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.

. • Readjustment of blood volume – Occur the first 3-4 hours after birth with heamoconcentration to compensate for expansion of intravascular volume. • Ranges between 75-100 ml/kg.Placental Transfusion • Average blood volume 85-90ml/kg.

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 .

• Causes: – Lack of erythropoietin – Hemodilution – Iron deficiency – Haemolysis . severe and prolonged.Anaemia of prematurity (2) • Defined as: physiological anemia occurring in the preterm infant which occur earlier.

• Due to relatively hypoxic fetal state to hyperoxic stage. • This suppresses erythropoietin secretion for the first 7-8 weeks.Anaemia of prematurity (2) Lack of erythropoietin. . • 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.

• Infant of 1. • This account for ‘late anemia’ seen at 4 months of age.Anaemia of prematurity (3) Iron deficiency: • In preterm the iron stores are exhausted more quickly due to rapid growth. .0 kg infant.5 kg has half the iron stores at birth compared with a 3.

• In preterm it occurs earlier and last longer with a nadir 7-8 g. . • Treatment with vit.Anaemia of prematurity (2) Haemolysis: • Due to vitamin E deficiency. lowest Hb occurs between 6 –10 weeks when it falls to 10-11 g/dl. • In term. E may reduce the extent of late anemia of prematurity.

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. . • Recombinant human erythropoietin. • Blood transfusion 10ml/kg if Hb < 8 g or if symptomatic. • Elemental iron 1-2 mg/kg is recommended until age 12 months of age.

Anemia base on Hematocrit – indication for blood transfusion • • • • Hct < 35 + ventilated Hct <30 + on Oxygen Hct <25 + symptomatic Hct <20 – all babies .

Haemorrhage (3) .

lung or bowel – Haemorrhagic disease of newborn .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.

abdomen. . • Investigations include:– – – – – – Haemoglobin and haematocrit Blood group Cross match blood Kleihauer’s test Coagulation studies Ultrasound cranium. stools for blood.Management of Haemorrhage • Clinical assessment for shock and hypovolaemia.

Haemorrhagic Disease of Newborn .

Australia. Vitamin K isolated from alfalfa by Dam and Doisy (Nobel Prize. 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. 1942).History • Townsend in Boston (1864) described 50 cases of “hemorrhagic disease of the newborn” during first 2 weeks of life • In 1929. Canada. New Zealand and others . ACOG. and conducted clinical trials showing Vitamin K protects against HDN • 1961.

Haemorrhagic disease of newborn • Early • Classical – due to deficiency of vitamin K dependent clotting factors • Late onset .

(Factors II.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.5 to 17. 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 2.0 per thousand newborns not given vitamin K prophylactically .

Haemorrhagic disease of newborn • Classical haemorrhagic disease of the newborn is due to deficiency of vit. • Decline due to routine IM vitamin K at birth. • Vitamin K is produced by bacterial flora of the gut which there is little production during first week of life. .K dependent clotting factors.

Late HDN • Between 2-12 weeks of life.000 live births . • Especially in breast-fed babies.2/100. • 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.

Common Clinical Manifestations • Bleeding in the – gastrointestinal tract – urinary tract – umbilical stump – nose – scalp – intracranial hemorrhage – Shock – death .

– Differentiate by APT’s Test. • Occurs late in first week of life esp to breastfed infant.Clinical features: • Spontaneous bleeding usually GIT. • Umbilical bleeding or postcircumcision. • DD from bleeding due to swallow blood. .

• 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 . and by the American College of Obstetricians and Gynecologists since 1961.American Academy of Pediatrics 1961 • Prophylactic use of Vit K recommended by the American Academy of Pediatrics.

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. .

. 1 mg im or iv • Blood transfusion if indicated.Treatment • Vitamin K1.

Canada. Australasia and Middle East • HDN and vit K deficiency reported in both developed and developing countries where it is not routinely used.Renewed Interest in Vit K • Since the 1980s attention – UK. Japan. 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 . Europe.

Germany. 1988 . UK • Routine prophylactic Vitamin K for newborns adopted in – Canada – Australia – New Zealand – Croatia.Other Countries • Still not routine in Japan.

500 in all infants • Of these.g. Singapore and Taiwan • Thailand reports incidence of 35-72/100.700 in breast fed babies and 1:4.Public Health Importance • Japanese incidence of HDN reported as 1/1.000 births • ICH not always identified as HND related and may be significant factor in birth-related cerebral palsies . India. 82% were reported to have intracranial hemorrhage (ICH) • NDN still significant. Thailand. even more in developing countries e.

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. inexpensive preventive procedure that should be mandatory component of newborn care.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. .5-1.

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) + Mother’s antibodies Fetal RBC = destruction .

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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 . 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.Pathophysiology • Although transfer of maternal antibodies is good.

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 .

Due to:– Fetomaternal transfusion.Rhesus Haemolytic Disease • This occurs because the mother’s immune system has been sensitized by rhesus-positive cells from her fetus. . – 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 .

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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 .

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

Given to all rhesus-negative mum who gave birth to rhesus-positive infants within 72 hours.Prevention of Rh Haemolytic Disease • Anti-D gamma globulin 100-200 ug. . • Also given to at-risk rhesus negative mum after abortion or after amniocentesis esp if Kleihauer test shows a fetomaternal transfusion.

a maternal sample is screened within 1 hour of delivery (rosette test) .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.

Diagnosis & Management • • • • • Serologic Testing (mother & newborn) Amniocentesis and Cordocentesis Intrauterine Transfusion Early Delivery Phototherapy & Newborn Transfusions .

• Also if there is a previous infant affected and exchange transfusion was done. an amniocentesis may be indicated. • Amniocentesis is commonly done at 30-32 weeks. • If present.Management during pregnancy • Routine testing of rhesus antibodies. and previous stillbirth. .

• Using spectrophotometric technique at wavelength of 450nm. • The optical density difference between patient’s amniotic fluid and normal amniotic fluid at specific gestational age is plotted on the Liley chart .Management during pregnancy • Assessment of bilirubin in liquor amnii. • This is the region of maximal bilirubin absorption.

Liley chart (Liley. • Also it help obstetrician to plan the delivery. • If fetus severely affected and too immature to deliver. . 1961) • Provides guidelines for severity of rhesus isoimmunization. treatment and expected cord blood haemoglobin. 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 .

. And platelet and total Serum Bilirubin.Management of the rhesus immunized infant • The infant should be assessed for maturity.ascites… • Placenta send for pathology examination. .DCT.pallor. jaundice. Hb. • Cord blood taken for HB.

Hydrops fetalis Cord bilirubin > 85umol/L Rapidly rising bilirubin crossing the level for exchange transfusion. .Indications for immediate/early exchange transfusion • • • • Cord haemoglobin < 8 g/dl. • Strong positive Coombs’ test.

. and tansfusions. Thrombocytopenia and DIC. Complications of exchange transfusion. Hypoalbuminaemia and lung oedema. Hyaline membrane disease. Inspissated bile syndrome.Complications of rhesus incompatibility • • • • • • • • Kernicterus and bilirubin encephalopathy. Anaemia: Folic acid. Beta cell hyperplasia leading to hypoglycaemia.

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.B in addition to having IgM anti-A and anti-B . the mother is type O and the child has the A or B antigen…Why? – Group O individuals have a high titer of IgG antiA.

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. infants may present with mild anemia or normal hemoglobin levels – Most infants will have hyperbilirubinemia and jaundice within 12 to 48 hours after birth . so there is less destruction by maternal antibodies – When delivered.

Late anemia is seldom a problem.Clinical features • • • • • Jaundice first 24 hours of life No hepatosplenomegaly Kernicterus unusual. Hydrops occasionally being reported. .

perform elution to ID antibody . Rh and DAT performed – Most cases will have a positive DAT • If DAT positive.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.

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. • Immune anti-A or anti-B may be elicated from fetal RBCs or cord blood. • Blood smear may show features of haemolysis.

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. • Due to deficiency of enzyme within RBC which render cells more susceptible to haemolysis. • Heterozygote female may manifest mild disease. . • Many variants to conditions.

quinine Nitrofurantion Sulphonamides Nalidixic acid Naphthalene Chloramphanicol Vitamin K (large doses) Fava beans (kachang parang/itek) .primaquine.Drugs that may cause haemolysis in infants with G6PD deficiency • • • • • • • • Antimalarials .

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. .

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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. – Coombs’ test and full blood count. – Kleihauer’s test. – 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). • Blood viscosity depends largely on packed cell volume. • Viscosity much more greater in small vessels than large vessels. during the first week. • Not equal to hyperviscous. • 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 .

apnoea.hypocalcemia. • Cardiovascular – Congestive heart failure. thrombocytopenia.pulmonary hypertension with Right to left shunting and cyanosis. • Neurological – Jitteriness. . • Gastrointestinal .Clinical features • Infants look plethoric.convulsions.NEC • Renal – renal vein thrombosis • Others: hypoglycaemia. jaundice.

Management • Anticipation • At risk infants haemotocrit should be measured. . • Symptomatics infants with venous PCV of 65-70% may require dilutional exchange transfusion. • Infants without symptoms but haematocrit > 70% should have a 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 .

. • Bruising.Clinical features • Bleeding from umbilical or venepuncture sites. 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 .

Analogous to Rh isoimmunization. • Platelets transfusion or exchange transfusion may be needed in severe cases. • Mother has normal platelet count. • Newborn may have severe thrombocytopenia but is transient.Isoimmune thrombocytopenia • Rare condition. . • Transfusion of fetal A1 antigen-positive platelets into maternal circulation may produce maternal IgG antibodies if the mother is platelet A1 antigen negative.

Maternal ITP • Due to transplacental maternal antibodies. . • Intracerebral bleed may occur before onset of labour. • Steroids and IVIG had been advocated for treatment. • Blood transfusion or platelet may be required if PC < 20. • Mother may have thrombocytopenia and the lower mum platelets count the more severe affected the infant is.000.

Causes of thrombocytopenia • Neonatal drug exposure – Thiazide diuretics – Quinine – Sulphonamides • • • • • • DIC TAR syndrome Kasabach Merritt syndrome Fanconi’s anaemia Leukaemia Pancytopenias .

V.VIII and fibrinogen.Disseminated Intravascular Coagulation (DIC) • DIC an acquired coagulation disorder charaterized by intravascular consumption of platelets and clotting factors II. • 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.

• Inherited disorders of coagulation – Haemophilia A (Factor VIII def) – Chrismas disease (Factor IX def) .Others coagulation disorders • Immaturity of clotting factors secondary to liver immaturity.