Differential diagnosis of neonatal jaundices. Hemolytic disease of newborn. Lecturer: Sakharova Inna.Ye., M.D., Ph.D.

Lecture plan: 1.Classification of neonatal jaundices. 2.Evaluation of jaundice severity. 3.Principles of the newborns management of different types of jaundices. 4.Complications of neonatal jaundices. 5.Treatment of neonatal jaundices. 6.Hemolytic disease of the newborn

Neonatal jaundice (jaundice of newborns) – appearance of a yellowish coloration of the skin, sclerae and/or mucouses of the infant because of serum bilirubin level increase.

Classification of jaundices: I. In general jaundice should be distinguished on: physiological pathological.

II. According to the time from birth there are:  Early jaundice (< 36 hours of age)  always pathological  usually due to haemolysis, with excessive production of bilirubin  babies can be born jaundiced with  o very severe haemolysis  o hepatitis (unusual)  causes of haemolysis (decreasing order of probability) o ABO incompatibility o Rh incompatibility o sepsis

 Rare causes  red cell enzyme defects e.g. G6PD deficiency  red cell membrane defects, e.g., hereditary spherocytosis

- Physiological (appears after 36 hours of age, usually on the 3-5 th day, lasts up to 14-th day of life) Total serum bilirubin concentration doesn’t exceed 205 mkmol/L (12 mg/dL). This type of jaundice can be complicated and uncomplicated, that is why observation and bilirubin level control are very important. Nota bene – 1 mg/dL of bilirubin = 17,1 mkmol/L of bilirubin

 Prolonged (protracted) jaundice is present after 14 days of life in term newborns and after 21 days of life in premature infant. breast milk jaundice (diagnosis of exclusion, cessation of brest feeding not necessary) continued poor milk intake haemolysis infection (especially pre-natal) hypothyroidism

 Late jaundice which appears after 7-th day of life. It is necessary to perform careful inspection of the newborn to find the reason of this jaundice.

Differential diagnostic of jaundices CriterionType of jaundice Conju- gated Hemo- lytic Mecha nical Parenchy- matous Appearance2-3-rd day1-st day1-2-nd week End of the 1-st week Hepatosple- nomegaly —+Gradu- ally + StoolYellowColouredAcholicColoured or light UreaLight yell.ColouredDark  Bilirubin Indirect DirectBoth;direct Anemia,re- ticulocytosis + —+ —

Estimation of the risk of severe hyperbilirubinemia development (Bhutani).

Kramer scale (jaundice appearance stages) Zone12345 TSB mg/L > 146

Criteria of the “dangerous” jaundice of newborns (WHO, 2003) Age of newborn (in hours) Localization of jaundice Conclusion 24Any“Dangerous” jaundice 24-48Extremities (zone 4) > 48Feet, wrists (zone 5)

The reasons of physiological jaundice (transient jaundice) are: increased production (1 gram of hemoglobin produces 35 mgr of bilirubin when hemolysed) decreased uptake and binding by liver cells decreased conjugation ( low activity of glucuronil transferase) decreased excretion increased enterohepatic circulation of bilirubin

Principles of the management of patient with physiological jaundice Clinical features Appears not earlier than end of the second day of life, is present in the 1-2 zones only Active baby Liver and spleen not enlarged Light-yellow uria, normal urination, coloured stool Examination and treatment Transcutaneous bilirubinometry (level of skin bilirubin Adequate brest feeding Further observation for the child

Principles of the management of patient with complicated physiological jaundice Clinical features Appears not earlier than end of the second day of life, is present in the 3-4 zones May be worsening of newborn’s state Liver and spleen may be enlarged Light-yellow urine, normal urination, coloured stool Examination and treatment In normal newborn’s state Estimate TSB level Decide fototherapy necessitivity Adequate brest feeding Further observation for the child In worsening of newborn’s state Immediate phototherapy

Principles of the management of patient with early or “dangerous” jaundice To start phototherapy immediately To estimate total and conjugated serum bilirubin concentration Baby's blood group, direct antiglobulin (Coombs') test (detects antibodies on the baby's red cells), and elution test to detect anti-A or anti-B antibodies on baby's red cells (more sensitive than the direct Coomb's test) Full blood examination, looking for evidence of haemolysis, reticulocytes level, unusually-shaped red cells, or evidence of infection

Principles of the management of patient with prolonged (protracted) and late jaundices Examination and treatment To estimate total and conjugated serum bilirubin concentration (TSB and CSB) In hepatomegaly to estimate AlT, AsT Adequate brest feeding Further observation for the child Immediate hospitalization in the case of: Worsening of newborn’s state TSB > 11,7 mg/dL CSB > 1,9 mg/dL (> 20 % of TSB) Liver or spleen enlargement Dark urine and/or acholic stool

Toxic action of unconjugated bilirubin in full- term newborns appears in mg/dL(in premature newborns – in mg/dL), it can lead to the bilirubin encephalopathy and kernicterus. Kernicterus is a preventable neurologic disorder caused by newborn jaundice that can result in cerebral palsy, mental development retardation, auditory processing problems (AN), gaze and vision abnormalities, and dental enamel hypoplasia.

Bilirubin staining of brain tissue

In newborns with jaundice there are specific clinical signs, which can appear in bilirubin encephalopathy. The early symptoms of brain injury are poor feeding, decreased alertness, alteration of muscle tone, and a high-pitched cry. Later symptoms of bilirubin toxicity include shrill cry, inability to feed, mild or deep stupor, abnormal or uncoordinated movements, and seizures.

Risk Factors for High Bilirubin Levels: Blood group incompatibility Gestational age less than 37 weeks Previous sibling received phototherapy/family history of jaundice East Asian ethnicity Presence of bruising or cephalohematoma Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive (> 10% of birth weight)

Risk factors for kernicterus appearance: Asphyxia Acidosis Prematurity Acute hemolysis Not effective therapy of jaundice Hypoalbuminemia.

American Academy of Pediatrics recommendations for healthy term newborns (TSB, mg/dL) Age, hours Consider photo- therapy Photo- therapy Exchange transfusion if intensive photothe- rapy fails Exchange transfu- sion and intensive photother apy  12  15  20   15  18  25  30 > 72  17  20  25  30

There are several types of phototherapy: - fiber-optical (using of special matress or diaper), - classic (ultra-violet lamps), - spotted (local) - intensive. Intensive phototherapy suggests at least two sources of light: photomattress and lamp.

Intensive phototherapy should produce a decline of TSB of 1-2 mg/dl within 4-6 hours, and the TSB level should continue to fall. If this doesn’t occur, it’s considered a failure of phototherapy.

Hemolytic disease of the newborn (HDN, erythroblastosis fetalis)  Common causes for HDN - Rh blood group incompatibility - ABO blood group incompatibility  Uncommon causes  - Kell system antibodies presence  Rare causes - Duffy system antibodies presence

Clinical types of HDN: Icteric type is the most frequent type of jaundice. Clinical feature is jaundice of skin and mucoses. Anemic type is present in % of newborns. Diagnostic criteria are paleness, HB level <120 g/L, haematocrit < 40% in birth. Hydropic type (hydrops foetalis) is the most severe type, approximately always is connected with Rh blood group incompatibilitiy. Clinical features are generalized edemas and anemia in birth. Mixed type.

HDN diagnosis criteria: 1. Family history of hemolitic disease. 2. Generalized edemas, HB level <120 g/L, haematocrit < 40% in birth, reticulocytosis 3. Onset of jaundice before 24 hours, positive direct antiglobulin (Coombs') test. 4. Level of unconjugated bilirubin in umbilical blood > 2,9 (50 mkmol/L) mg/dL, bilirubin rise in serum > 0.5 mg/dL/hour (> 8,55 mkmol/L). 5. Changes in peripheral smear (microspherocyrosis, anisocytosis, terget cells).

This photograph shows normal RBCs, damaged RBCs, and immature RBCs that still contain nuclei.

Principles of the management of the newborn with hemolytic disease To start phototherapy immediately To estimate total and conjugated serum bilirubin concentration (TSB and CSB) To decide exchange blood transfusions necessitivity according to special tables In the case of intensive phototherapy fails after 4-6 hours to performe exchange blood transfusions (under the control of TSB according to special tables)

Indications for exchange blood transfusions in term babies with HDN FactorsIndexes Level of total bilirubin level in umbilical blood > 80 mkmol/L Bilirubin rise in serum (during phototherapy) - Rh incompatibility - ABO incompatibility ≥ 7 mkmol/L ≥ 10 mkmol/L Anemia in the first day of life Нb  100 g/л, Ht <35%

Indications for exchange blood transfusions in term babies with HDN continuation FactorsIndexes Ratio of TSB (mkmol/L) and albumin (g/L) depending on the weight of baby < 1250 g g g g > 2500 g Bilirubin mkmol/L Albumin g/L 6,8 8,8 10,2 11,6 12,2

In the case of Rh blood group incompatibility can be used Rh negative blood of the same group (with baby) or Rh negative packed red cells О (I) in the plasma of AB (IV). In the case of ABO blood group incompatibility can be used the Rh same (with baby) packed red cells О (I) in the plasma of AB (IV). In the case of both of Rh blood group incompatibility and ABO blood group incompatibility can be used Rh negative packed red cells О (I) in the plasma of AB (IV).