hematological disorders of newborn
TRANSCRIPT
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Haematological Disorders of
Newborn
Hasmawati bt HassanConsultant Neonatologist
HRPZII
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Common Hematological Disorders
• Anaemia
• Polycythaemia
• Bleeding and Coagulation Disorders
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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
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Placental Transfusion
• Occurs within 3 min. of delivery
• Contributes 25% of total neonatal bloodvolume.
• 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.
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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.
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Neonatal Anaemia
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Neonatal Anaemia
• Defined as: Hb. Less than 13 g%
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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)
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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
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Anaemia of prematurity (2)
• Defined as: physiological anemia occurring inthe preterm infant which occur earlier, severeand prolonged.
• Causes: – Lack of erythropoietin
– Hemodilution
– Iron deficiency – Haemolysis
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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.
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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.’
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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.
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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 –10weeks when it falls to 10-11 g/dl.
• In preterm it occurs earlier and last longerwith a nadir 7-8 g.
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Symptoms of Anaemia in Preterm
• Breathlessness with feeds
• Tachycardia
• Apnoea• Bradycardia
• Failure to gain weight
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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.
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Anemia base on Hematocrit –
indication for blood transfusion
• Hct < 35 + ventilated
• Hct <30 + on Oxygen
• Hct <25 + symptomatic
• Hct <20 – all babies
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Haemorrhage (3)
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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
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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.
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Haemorrhagic Disease of Newborn
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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 showingVitamin K protects against HDN
• 1961, Am Acad Pediatrics and Am College Obstetrics andGynecology 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
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Haemorrhagic disease of newborn
• Early
• Classical – due to deficiency of vitamin K
dependent clotting factors
• Late onset
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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 vitaminK dependent clotting factors, (Factors II, VII, IX and X)caused by vitamin K deficiency
• An exaggerated of physiologic deficiency of clottingfactors normal in the first few days of life
• Incidence between 2.5 to 17.0 per thousand newbornsnot given vitamin K prophylactically
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Haemorrhagic disease of newborn
• Classical haemorrhagic disease of thenewborn is due to deficiency of vit.Kdependent clotting factors.
• Vitamin K is produced by bacterial flora of thegut which there is little production during firstweek of life.
• Decline due to routine IM vitamin K at birth.
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Late HDN
• Between 2-12 weeks of life,
• Especially in breast-fed babies.
• Immaturity of liver affects production of clottingfactors
• Late HDN primarily in breast fed infants without
or inadequate vitamin K rates of 4.4-7.2/100,000
live births
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Common Clinical Manifestations
• Bleeding in the
– gastrointestinal tract
– urinary tract
– umbilical stump – nose
– scalp
– intracranial hemorrhage – Shock
– death
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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.
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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
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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.
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Treatment
• Vitamin K1, 1 mg im or iv
• Blood transfusion if indicated.
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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 developedand developing countries where it is not routinely used,or where use may be waning
• Controversy re oral versus parenteral use of routine VitK largely resolved
• Intramuscular administration within the first 6 hoursafter birth more effective in preventing both early andlate HDN
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Other Countries
• Still not routine in Japan, Germany, UK
• Routine prophylactic Vitamin K for newborns
adopted in – Canada
– Australia
– New Zealand
– Croatia, 1988
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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
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Summary
• Deficiency of Vit K remains a significant worldwide causeof neonatal morbidity and mortality
• Routine prophylactic use of vitamin K should always beused 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 4weeks of life
• Vit K showing up in literature on osteoporosis• A safe, inexpensive preventive procedure that should bemandatory component of newborn care.
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Haemolysis (4)
(Hemolytic Disease of Newborn,
HDN)
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Causes of neonatal haemolysis
Immune haemolysis (positive Coombs’ test)
Rhesus incompatibility
ABO incompatibility
Minor blood group
Maternal SLE
Non-Immune haemolysis
Congenital infectionDIC
G6PD def
Pyruvate kinase
Alpha Thal
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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
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Pathophysiology
• Although transfer of maternal antibodies isgood, transfer of antibodies involved in HDNare 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 fromany blood group system
• Remember: The fetus is POSITIVE for anantigen and the mother is NEGATIVE for thesame antigen
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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
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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.
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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 thefirst Rh-positive child is not affected
– Bleeds most often occur at delivery
– Mother is sensitized
– Subsequent offspring that are D-positive will be affected
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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
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Pathogenesis
• Maternal IgG attaches to antigens on fetalcells
– 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 bonemarrow to release erythroblasts, hence the
name “erythroblastosis fetalis”)
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Pathogenesis
• When erythroblasts areused up in the bonemarrow, erythropoiesis inthe spleen and liver are
increased – Hepatosplenomegaly
(enlarged liver & spleen)
– Hypoproteinemia (fromdecreased liver function)leads to cardiac failureedema, etc called“Hydrops fetalis”
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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
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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.
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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 screenedwithin 1 hour of delivery (rosette test)
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Diagnosis & Management
• Serologic Testing (mother & newborn)
• Amniocentesis and Cordocentesis
• Intrauterine Transfusion
• Early Delivery
• Phototherapy & Newborn Transfusions
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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 previousstillbirth.
• Amniocentesis is commonly done at 30-32
weeks.
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Management during pregnancy
• Assessment of bilirubin in liquor amnii.
• Using spectrophotometric technique at wavelengthof 450nm.
• This is the region of maximal bilirubin absorption.• The optical density difference between patient’samniotic fluid and normal amniotic fluid at specificgestational age is plotted on the Liley chart
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Liley chart (Liley, 1961)
• Provides guidelines for severity of rhesusisoimmunization, treatment and expectedcord 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 lifesaving.
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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
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Liley graph
a ΔOD of .206 nm at
35 weeks correlates
with severe HDN*
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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.
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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.
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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.
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ABO HDN
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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
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ABO Incompatibility
Mother
O A
B
Infant
A or BB or AB
A or AB
Frequency
CommonRare
Rare
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ABO HDN
• ABO HDN can occur during the FIRSTpregnancy b/c prior sensitization is notnecessary
• ABO HDN is less severe than Rh HDN becausethere is less RBC destruction
– Fetal RBCs are less developed at birth, so there isless destruction by maternal antibodies
– When delivered, infants may present with mildanemia or normal hemoglobin levels
– Most infants will have hyperbilirubinemia and
jaundice within 12 to 48 hours after birth
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Clinical features
• Jaundice first 24 hours of life
• No hepatosplenomegaly
• Kernicterus unusual.
• Hydrops occasionally being reported.
• Late anemia is seldom a problem.
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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
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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.
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Treatment of ABO HDN
• Only about 10% require therapy
• Phototherapy is sufficient
• Rarely is exchange transfusion needed
• Phototherapy is exposure to artificial orsunlight to reduce jaundice
• Exchange transfusion involves removingnewborn’s RBCs and replacing them withnormal fresh donor cells
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Phototherapy
Fluorescent blue light inthe 420-475 nm range
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Exchange transfusion
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Non-immune hemolysis – G6PD
Glucose 6 phosphate dehydrogenase
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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
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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)
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Others condition causing haemolysis
• Pyruvate kinase deficiency
• Hereditary spherocytosis
• Alpha Thallasaemia
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Hydrops Fetalis
• This term is used to describe an infant who
shows severe and generalized oedema, ascites
and pleural effusions at birth.
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Causes of Hydrops Fetalis
• Immune: severe haemolytic disease of
newborn.
• Non-immune
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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.
f
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Causes of Hydrops Fetalis
• Non-immune:
– Congenital infections
– Congenital malformations; obstructive uropathy
– Parvovirus B19
– Idiopathic: 50% of cases.
f d l
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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
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Polycythaemia
l h i
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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 cellvolume.
• Viscosity much more greater in small vessels thanlarge vessels.
• Daignosed on free flowing venous specimen and notfrom heel prick sample.
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Causes of neonatal polycythaemia
Chronic intrauterine hypoxia:
SGA infants
Postmaturity
Excessive tranfusion of blood
Delayed clamping
Twin twin transfusion
Infants of Diabetic mothersDown’s syndrome
Neonatal thyrotoxicosis
CAH
Cli i l f
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Clinical features
• Infants look plethoric.• Neurological
– Jitteriness,apnoea,convulsions.
• Cardiovascular
– Congestive heart failure,pulmonary hypertension withRight to left shunting and cyanosis.
• Gastrointestinal - NEC
• Renal – renal vein thrombosis• Others: hypoglycaemia, thrombocytopenia,
jaundice,hypocalcemia.
M
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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.
Dil ti l h t f i
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Dilutional exchange transfusion
• Performed using normal saline / plasma andaimed at reducing the haematocrit to about
50% using formula:
• Volume = actual Hct – desired Hct / actual Hctx weight (kg) x blood volume.
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Bleeding and Coagulation disorders
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Bleeding and coagulation disorders
• May be due:
– Thrombocytopenia
– Deficiency of clotting factors
– Abnormal capillaries
– Combination of all
Cli i l f t
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Clinical features
• Bleeding from umbilical or venepuncture sites.
• Bruising, purpura or petechial haemorrhages.
C f th b t i
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Causes of thrombocytopenia
• Infection – Bacterial infection
– TORCH infections
• Isoimmune
• Maternal disease – ITP
– SLE
– Drug induced
• Neonatal drug exposure
– Thiazide diuretics – Quinine
– Sulphonamides
I i th b t i
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Isoimmune thrombocytopenia
• Rare condition. Analogous to Rh isoimmunization.• Transfusion of fetal A1 antigen-positive platelets into
maternal circulation may produce maternal IgGantibodies if the mother is platelet A1 antigen
negative.• Mother has normal platelet count.
• Newborn may have severe thrombocytopenia but istransient.
• Platelets transfusion or exchange transfusion may beneeded in severe cases.
M t l ITP
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Maternal ITP
• Due to transplacental maternal antibodies.• Mother may have thrombocytopenia and the lower
mum platelets count the more severe affected theinfant 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
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Causes of thrombocytopenia
• Neonatal drug exposure – Thiazide diuretics
– Quinine
– Sulphonamides
• DIC• TAR syndrome
• Kasabach Merritt syndrome
• Fanconi’s anaemia
• Leukaemia• Pancytopenias
Di i t d I t l C l ti (DIC)
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Disseminated Intravascular Coagulation (DIC)
• DIC an acquired coagulation disordercharaterized 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 tohaemorrhage.
Neonatal conditions and DIC
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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
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Investigations for DIC
• Blood film shows haemolysis with fragmentedand distorted red cells.
• Thrombocytopenia.
• Prolonged PT,PTT and thrombin time.
• Low fibrinogen.
• Increased FDPs.
Presence of three or more makes DIC likely.
Treatment
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Treatment
• Very complex
• Treat underlying disease process
• Treatment of the haematological abnormality.
Others coagulation disorders
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Others coagulation disorders
• Immaturity of clotting factors secondary toliver immaturity.
• Inherited disorders of coagulation
– Haemophilia A (Factor VIII def)
– Chrismas disease (Factor IX def)