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 Kleihauers 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 breastfed infant. DD from bleeding due to swallow blood.
Differentiate by APTs 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). Apts 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)

+
Mothers antibodies

Fetal RBC

destruction

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 childs 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 mothers 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 g 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 patients 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 OD 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 OD 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 antigenWhy?
Group O individuals have a high titer of IgG antiA,B in addition to having IgM anti-A and anti-B

ABO Incompatibility
Mother
O A B

Infant
A or B B or AB A or AB

Frequency
Common Rare 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 Whartons 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 newborns 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. Kleihauers 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 Downs 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 Fanconis 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)