and X
and anticoagulant proteins C and S are characteristic of the newborn period and may be
accentuated by the following:
a. The administration of total parenteral alimentation or antibiotics
b. Term infants may develop vitamin K deficiency by day 2 or 3 if they are not
supplemented with vitamin K parenterally because of negligible stores and inadequate
intake.
c. Liver disease may interfere with the production of clotting factors

41. cont...
d. Transplacental exposure to certain drugs can cause bleeding in the first 24 hours of life.
• i. Phenytoin (Dilantin), phenobarbital, and salicylates interfere with the effect of vitamin
K on clotting factor synthesis.
• ii. Warfarin and related compounds given to the mother interfere with the synthesis of
vitamin K–dependent clotting factors by both the maternal and fetal livers; bleeding may
not be immediately reversed by administration of vitamin K

42. 2. Disturbances of clotting
a. Disseminated intravascular coagulation (DIC) may be due to
infection, shock, anoxia
necrotizing enterocolitis (NEC), renal vein thrombosis (RVT), or
the use of vascular catheters
b. Extracorporeal membrane oxygenation (ECMO) in neonates with
critical cardiopulmonary disease is a special case of coagulopathy related to the
consumption of clotting factors in the bypass circuit in addition to therapeutic
anticoagulation

43. 3. Inherited abnormalities of clotting factors
a. X-linked recessive (expressed predominantly in males; Turner’s syndrome, partial X deletions, or
nonrandom X chromosome inactivation)
• One-third of patients with severe hemophilia have “new mutations,” so family history alone cannot exclude
the diagnosis
i. Factor VIII levels are decreased in the newborn with hemophilia A (1 in 5,000 males).
ii. Hemophilia B, or Christmas disease, is due to a deficiency of factor IX (1 in 25,000 males)
b. Autosomal dominant (expressed in boys and girls with one parent affected)
i. von Willebrand disease (VWD) is caused by decreased levels or functional activity of von Willebrand
factor (VWF)
• VWF levels are elevated in neonates compared to older children and nonpregnant adults because of
maternal estrogen
ii. Dysfibrinogenemia (very rare) is due to fibrinogen structural mutations

44. cont...
c. Autosomal recessive
• deficiencies of factors XI, VII, V, X, II, fibrinogen, and factor XIII are all encoded by autosomal
genes
• In factor XII deficiency, there is a prolonged partial thromboplastin time with no bleeding
• Combined factor V and VIII deficiency is caused by a transport gene mu_x0002_tation, not
mutations of the factor V and factor VIII genes.
i. Severe factor VII or factor XIII deficiency can present as intracranial hemorrhage in neonates.
Bleeding from the umbilical stump is also a feature of factor XIII deficiency.
ii. Factor XI deficiency is incompletely recessive because heterozygotes may have unpredictable
bleeding problems with surgery or trauma.
iii. VWD type III (rare, complete absence of VWF)

45. B. Platelet problems
1. Qualitative disorders include hereditary conditions
• e.g., storage pool defects, Glanzmann thrombasthenia, Bernard–Soulier syndrome, platelet-type
VWD and
• transient disorders that result from maternal use of antiplatelet agents
2. Quantitative disorders include the following:
a. Immune thrombocytopenia (maternal idiopathic thrombocytopenic purpura [ITP] or neonatal
alloimmune thrombocytopenia [NAIT])
b. Maternal preeclampsia or hemolysis, elevated liver enzymes, and low platelets (HELLP)
syndrome (see Chapter 3) or severe uteroplacental vascular insufficiency
c. DIC

46. cont...
d. Inherited marrow failure syndromes, including Fanconi anemia and congenital
amegakaryocytic thrombocytopenia
e. Congenital leukemia
f. Inherited thrombocytopenia syndromes, including gray platelet syndrome and the
macrothrombocytopenias (e.g., MYH9-related disorders, May–Hegglin syndrome)
g. Consumption of platelets, i.e., catheter-related thrombosis, RVT, NEC, or vascular
anomalies, such as Kasabach–Merritt phenomenon (KMP) from kaposiform
hemangioendothelioma or tufted angioma
h. Heparin-induced thrombocytopenia (HIT) results from antibody development to the
complex of heparin with platelet factor IV. It is probably rare in neonates, although the
antibody can be detected by enzyme-linked immunosorbent assay (ELISA) after cardiac

47. C. Other potential causes of bleeding
1. Vascular anomalies may cause central nervous system, gastrointestinal (GI), or pulmonary
hemorrhage.
2. Trauma
a. Rupture of spleen or liver associated with breech delivery
b. Retroperitoneal or intraperitoneal bleeding may present as scrotal ecchymosis.
c. Subdural hematoma, cephalohematoma, or subgaleal hemorrhage (the latter may be
associated with vacuum extraction)

48. DIAGNOSTIC WORKUP OF THE BLEEDING INFANT
A. History
1. Family history of excessive bleeding or clotting
2. Maternal medications (e.g., aspirin, phenytoin)
3. Pregnancy and birth history
4. Maternal history of a prior infant with a bleeding disorder
5. Illness, medication, anomalies, or procedures performed on the infant

49. cont...
B. Examination
The crucial decision in diagnosing and managing the bleeding infant is determining whether
the infant is sick or well
1. Sick infant
• Consider DIC, viral or bacterial infection, or liver disease
• Hypoxic/ischemic injury may lead to DIC
2. Well infant
• Consider vitamin K deficiency, isolated clotting factor deficiencies, or immune
thrombocytopenia
• Swallowed maternal blood during labor or delivery or from a bleeding breast will not
cause symptoms in the infant

50. Clinical clues
a. Petechiae, small superficial ecchymosis, or mucosal bleeding suggests a platelet problem
or VWD
b. Large bruises suggest deficiency of clotting factors, DIC, liver disease, or vitamin K
deficiency
c. Enlarged spleen suggests possible congenital infection or erythroblastosis
d. Jaundice suggests infection, liver disease, or resorption of a large hematoma
e. Abnormal retinal findings suggest infection

51. Laboratory tests
• Cord blood samples may be sent for coagulation testing if there is a suspicion for an
inherited bleeding disorder at birth
1. The Apt test is used to rule out maternal blood. If the infant is well and only “GI bleeding”
is noted
• an Apt test is performed on gastric aspirate or stool to rule out the presence of maternal
blood swallowed during labor or delivery or from a bleeding breast

52. cont...
2. Peripheral blood smear
• to assess the number, size, and granulation of platelets and the presence of fragmented red
blood cells (RBCs) as seen in DIC
• Large platelets reflect either a congenital macrothrombocytopenia or young platelets,
suggesting an immune-mediated or destructive thrombocytopenia
3. Platelet count
• Platelet counts of 20 to 30,000/mm3 are considered safe and may not be associated with
bleeding, however in NAIT platelet counts must be maintained above 50,000/mm3

53. cont...
4. Platelet function analysis using instruments such as the PFA100 may be useful as a
screening test for VWD or platelet dysfunction in some settings, but confirmatory assays are
required for positive tests
5. PT
• a test of the “extrinsic” clotting system, integrating activation of factor X by factor VII and
tissue factor
• Factor Xa, with factor Va as a cofactor, activates prothrombin (factor II) to form thrombin
• Thrombin cleaves fibrinogen to fibrin

54. cont...
6. PTT
• a test of the “intrinsic” clotting system and of the activation of factor X by factors XII, XI,
IX, and VIII as well as the downstream factors of the common coagulation pathway (factor
V, prothrombin, and fibrinogen)
7. Fibrinogen can be measured on the same sample used for PT and PTT
• may be decreased in liver disease and consumptive states
• The usual functional assay is low in dysfibrinogenemia

55. cont...
8. d-Dimer assays measure degradation products of fibrin found in the plasma
• are derivatives of cross-linked fibrin generated by the action of plasmin on fibrin clot
• Levels are increased in patients with liver disease who have problems clearing fibrin split
products, thromboembolism, and DIC
9. Specific factor assays and von Willebrand panel for patients with positive family history
10. Bleeding time is not recommended in neonates.

57. TREATMENT OF NEONATES WITH ABNORMAL COAGULATION LABS WITHOUT
CLINICAL BLEEDING
• clinically ill infants or infants weighing <1,500 g with fresh frozen plasma (FFP; 10 mL/kg) if
the PT or PTT or both are ≥2 times normal for age and with platelets (10 to 15 mL/kg)
• if the platelet count is ≤25,000/mm3
• will vary with the clinical situations
• Some neonates will receive platelets if their platelet count is <50,000/mm3, particularly in
NAIT
• In rare cases such as KMP, attempt at correction of the platelet count in the absence of
bleeding can actually cause enlargement of the underlying vascular anomaly and worsening
of symptoms

58. TREATMENT OF NEONATES WITH CLINICAL BLEEDING
A. Replacement therapies
• 1. Vitamin K
• An intravenous (IV) or intramuscular (IM) dose of 1 mg is administered if the neonate
has not received vitamin K at birth
• Infants receiving total parenteral nutrition and infants receiving antibiotics for more than
2 weeks should be given at least 0.5 mg of vitamin K1(IM or IV) weekly to prevent
vitamin K depletion
• If bleeding is minimal, vitamin K (rather than FFP) should be given for prolonged PT
and PTT due to vitamin K deficiency
• FFP should be reserved for significant or emergent bleeding; correction using IV or IM
vitamin K can take 12 to 48 hours

59. cont...
2. FFP and cryoprecipitate
• FFP (10 mL/kg) is given intravenously for active bleeding and is repeated every 8 to 12
hours as needed
• FFP replaces all the clotting factors; however, 10 mL/kg of FFP will transiently raise
the factor levels approximately to 20% of adult control, so specific factor
deficiencies should be treated with factor concentrate when available
• Cryoprecipitate contains only factor VIII, VWF, fibrinogen, and factor XIII. It is the
most practical source of fibrinogen or factor XIII for neonates until a specific diagnosis
is made

60. cont...
3. Platelets
• In the absence of platelet destruction (such as DIC, immune destruction, or sepsis), 1 unit
of random donor platelets should raise the platelet count by 50,000 to 100,000/mm3 in a
neonate
• The platelet count will drop over 3 to 5 days unless platelet production increases
• For alloimmune platelet destruction, either maternal platelets or platelets from a known
platelet-compatible donor should be used if available
• In the setting of bleeding, random donor platelets can be used

61. cont...
4. Fresh whole blood
• Initial transfusion may be 10 mL/kg but should be tailored to the clinical situation
• Reconstituted components (FFP, packed red blood cell [PRBC], cryoprecipitate, and
platelets) are more flexible and readily dosed than fresh whole blood
5. Clotting factor concentrates
• Factor concentrates are available for factors VIII, IX, VII, and XIII

62. B. Treatment of specific disorders
1. DIC
• appears ill and may have petechiae, GI hemorrhage, oozing from venipuncture sites, signs of
infection, asphyxia, or hypoxia
• The platelet count is decreased; PT and PTT are increased
• Fibrinogen is decreased, and d-dimers are increased. Fragmented RBCs are seen on the blood
smear.
• Treatment involves the following steps:
• a. Identify and treat the underlying cause (e.g., sepsis, NEC, herpes)
• b. Confirm that vitamin K has been given
• c. Administer platelets and FFP as needed to keep the platelet count ≥50,000/mL and to
control bleeding

63. cont...
d. For persistent bleeding, consider
• i. Continued transfusion with platelets, PRBCs, and FFP as needed
• ii. Administration of cryoprecipitate (1 to 2 units per 10 kg) for hypofibrinogenemia
e. For consumptive coagulopathy secondary to large-vessel thrombosis without concurrent
bleeding, consider treatment with unfractionated heparin (UFH) infusion without a bolus
• Administer platelets and FFP after heparin initiation to maintain platelet counts
≥50,000/mL and provide antithrombin and anticoagulant proteins essential to heparin
function
• Anticoagulation is generally contraindicated in the presence of intracranial hemorrhage

64. cont...
2. Hemorrhagic disease of the newborn (HDN)
• occurs in 1 out of every 200 to 400 neonates not given vitamin K prophylaxis
a. In the healthy infant, HDN may occur when the infant is not given vitamin K
b. If the mother has been treated with phenytoin (Dilantin), primidone (Mysoline),
methsuximide (Celontin), or phenobarbital, the infant may be vitamin K deficient and bleed
during the first 24 hours

65. Hemolytic Disease of
the Fetus and Newborn

66. HDFN
• Hemolytic disease of the fetus and newborn (HDFN ), also known as erythroblastosis fetalis
• caused by the transplacental passage of maternal antibodies directed against paternally
derived red blood cell (RBC) antigensn →causes increased RBC destruction (hemolysis)
in the infant
• an important cause of anemia and jaundice in newborn infants, and early recognition and
diagnosis are crucial for proper management

67. Hemolytic Disease Caused by Rh Incompatibility
• Rh antigenic determinants are genetically transmitted from each parent and determine the
Rh blood type by directing the production of Rh proteins (C, c, D, E, and e) on the RBC
surface
• RhD is responsible for 90% of HDFN

68. Pathogenesis
• When Rh-positive blood is infused into an unsensitized Rh-negative woman, antibody
formation against the mismatched Rh antigen is induced in the recipient
• can occur through transfusion, but the typical scenario is when small quantities (usually >1
mL) of Rh-positive fetal blood, inherited from an Rh-positive father, enter the maternal
circulation during pregnancy, through spontaneous or induced abortion, or at delivery
• Once sensitization has occurred, considerably smaller doses of antigen can stimulate an
increase in antibody titer

69. Pathogenesis ....
• Initially, a rise in immunoglobulin (Ig) M antibody occurs, which is later replaced by IgG antibody
• Unlike IgM antibodies, IgG readily crosses the placenta to cause hemolytic manifestations
• HDFN requires Rh-antigen mismatch between the infant and the mother, with prior maternal
exposure to RBCs expressing the cognate antigen
• Hemolytic disease rarely occurs during a first pregnancy because transfusion of Rh-positive fetal
blood into an Rh-negative mother usually occurs near the time of delivery
• which is too late for the mother to become sensitized and transmit antibody to that infant before
delivery

70. Pathogenesis ....
• fetal-to-maternal transfusion is thought to occur in only 50% of pregnancies, so Rh
incompatibility does not always lead to Rh sensitization
• Another important factor is the allele frequency of the RhD antigen because homozygous
Rh-positive fathers must transmit the antigen to the fetus, whereas heterozygous fathers have
only a 50% chance of having Rh- positive offspring
• The outcome for Rh-incompatible fetuses varies greatly, depending on the characteristics of
both the RBC antigen and the maternal antibodies

71. Pathogenesis ....
• Not all maternal-fetal antigen incompatibility leads to alloimmunization and hemolysis
• when the mother and fetus are also ABO incompatible, the Rh- negative mother is partially
protected against sensitization due to rapid removal of the fetal Rh-positive cells by maternal
isohemagglutinins (preexisting IgM anti-A or anti-B antibodies that do not cross the
placenta)
• Once a mother has been sensitized, all subsequent infants expressing that cognate antigen on
RBCs are at risk for HDFN

72. • The severity of Rh illness typically worsens with successive pregnancies because of repeated
immune stimulation
• Rh sensitization affects a mother's childbearing potential argues urgently for the prevention
of sensitization
• anti-Rh immune globulin (RhoGAM) into the Rh-negative mother, both during pregnancy
and immediately after the delivery of each Rh-positive infant, reduces HDFN caused by
RhD alloimmunization

73. Clinical Manifestations
• severity of HDFN is variable
• ranging from only laboratory evidence of mild hemolysis to severe anemia with
compensatory hyperplasia of erythropoietic tissues, leading to massive enlargement of
the liver and spleen
• When hemolysis exceeds the compensatory capacity of the hematopoietic system
• profound anemia occurs and results in pallor, signs of cardiac decompensation
(cardiomegaly, respiratory distress), massive anasarca, and circulatory collapse

74. Clinical Manifestations...
• excessive abnormal fluid in 2 ormore fetal compartments
• skin, pleura, pericardium, placenta, peritoneum, amniotic fluid → hydrops fetalis ,
frequently results in death in utero or shortly after birth
• severity of hydrops is related to the level of anemia and the degree of edema caused by a
reduction in serum albumin (oncotic pressure), which is partly a result of hepatic congestion
and hepatic dysfunction
• Failure to initiate spontaneous effective ventilation because of pulmonary edema or bilateral
pleural effusions results in birth asphyxia

75. Clinical Manifestations...
• Petechiae, purpura, and thrombocytopenia may also be present in severe cases, as a result of
decreased platelet production or the presence of concurrent DIC
• Jaundice may be absent at birth because of effective placental clearance of lipid-soluble
unconjugated bilirubin, but in severe cases, bilirubin pigments can stain the amniotic fluid,
cord, and vernix caseosa
• Jaundice is generally evident in the initial 24 hr of life, which is always pathologic
• risk of development of kernicterus from HDFN is greater than from comparable
nonhemolytic hyperbilirubinemia

76. Clinical Manifestations...
• Hypoglycemia - with severe HDFN and may be related to hyperinsulinism and hypertrophy
of the pancreatic islet cells
• with signs of severe disease in utero (hydrops, severe fetal anemia) may benefit from
intrauterine transfusion

77. Laboratory Data
• direct antiglobulin test (DAT), or Coombs test
• initial reticulocyte count is increased
• CBC- white blood cell count usually normal may be elevated, and thrombocytopenia in
severe cases
• peripheral blood smear →polychromasia with a marked increase in nucleated RBCs
• Cord bilirubin
• Indirect-reacting bilirubin content rises rapidly to high levels in the 1st 6-12 hr of life

78. Diagnosis
• Definitive diagnosis requires
• demonstration of blood group incompatibility between mother and infant and
• corresponding maternal antibody bound to the infant's RBCs

79. Antenatal Diagnosis
• Without proof of immunoglobulin prophylaxis, any Rh-negative women with
• previous pregnancy or abortion
• prior exposure to transfused blood, or
• receipt of an organ transplant should be considered at risk for Rh sensitization
• During pregnancy, the expectant parents should have blood tested for potential incompatibility,
particularly for ABO and Rh antigens
• maternal antibody titers are often used to predict the risk of HDFN
• there is a poor correlation between the anti-D titer level and the severity of the disease, especially
in subsequent pregnancies

80. Antenatal Diagnosis....
• Fetal RBC genotyping provides an accurate prediction for the development of HDFN in
sensitized mothers
• severity of fetal anemia should be monitored by Doppler ultrasonography (US) of the middle
cerebral artery (MCA) and then percutaneous umbilical blood sampling (PUBS) if indicated
• Real-time US is used to detect signs of hydrops (skin or scalp edema, pleural or pericardial
effusions, and ascites) and fetal heart rate monitoring
• Hydrops is typically present when fetal hemoglobin level is <5 g/dL
• Amniocentesis was the classic method for assessing fetal hemolysis

81. Postnatal Diagnosis
• blood from the umbilical cord or the infant
• for ABO blood group, Rh type, hematocrit and hemoglobin, reticulocyte count, serum
bilirubin, and the DAT
• positive DAT result indicates the presence of maternal antibody on the infant RBC, and
the incompatible RBC antigen must be identified
• maternal serum should also be screened for RBC antibodies

82. Treatment
• main goals of therapy for HDFN are
• 1) to prevent intrauterine or extrauterine death from severe anemia and hypoxia
• 2) to prevent neurodevelopmental damage in affected children, and
• 3) to avoid neurotoxicity from hyperbilirubinemia

83. Treatment of the Unborn Fetus
• Intravascular (umbilical vein) transfusion of packed erythrocytes (PRBCs) is the preferred
treatment of choice for fetal anemia
• intrauterine transfusion into the fetal peritoneal cavity is also effective
• Hydrops or fetal anemia (hematocrit <30%) is an indication for umbilical vein transfusion in
infants with pulmonary immaturity

84. Treatment of the Liveborn Infant
• clinical signs of severe hemolytic anemia (pallor, hepatosplenomegaly, edema, petechiae,
ascites) are evident at birth
• immediate resuscitation and supportive therapy
• temperature stabilization, and
• monitoring before proceeding with exchange transfusion may save severely affected infants
• Fresh, leukoreduced, and irradiated group O and Rh-negative blood, which has been cross-
matched against maternal serum, should be immediately available

85. Treatment of the Liveborn Infant...
Exchange Transfusion
Intravenous Immune Globulin
 interfere with immune-mediated clearance of antibody- sensitized RBCs
 can prevent immune hemolysis
lower peak serum bilirubin levels
shorten the duration of phototherapy, and
reduce both length of hospitalization and need for exchange transfusion
IVIG does not effectively prevent anemia, which results from both immune-mediated
RBC destruction and inadequate erythropoiesis

86. Late Complications
• Late anemia
• defined as occurring after the 1st 4-6 wk of life, can result from either persistent
hemolysis caused by circulating maternal alloantibodies or from effects on the bone
marrow
• Late hyporegenerative anemia in HDFN results
• from suppression of erythropoiesis
• in part from the higher hemoglobin concentration provided through an intrauterine or
exchange transfusion
• distinguished from hemolytic anemia by a low or absent reticulocyte count and a normal
bilirubin level

87. Late Complications...
• Inspissated bile syndrome
• rare occurrence of persistent icterus in association with significant elevations in both
direct and indirect bilirubin levels in infants with hemolytic disease
• cause is unclear, but jaundice clears spontaneously within a few weeks or months with
conservative management
• Portal vein thrombosis and portal hypertension
• may occur in children who have been subjected to exchange transfusion as newborn
infants
• It is probably associated with prolonged, traumatic, or septic umbilical vein
catheterization

88. Prevention of Rh Sensitization
• risk of initial sensitization of Rh-negative mothers has been reduced to less than 0.1% by the
routine administration of Rh-immunoglobulin to mothers
• intramuscular injection of 300 µg (1 mL) of human anti-D globulin within 72 hr of
delivery of an Rh-positive infant
• other clinical indications for RhoGAM administration include ectopic pregnancy,
abdominal trauma during pregnancy, amniocentesis, chorionic villus biopsy, or abortion
• use appropriately matched blood for all transfusions to Rh- negative girls and young women
of childbearing years

89. Hemolytic Disease Caused
by Blood Group A and B
Incompatibility

90. Hemolytic Disease Caused by Blood Group A and B
Incompatibility
• ABO incompatibility is the most common cause of HDFN
• usually much milder than Rh disease
• rarely requires aggressive clinical management or therapeutic intervention
• 20% of live births are at theoretical risk for immune-mediated hemolysis based on ABO
mismatch
• most often the mother being group O and the infant either group A or B
• Less often, the mother will be group A and the infant group B, or vice versa

91. cont...
• clinical manifestations of hemolysis develop in only 1–10% of at- risk infants
• naturally occurring maternal antibodies against ABO blood group
• antigens are almost exclusively IgM and therefore do not cross the placenta
• Some group O mothers will produce IgG antibodies against blood group A or B antigens, and
these can cross the placenta and cause immune-mediated hemolysis

92. Clinical Manifestations
• Most cases of ABO incompatibility are mild
• infant is not generally affected at birth but will develop jaundice in the 1st 24 hr, which is
always abnormal
• Pallor and hepatosplenomegaly are not present
• development of hydrops fetalis or kernicterus is extremely rare

93. Diagnosis
• presumptive diagnosis is based on
• the presence of serologic ABO incompatibility between the mother and infant, plus
• a weakly to moderately positive DAT result
• Hyperbilirubinemia
• 10–20% of affected infants, the unconjugated serum bilirubin level may reach 20 mg/dL or
more unless phototherapy is administered
• mild anemia and reticulocytosis
• peripheral blood smear may show polychromasia, nucleated RBCs, and spherocytes
• hemolytic anemia or spherocytosis beyond 2 wk should suggest an alternative diagnosis, such as
hereditary (congenital) spherocytosis

94. Treatment
• Phototherapy - mlowering serum bilirubin levels
• In severe cases, IVIG administration
• reduce the rate of hemolysis and the need for exchange transfusion
• Exchange transfusions with group O and Rh-compatible blood type
• may be needed in some cases to correct dangerous degrees of anemia or
hyperbilirubinemia
• Some infants with ABO hemolytic disease may require transfusion of PRBC at several weeks
of age because of hyporegenerative or slowly progressive anemia
• Postdischarge monitoring of hemoglobin or hematocrit is essential in newborns with ABO
hemolytic disease