Haematological Disorders of

Newborn

Hasmawati bt Hassan
Consultant Neonatologist
HRPZII
 Common Hematological Disorders
• Anaemia
• Polycythaemia
• Bleeding and Coagulation Disorders
 Introduction
• Blood volume and red cell mass at birth and in
neonatal period depend on
– Volume of placental transfusion and,
– Subsequent readjustments of blood volume
 Placental Transfusion
• Occurs within 3 min. of delivery
• Contributes 25% of total neonatal blood
volume.
• This amount will be increased in:
– Elevated maternal blood pressure
– Use of oxytocic drugs
– Late clamping or milking of the cord
– Infant held in a low dependent position.
 Placental Transfusion
• Average blood volume 85-90ml/kg.
• Ranges between 75-100 ml/kg.
• Readjustment of blood volume
– Occur the first 3-4 hours after birth with
heamoconcentration to compensate for expansion
of intravascular volume.
Neonatal Anaemia
 Neonatal Anaemia
• Defined as: Hb. Less than 13 g%
 Causes of Neonatal Anaemia
• Physiological anaemia (1)
• Anaemia of prematurity (2)
• Haemorrhage (3)
– Antepartum haemorrhage
– Fetomaternal transfusion
– Twin twin transfusion
– Neonatal internal haemorrhage –Hemorrhagic Disease of
Newborn
• Haemolysis (4)
• Aplasia (5)
 Physiological anaemia (1)
• Term born with Hb range 15-23.5g%
• Preterm slightly lower
• Slight increase due to hemoconcentration
• Over 1 week Hb drops and remains low for
most of the first year.
• Also known as physiological anaemia
 Anaemia of prematurity (2)
• Defined as: physiological anemia occurring in
the preterm infant which occur earlier, severe
and prolonged.
• Causes:
– Lack of erythropoietin
– Hemodilution
– Iron deficiency
– Haemolysis
 Anaemia of prematurity (2)
Lack of erythropoietin.
• Due to relatively hypoxic fetal state to
hyperoxic stage.
• This suppresses erythropoietin secretion for
the first 7-8 weeks.
• Bone marrow resistant to stimulation of
erythropoietin.
 Anaemia of prematurity (2)
Haemodilution – increase of plasma volume
over the first months of life.
• Poor red cell production -the haemoglobin
falls.
• Also referred as ‘early anaemia.’
 Anaemia of prematurity (3)
Iron deficiency:
• In preterm the iron stores are exhausted more
quickly due to rapid growth.
• Infant of 1.5 kg has half the iron stores at
birth compared with a 3.0 kg infant.
• This account for ‘late anemia’ seen at 4
months of age.
 Anaemia of prematurity (2)
Haemolysis:
• Due to vitamin E deficiency.
• Treatment with vit. E may reduce the extent of
late anemia of prematurity.
• In term, lowest Hb occurs between 6 –10
weeks when it falls to 10-11 g/dl.
• In preterm it occurs earlier and last longer
with a nadir 7-8 g.
 Symptoms of Anaemia in Preterm
• Breathlessness with feeds
• Tachycardia
• Apnoea
• Bradycardia
• Failure to gain weight
 Treatment of anaemia of prematurity
• Iron given to preterm from 2 weeks of age.
• Elemental iron 1-2 mg/kg is recommended
until age 12 months of age.
• Blood transfusion 10ml/kg if Hb < 8 g or if
symptomatic.
• Recombinant human erythropoietin.
 Anemia base on Hematocrit –
indication for blood transfusion
• Hct < 35 + ventilated
• Hct <30 + on Oxygen
• Hct <25 + symptomatic
• Hct <20 – all babies
Haemorrhage (3)
 Causes of haemorrhage
• Haemorrhage before and during delivery
– Placental praevia
– Cord – rupture or torn vessels
– Fetal – fetomaternal, twin twin transfusion
• Neonatal haemorrhage
– Bleeding into brain, lung or bowel
– Haemorrhagic disease of newborn
 Management of Haemorrhage
• Clinical assessment for shock and hypovolaemia.
• Investigations include:-
– Haemoglobin and haematocrit
– Blood group
– Cross match blood
– Kleihauer’s test
– Coagulation studies
– Ultrasound cranium, abdomen, stools for blood.
Haemorrhagic Disease of Newborn
 History

• Townsend in Boston (1864) described 50 cases of

“hemorrhagic disease of the newborn” during first 2
weeks of life
• In 1929, Vitamin K isolated from alfalfa by Dam and Doisy
(Nobel Prize, 1942), and conducted clinical trials showing
Vitamin K protects against HDN
• 1961, Am Acad Pediatrics and Am College Obstetrics and
Gynecology recommended routine prophylaxis with Vit K
for all newborns
• Controversy in Britain in 1990s resolved to satisfaction of
AAP, ACOG, Canada, Australia, New Zealand and others
 Haemorrhagic disease of newborn
• Early
• Classical – due to deficiency of vitamin K
dependent clotting factors
• Late onset
 Primary HDN
• Often fatal condition
• Diffuse hemorrhage in otherwise healthy infant
• During the first week of life
• Particularly in low birth weight babies
• Results of low levels of prothrombin and other vitamin
K dependent clotting factors, (Factors II, VII, IX and X)
caused by vitamin K deficiency
• An exaggerated of physiologic deficiency of clotting
factors normal in the first few days of life
• Incidence between 2.5 to 17.0 per thousand newborns
not given vitamin K prophylactically
 Haemorrhagic disease of newborn
• Classical haemorrhagic disease of the
newborn is due to deficiency of vit.K
dependent clotting factors.
• Vitamin K is produced by bacterial flora of the
gut which there is little production during first
week of life.
• Decline due to routine IM vitamin K at birth.
 Late HDN

• Between 2-12 weeks of life,

• Especially in breast-fed babies.
• Immaturity of liver affects production of clotting
factors
• Late HDN primarily in breast fed infants without
or inadequate vitamin K rates of 4.4-7.2/100,000
live births
 Common Clinical Manifestations

• Bleeding in the
– gastrointestinal tract
– urinary tract
– umbilical stump
– nose
– scalp
– intracranial hemorrhage
– Shock
– death
 Clinical features:
• Spontaneous bleeding usually GIT.
• Umbilical bleeding or postcircumcision.
• Occurs late in first week of life esp to breast-
fed infant.
• DD from bleeding due to swallow blood.
– Differentiate by APT’s Test.
 American Academy of Pediatrics 1961

• Prophylactic use of Vit K recommended by the

American Academy of Pediatrics, and by the American
College of Obstetricians and Gynecologists since 1961.
• Up until 1987, administration of vit K at birth was
mandatory in only five states in the US
• AAP recommendation renewed in 1993 and remains
current
 Investigations:
• The diagnosis is confirmed by a prolonged
prothrombin time (PT) but normal partial
thromboplastin time (PTT).
• Apt’s test – resistance of Fetal RBCs to
denaturation by sodium hydroxide.
 Treatment
• Vitamin K1, 1 mg im or iv
• Blood transfusion if indicated.
 Renewed Interest in Vit K

• Since the 1980s attention – UK, Europe, Japan, Canada,

Australasia and Middle East
• HDN and vit K deficiency reported in both developed
and developing countries where it is not routinely used,
or where use may be waning
• Controversy re oral versus parenteral use of routine Vit
K largely resolved
• Intramuscular administration within the first 6 hours
after birth more effective in preventing both early and
late HDN
 Other Countries

• Still not routine in Japan, Germany, UK

• Routine prophylactic Vitamin K for newborns
adopted in
– Canada
– Australia
– New Zealand
– Croatia, 1988
 Public Health Importance
• Japanese incidence of HDN reported as 1/1,700 in
breast fed babies and 1:4,500 in all infants
• Of these, 82% were reported to have intracranial
hemorrhage (ICH)
• NDN still significant; even more in developing countries
e.g. India, Thailand, Singapore and Taiwan
• Thailand reports incidence of 35-72/100,000 births
• ICH not always identified as HND related and may be
significant factor in birth-related cerebral palsies
 Summary
• Deficiency of Vit K remains a significant worldwide cause
of neonatal morbidity and mortality
• Routine prophylactic use of vitamin K should always be
used to prevent HDN (“good public health practice”)
• Administration by intramuscular injection (0.5-1.0 mgm)
within 6 hours of birth is preferable
• May be given orally as 3 doses spread over the first 4
weeks of life
• Vit K showing up in literature on osteoporosis
• A safe, inexpensive preventive procedure that should be
mandatory component of newborn care.
 Haemolysis (4)

(Hemolytic Disease of Newborn,

HDN)
 Causes of neonatal haemolysis

Immune haemolysis (positive Coombs’ test)

Rhesus incompatibility
ABO incompatibility
Minor blood group
Maternal SLE
Non-Immune haemolysis
Congenital infection
DIC
G6PD def
Pyruvate kinase
Alpha Thal
 What is HDN?
• Destruction of the RBCs of the fetus and
newborn by antibodies produced by the
mother
• Only IgG antibodies are involved because it
can cross the placenta (not IgA or IgM)

Fetal =
+ RBC
destruction

Mother’s
antibodies
 Pathophysiology
• Although transfer of maternal antibodies is
good, transfer of antibodies involved in HDN
are directed against antigens on fetal RBCs
inherited by the father
• Most often involves antigens of the Rh and
ABO blood group system, but can result from
any blood group system
• Remember: The fetus is POSITIVE for an
antigen and the mother is NEGATIVE for the
same antigen
 Pathophysiology
• HDN develops in utero
• The mother is sensitized to the foreign antigen
present on her child’s RBCs usually through
some seepage of fetal RBCs (fetomaternal
hemorrhage) or a previous transfusion
• HDN occurs when these antibodies cross the
placenta and react with the fetal RBCs
 Rhesus Haemolytic Disease
• This occurs because the mother’s immune
system has been sensitized by rhesus-positive
cells from her fetus. Due to:-
– Fetomaternal transfusion.
– Rhesus incompatible transfusions.
• 95% due to antigen D.
• 83% of population are D positive.
 Rh HDN
• Mother is D negative (d/d) and child is D positive (D/d)
• Most severe form of HDN
• 33% of HDN is caused by Rh incompatibility
• Sensitization usually occurs very late in pregnancy, so the
first Rh-positive child is not affected
– Bleeds most often occur at delivery
– Mother is sensitized
– Subsequent offspring that are D-positive will be affected
 FetoMaternal Hemorrhage
• Sensitization occurs as a result of seepage of
fetal cells into maternal circulation as a result
of a fetomaternal hemorrhage
– Placental membrane rupture (7%)
– Trauma to abdomen
– Delivery (>50%)
– Amniocentesis
– Abortion
 Pathogenesis
• Maternal IgG attaches to antigens on fetal
cells
– Sensitized cells are removed by macrophages in
spleen
– Destruction depends on antibody titer and
number of antigen sites
– IgG has half-life of 25 days, so the condition can
range from days to weeks
• RBC destruction and anemia cause bone
marrow to release erythroblasts, hence the
name “erythroblastosis fetalis”)
 Pathogenesis
• When erythroblasts are
used up in the bone
marrow, erythropoiesis in
the spleen and liver are
increased
– Hepatosplenomegaly
(enlarged liver & spleen)
– Hypoproteinemia (from
decreased liver function)
leads to cardiac failure
edema, etc called
“Hydrops fetalis”
 Bilirubin
• Hemoglobin is metabolized to bilirubin
– Before birth, “indirect” bilirubin is transported
across placenta and conjugated in maternal liver
(“direct”) where it is excreted
– After birth, the newborn liver is unable to
conjugate the bilirubin
• Unconjugated (“indirect”) bilirubin can reach toxic
levels (18-20 mg/dL)
• This is called kernicterus and can lead to permanent
brain damage
 Prevention of Rh Haemolytic Disease
• Anti-D gamma globulin 100-200 ug. Given to
all rhesus-negative mum who gave birth to
rhesus-positive infants within 72 hours.
• Also given to at-risk rhesus negative mum
after abortion or after amniocentesis esp if
Kleihauer test shows a fetomaternal
transfusion.
 Dose
• Each vial of RhIg contains enough anti-D to
protect against a FMH of 30 mL
– One vial contains 300 μg of anti-D
– Given intramuscularly of intravenously
– Massive fetomaternal hemorrhage (>30 mL)
requires more than one vial
– To assess a FMH, a maternal sample is screened
within 1 hour of delivery (rosette test)
 Diagnosis & Management
• Serologic Testing (mother & newborn)
• Amniocentesis and Cordocentesis
• Intrauterine Transfusion
• Early Delivery
• Phototherapy & Newborn Transfusions
 Management during pregnancy
• Routine testing of rhesus antibodies.
• If present, an amniocentesis may be indicated.
• Also if there is a previous infant affected and
exchange transfusion was done, and previous
stillbirth.
• Amniocentesis is commonly done at 30-32
weeks.
 Management during pregnancy
• Assessment of bilirubin in liquor amnii.
• Using spectrophotometric technique at wavelength
of 450nm.
• This is the region of maximal bilirubin absorption.
• The optical density difference between patient’s
amniotic fluid and normal amniotic fluid at specific
gestational age is plotted on the Liley chart
 Liley chart (Liley, 1961)
• Provides guidelines for severity of rhesus
isoimmunization, treatment and expected
cord blood haemoglobin.
• Also it help obstetrician to plan the delivery.
• If fetus severely affected and too immature to
deliver, then in utero transfusion may be life
saving.
 Liley graph
• The ΔOD is plotted on the Liley graph
according to gestational age
• Three zones estimate the severity of HDN
– Lower: mildly or unaffected fetus (Zone 1)
– Midzone: moderate HDN, repeat testing (Zone 2)
– Upper: severe HDN and fetal death (Zone 3)
Liley graph

a ΔOD of .206 nm at
35 weeks correlates
* with severe HDN
 Management of the rhesus immunized infant
• The infant should be assessed for
maturity,pallor, jaundice,ascites…
• Placenta send for pathology examination.
• Cord blood taken for HB.,DCT, Hb. And platelet
and total Serum Bilirubin.
Indications for immediate/early exchange transfusion

• Cord haemoglobin < 8 g/dl.

• Hydrops fetalis
• Cord bilirubin > 85umol/L
• Rapidly rising bilirubin crossing the level for
exchange transfusion.
• Strong positive Coombs’ test.
 Complications of rhesus incompatibility
• Kernicterus and bilirubin encephalopathy.
• Hyaline membrane disease.
• Beta cell hyperplasia leading to hypoglycaemia.
• Hypoalbuminaemia and lung oedema.
• Thrombocytopenia and DIC.
• Inspissated bile syndrome.
• Complications of exchange transfusion.
• Anaemia: Folic acid, and tansfusions.
ABO HDN
 ABO HDN
• ABO incompatibilities are the most common
cause of HDN but are less severe
– About 1 in 5 pregnancies are ABO-incompatible
– 65% of HDN are due to ABO incompatibility
• Usually, the mother is type O and the child has
the A or B antigen…Why?
– Group O individuals have a high titer of IgG anti-
A,B in addition to having IgM anti-A and anti-B
 ABO Incompatibility

Mother Infant Frequency

O A or B Common
A B or AB Rare
B A or AB Rare
 ABO HDN
• ABO HDN can occur during the FIRST
pregnancy b/c prior sensitization is not
necessary
• ABO HDN is less severe than Rh HDN because
there is less RBC destruction
– Fetal RBCs are less developed at birth, so there is
less destruction by maternal antibodies
– When delivered, infants may present with mild
anemia or normal hemoglobin levels
– Most infants will have hyperbilirubinemia and
jaundice within 12 to 48 hours after birth
 Clinical features
• Jaundice first 24 hours of life
• No hepatosplenomegaly
• Kernicterus unusual.
• Hydrops occasionally being reported.
• Late anemia is seldom a problem.
 Diagnosis of ABO HDN
• Infant presents with jaundice 12-48 hrs after
birth
• Testing done after birth on cord blood
samples:
– Sample is washed 3x to remove Wharton’s jelly
– Anticoagulated EDTA tube (purple or pink)
– ABO, Rh and DAT performed
– Most cases will have a positive DAT
• If DAT positive, perform elution to ID antibody
 Investigations:
• Suspected in mother who is blood group O and
infant either group A or less commonly group B.
• DCT usually negative but indirect coombs test may
be positive.
• Blood smear may show features of haemolysis.
• Immune anti-A or anti-B may be elicated from fetal
RBCs or cord blood.
 Treatment of ABO HDN
• Only about 10% require therapy
• Phototherapy is sufficient
• Rarely is exchange transfusion needed

• Phototherapy is exposure to artificial or

sunlight to reduce jaundice
• Exchange transfusion involves removing
newborn’s RBCs and replacing them with
normal fresh donor cells
 Phototherapy

Fluorescent blue light in

the 420-475 nm range
Exchange transfusion
Non-immune hemolysis – G6PD
 Glucose-6-phosphate dehydrogenase
deficiency
• X-linked recessive thus occur in male.
• Heterozygote female may manifest mild
disease.
• Due to deficiency of enzyme within RBC which
render cells more susceptible to haemolysis.
• Many variants to conditions.
Drugs that may cause haemolysis in infants
with G6PD deficiency
• Antimalarials - primaquine, quinine
• Nitrofurantion
• Sulphonamides
• Nalidixic acid
• Naphthalene
• Chloramphanicol
• Vitamin K (large doses)
• Fava beans (kachang parang/itek)
 Others condition causing haemolysis
• Pyruvate kinase deficiency
• Hereditary spherocytosis
• Alpha Thallasaemia
 Hydrops Fetalis
• This term is used to describe an infant who
shows severe and generalized oedema, ascites
and pleural effusions at birth.
 Causes of Hydrops Fetalis
• Immune: severe haemolytic disease of
newborn.
• Non-immune
 Causes of Hydrops Fetalis
• Non-immune:
– Fetal onset SVT
– Severe anemia in utero
– Chronic twin-twin transfusion
– Severe CHD
– Premature closure of foramen ovale and ductus
arteriosus
– Congenital Nephrotic syndrome.
 Causes of Hydrops Fetalis
• Non-immune:
– Congenital infections
– Congenital malformations; obstructive uropathy
– Parvovirus B19
– Idiopathic: 50% of cases.
 Management of Hydrops Fetalis
• May include:
– Haemoglobin electrophoresis.
– Kleihauer’s test.
– Coombs’ test and full blood count.
– TORCH investigations.
– Total serum proteins and serum albumin
Polycythaemia
 Polycythaemia
• Common and is defined as a venous haemotocrit of
65% or more (= Hb 22g/dl), during the first week.
• Not equal to hyperviscous.
• Blood viscosity depends largely on packed cell
volume.
• Viscosity much more greater in small vessels than
large vessels.
• Daignosed on free flowing venous specimen and not
from heel prick sample.
 Causes of neonatal polycythaemia
Chronic intrauterine hypoxia:
SGA infants
Postmaturity
Excessive tranfusion of blood
Delayed clamping
Twin twin transfusion
Infants of Diabetic mothers
Down’s syndrome
Neonatal thyrotoxicosis
CAH
 Clinical features
• Infants look plethoric.
• Neurological
– Jitteriness,apnoea,convulsions.
• Cardiovascular
– Congestive heart failure,pulmonary hypertension with
Right to left shunting and cyanosis.
• Gastrointestinal - NEC
• Renal – renal vein thrombosis
• Others: hypoglycaemia, thrombocytopenia,
jaundice,hypocalcemia.
 Management
• Anticipation
• At risk infants haemotocrit should be measured.
• Infants without symptoms but haematocrit > 70%
should have a dilutional exchange transfusion.
• Symptomatics infants with venous PCV of 65-70%
may require dilutional exchange transfusion.
 Dilutional exchange transfusion
• Performed using normal saline / plasma and
aimed at reducing the haematocrit to about
50% using formula:
• Volume = actual Hct – desired Hct / actual Hct
x weight (kg) x blood volume.
Bleeding and Coagulation disorders
 Bleeding and coagulation disorders
• May be due:
– Thrombocytopenia
– Deficiency of clotting factors
– Abnormal capillaries
– Combination of all
 Clinical features
• Bleeding from umbilical or venepuncture sites.
• Bruising, purpura or petechial haemorrhages.
 Causes of thrombocytopenia
• Infection
– Bacterial infection
– TORCH infections
• Isoimmune
• Maternal disease
– ITP
– SLE
– Drug induced
• Neonatal drug exposure
– Thiazide diuretics
– Quinine
– Sulphonamides
 Isoimmune thrombocytopenia
• Rare condition. Analogous to Rh isoimmunization.
• Transfusion of fetal A1 antigen-positive platelets into
maternal circulation may produce maternal IgG
antibodies if the mother is platelet A1 antigen
negative.
• Mother has normal platelet count.
• Newborn may have severe thrombocytopenia but is
transient.
• Platelets transfusion or exchange transfusion may be
needed in severe cases.
 Maternal ITP
• Due to transplacental maternal antibodies.
• Mother may have thrombocytopenia and the lower
mum platelets count the more severe affected the
infant is.
• Steroids and IVIG had been advocated for treatment.
• Blood transfusion or platelet may be required if PC <
20,000.
• Intracerebral bleed may occur before onset of labour.
 Causes of thrombocytopenia
• Neonatal drug exposure
– Thiazide diuretics
– Quinine
– Sulphonamides
• DIC
• TAR syndrome
• Kasabach Merritt syndrome
• Fanconi’s anaemia
• Leukaemia
• Pancytopenias
Disseminated Intravascular Coagulation (DIC)

• DIC an acquired coagulation disorder

charaterized by intravascular consumption of
platelets and clotting factors II,V,VIII and
fibrinogen.
• Intravascular coagulation results from
deposition of thrombi in small vessels and
consumption of clotting factors leading to
haemorrhage.
 Neonatal conditions and DIC
• Septicaemia
• Severe shock
• Severe perinatal asphyxia
• IRDS in VLBW infants
• Severe Rhesus disease
• TORCH infections
• Hypothermia
• Maternal DIC with transplacental effect.
 Investigations for DIC
• Blood film shows haemolysis with fragmented
and distorted red cells.
• Thrombocytopenia.
• Prolonged PT,PTT and thrombin time.
• Low fibrinogen.
• Increased FDPs.
Presence of three or more makes DIC likely.
 Treatment
• Very complex
• Treat underlying disease process
• Treatment of the haematological abnormality.
 Others coagulation disorders
• Immaturity of clotting factors secondary to
liver immaturity.
• Inherited disorders of coagulation
– Haemophilia A (Factor VIII def)
– Chrismas disease (Factor IX def)