Neonatal Jaundice HOPE. Doa'a Al Zou'bi & Nadeen Al-share'

Transcription

1 Neonatal Jaundice HOPE Doa'a Al Zou'bi & Nadeen Al-share'

2 Neonatal Jaundice Hyperbilirubinemia is a newborn hemolytic disease. Hyperbilirubinemia is a very common disease affect 60% of all term babies and 80% of all preterm. Bilirubin Metabolism RBCs Hemoglobin Heme & globin ( protein ). Bilirubin is a product of heme catabolism 80% coming from hemoglobin breakdown and 20% from cytochromes metabolism. Two steps for birubin production : First step Heme [ 1 gram ] biliverdin + carbon monoxide ( CO ) By Heme oxygenase enzyme. ( carbon monoxide measurement can idicate the rate of bilirubin production) Second step Biliverdin bilirubin ( Indirect ) [ 35 gram ] by biliverdin reductase. (( One gram of hemoglobin produces 35 mg of bilirubin )) This Bilirubin has 3 distinct features : 1. Lipid soluble / Water insoluble << this limits its excretion. 2. Unconjugated / reacts as Indirect agent in Bergh test. 3. Toxic to CNS ( free bilirubin can cross the blood brain barrier ) and may cause Kernicterus. Bilirubin either to bind albumin and so become inactive, if not bind albumin ; free bilirubin become available to enter CNS. it may not bind or displaced by drug as sulfisoxazole.

3 In hepatocyte ; bilirubin bind to Ligandin (cytoplasm liver protein ) in a process called Conjugation by UDP- glucuronsyltransferese enzyme giving Bilirubin Diglucuronid (direct). Bilirubin Diglucuronid has 3 district features : 1. Water Soluble. 2. Conjugated / reacts as Direct agent in Bergh test. 3. Excreted in bile and urine. Most of Bilirubin Diglucuronid excreted in bile then to small intestine and by the effect of gut microflora converted to Sterobilinogen that excreted in stool and give it dark color, and to Urobilinogen which excreted in urine. This excretion limit the bilirubin reabsorption. Intestinal mucosa have glcorunodase enzyme, this enzyme deconjugate some direct bilirubin, this result in indirect bilirubin which can reabsorbed by intestinal cells and go to circulation again, this called enterohepatic cirulation. Direct bilirubin can`t be absorbed by intestinal cells ** Any problem in any of these steps will lead to elevation of bilirubin level ( Hperbilirubinemia ) / Jaundice Clinical Manifestation : Jaundice may be present at birth or may appear at any time during the neonatal period Cephalocaudal progression. Dermal pressure can help to reveal the anatomic progression of jaundice Clinical examination cannot be depended on to estimate serum levels especially in babies with dark skin. Jaundice from deposition of indirect bilirubin in the skin tends to appear bright yellow or orange. Jaundice (yellowish discoloration of skin and sclera ) appear on physical exam when TSB is 5 mg/dl in newborns Conjugated ( Direct ) Vs. un conjugated ( indirect ) : Unconjugated Hyperbilirubinemia

4 Hemolysis present Blood group incompatibility Hemolysis absent Physiologic jaundice (common cause ) Infections(sepsis ) RBC enzyme defect Hemoglobinopathy RBC membrane disorders breast milk jaundice Polycythemia Internal hemorrhage Hypothyroidism gilbert and crigler najjar syndrome stenosis pyloric Conjugated Hperbilirubinemia Common Uncommon TORCH Infection Cystic Fibrosis Neonatal hepatitis Biliary Atresia Sepsis Inborn Error of Metabolism Hperalimentation cholestasis (parenteral nutrition ) Alpha one Antitrypsin deficiency result of : 1. Increased RBCs mass, so increase bilirubin production. 2. Shortened RBC life span to instead of 120 days.

5 3. Hepatic immaturity of lingandin & glucuronosyl transferase. 4. Increase enterohepatic circulation of bilirubin due to absence of anerobic flora in the neonatal intestine. 5. More in Greek and Asian infants. - Maximum intensity by 4th-5th day in term & 7th day in preterm Clinical picture : 1. Visible jaundice appearing after 24 hours of age ( NOT in the first day ) - Serum level less than 15 ( peak ) ** past lec. 2. (NELSON ) Peak Indirect bilirubin level of no more than 12 mg/dl on day 3 of life. ( direct hyperbilitubinemia always pathological ) * in preterm the peak is 15mg/dl in the 5 th day. * in breast milk fed is 15-17mg/dl, higher in breast milkfed infants than in formula-fed infants because of decreased fluid intake. 3. Disappearance without treatment by 7 th or 10 th day of life 4. Total bilirubin rises by < 5 mg/dl (86 mmol/l) per day Clinical Picture : 1. Occur in the 1 st 24 hours 2. Persist for more than 14 days. 3. Bilirubin level is rising at greater rate than 0.5 mg/dl. 4. Peak is more than 13 mg/dl in term infant. 5. There are signs of underlying illness ( ex : anemia, hepatosplenomegaly ). 6. Dark urine and caly ( acholic ) stool. Result of :

6 Pathological Unconjugated Hypebilirubinemia Overproduction of bilirubin Decrease rate of conjugation Hemolytic causes High reticylocyte count Non-hemolytic Nr. reticylocyte count * Crigle-Nijjar * Gilbert * Hypothyroidism?? 1- Immune- Mediated + direct antibodies ( DAT, coomb ) test 1- Extravascular : Cephalohematoma, intracranial hemorrhage,extensive brusing 2- Non-Immune - direct antibodies ( DAT, coomb ) test 3- pt. with bacterial & viral sepsis. 2- Polycythemia 3- Exaggarated enterohepatic circulation : Bowel obstruction, fuctional ilius 4- Breast milk associated

7 1- Decrease Rate of conjugation : Crigle-Najjar Syndrome Rare & serious inherited form of nonhemolytic jaundice. UDPGT deficiency: Crigler-Najjar syndrome type I (complete deficiency, autosomal recessive) and type II (partial deficiency, autosomal dominant). Autosomal dominant form respond to phenobarb ( which increase enzyme activity ), autosomal recessive form does not respond to phenobarb. Both are rare but can cause sever unconjugated Hperbilirubinemia, bilirubin encephalopathy & death if untreated. Liver transplantation is curative. Gilbert Disease Is due to mutation of the promotor region of UDPGT, lead to dec. hepatic UDPGT activity, result in mild unconjugated hyperbilirubinemia. 2- Over production of bilirubin : Hemolytic Causes : 1- Antibody-me v diated hemolysis (Coombs test positive) a. Rh Isoimmunization The fetus is Rhesus positive and the mother Rhesus negative. The mother have been sensitized in a previous pregnancy by the passage of fetal red blood cells into her circulation, either at delivery or during a threatened miscarriage. Most Rh-negative women have no anti-rh antibodies at the time of their first pregnancy,,,so usually it is a disease of a second & subsequent pregnancies. It increases in severity with each immunized pregnancy because of increased maternal IgG antibody production. Most Rh disease can be prevented by treating the mother during pregnancy or promptly (within 72 hours) after childbirth,,, by

8 giving the mother an intramuscular injection of anti-rh antibodies (Rho(D) Immune Globulin), by this the fetal Rhesus D positive erythrocytes are destroyed before her immune system can discover them. Neonates are often anemic at birth, and hemolysis rapidly causes hyperbilirubinemia and more severe anemia. The most severe form of Rh isoimmunization, erythroblastosis fetalis, is characterized by life-threatening anemia, generalized edema, and fetal or neonatal heart failure. Without antenatal intervention, fetal or neonatal death may result. The cornerstone of antenatal management is transfusion of the fetus with Rh-negative cells, either directly into the umbilical vein or into the fetal abdominal cavity. Phototherapy is usually started in these infants upon delivery, with exchange transfusion given if needed. Intravenous immune globulin (IVIG; g/kg) given to the infant as soon as the diagnosis is made decreases the need for exchange transfusion. Ongoing hemolysis occurs until all maternal antibody is gone; therefore, these infants require monitoring for 2 3 months for anemia severe enough to require transfusion. Most Rh disease can be prevented by giving high-titer Rho (D) immune globulin to the Rh negative woman after invasive procedures during pregnancy or after miscarriage, abortion, or delivery of an Rh-positive infant. b. ABO blood group incompatibility ** This finding can accompany any pregnancy in a type O mother. Hemolysis is usually mild, but the severity is unpredictable because of variability in the amount of naturally occurring maternal anti-a or anti-b IgG antibodies. Because many mothers who have blood group O have IgG antibodies to A and B before pregnancy, the firstborn infant of A or B blood type may be affected. In contrast to Rh disease, ABO hemolytic disease does not become more severe with subsequent pregnancies. Hemolysis with ABO incompatibility is less severe than hemolysis in Rh-sensitized pregnancy, either because the anti-a or anti-b antibody may bind to nonerythrocytic cells that contain A or B antigen or because fetal

9 erythrocytes have fewer A or B antigenic determinants than they have Rh sites. With the declining incidence of Rh hemolytic disease, ABO incompatibility has become the most common cause of neonatal hyperbilirubinemia requiring therapy-currently accounting for approximately 20% of clinically significant jaundice in the newborn. " Causes : Environmental exposure Anti-A and anti-b antibodies are usually IgM and do not pass through the placenta, but some mothers "naturally" have IgG anti-a or IgG anti-b antibodies, which can pass through the placenta. Exposure to A-antigens and B-antigens, which are both widespread in nature, usually leads to the production of IgM anti-a and IgM anti-b antibodies but occasionally IgG antibodies are produced. Fetal-maternal transfusion Some mothers may be sensitized by fetal-maternal transfusion of ABO incompatible red blood and produce immune IgG antibodies against the antigen they do not have and their baby does. For example, when a mother of genotype OO (blood group O) carries a fetus of genotype AO (blood group A) she may produce IgG anti-a antibodies. The father will either have blood group A, with genotype AA or AO, or more rarely, have blood group AB, with genotype AB. Blood transfusion It would be very rare for ABO sensitization to be caused by therapeutic blood transfusion as a great deal of effort and checking is done to ensure that blood is ABO compatible between the recipient and the donor. " WIKI 2- Non-immune hemolysis ( comb test negative ) Abnormal red cell shapes: spherocytosis, elliptocytosis, pyknocytosis, stomatocytosis.

10 Red cell enzyme abnormalities: glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, hexokinase, deficiency, other metabolic defects. Breast milk jaundice Breast fed jaundice Breast Milk Jaundice Jaundice related to milk nature. The etiology of breast-milk jaundice attributed to the presence of glucuronidase in breast milk,which increase enterohepatic circulation Unconjugated hyperbilirubinemia without evidence of hemolysis in the 1 st and 2 nd weeks of life. Bilirubin levels rarely increase to more than 20 mg/dl. Interruption of breastfeeding for 1 to 2 days results in a rapid decline of bilirubin levels, which do not increase significantly after breastfeeding resumes but, Generally mild and does not require intervention it should be monitored to ensure it remains uncongujated and does not increase. Breast feeding can continue with expectation of resolution by 12 weeks. If the diagnosis of breast milk jaundice is made there is no need to stop breast feeding routinely, if the TSB level is low.but if the TSB reach levels which needs treatment ( phototherapy ) the physician should consider stopping breast milk feeding. Although uncommon, kernicterus can occur in patients with breastmilk jaundice. Breast Fed Jaundice Jaundice related to feeding technique

11 Occurs in 1 st few days. Baby is not having enough feeding, so increase dehydration, decrease bowel motion and increase enterohepatic circulation. Treated by increase feeding frequency or using bottle feeding. Remember : Jaundice of the 1 st day of life is always pathological. Lab investigations for unconjugated hyperbilirubinemia : 1. TSB (total Serum Bilirubin) if more than 5mg/dl of 1 st To convert from Micromol to dl : micromole = dl/17. day of life, we depend on it to determine if we need therapy and which type of therapy needed. Values in mg/dl or micromol/l ; then do : 2. Blood typing 3. CBC ( complete blood cell count ) 4. Blood film 5. Coombs test & Reticulocyte count ( for hemolytic anemia). Diagnosis : Total serum Bilirubin ( TSB). Transcutaneous measurement of bilirubin. ETCO, end tidal carbon monoxide. Visible jaundice with a TSB greater than 5 mg/dl before 24 hours of age is most commonly a result of significant hemolysis. Or internat hemorrhage. Evaluation of Hyperalbuminemia Because most newborns are discharged at hours of age, before physiologic jaundice peaks and before maternal milk supply is established, a predischarge TSB or a transcutaneous bilirubin measurement (TcB) may help predict which infants are at risk for severe hyperbilirubinemia. In all infants, an assessment of risk for severe hyperbilirubinemia should be performed before discharge. Risk Factors for Development of Severe Hyperbilirubinemia in Infants of 35 or More Week's Gestation : Jaundice observed in the first 24 h

12 Blood group incompatibility with other known hemolytic disease (G6PD deficiency) Gestational age wk Previous sibling received phototherapy Cephalohematoma Exclusive breastfeeding, if nursing is not going well and weight loss is excessive. Management of UnConjugated Hyperbilirubinemia Phototherapy An effective and safe method for reducing indirect bilirubin levels, particularly when initiated before serum bilirubin increases to levels associated with kernicterus. In term infants, phototherapy is begin when indirect bilirubin levels are between mg/dl. Phototherapy is initiated in premature infants when bilirubin is at lower levels, to prevent bilirubin from reaching high concentration necessitating exchange transfusion. Blue lights and white light are effective in reducing bilirubin levels, light must be in range of nm wavelength baby, but being away from baby by 20cm By that Bilirubin transformed into isomers that are water soluble and easily excreted. Complication of phototherapy : 1. Water loss, diarrhea, dehydration. 2. Macular rash. 3. Retinal damage. 4. Lethargy. 5. Skin bronzing noted in direct jaundice. 6. Separation between the infant and his mother. Exchange Transfusion

13 Usually is reserved for infants with dangerously high indirect bilirubin levels who are at risk for kernicterus. As a rule of thumb, a level of 20mg/dl for indiect reacting bilirubin is the exchange number for infant with hemolysis who weigh more than 2000g. Asymptomatic infant with physiological or breast milk jaundice may not require exchange transfusion unless the indirect bilirubin level exceed 25 mg/dl. The exchangeable level of indirect bilirubin for other infants may be estimated by calculating 10% of the birth weight in grams: the level in an infant weighing 1500 g would be 15 mg/dl. Infants weighing less than 1000 g usually do not require an exchange transfusion until the bilirubin level exceeds 10 mg/dl. The exchange is performed through an umbilical venous catheter placed in the inferior vena cava, the level of serum bilirubin immediately declines after the exchange to levels that are half of those before the exchange. Complication of exchange transfusion : 1. Related to blood (transfusion reaction, metabolic instability, infections) 2. Related to catheter (vessel perforation, hemorrhage) 3. Related to procedure (Hypotension). IV albumin In case of sever hypoalbumenemia IV Ig ( Intravenous immunoglobulin ) Decrease the need of exchange transfusion in ABO & Rh hemolysis unresponsive to double phototherapy,, because it reduce hemolysis. ( Dose g/kg/dose repeat in 12 hrs) Note : double phototherapy means usage of two sources of light 1. Over-head light source.

14 2. Fiber-Optic blanket directly on skin. Metaloporphyrin Inhibit heme oxygenase enzyme. Data on efficacy, toxicity, and long-term benefit are currently being evaluated Never physiological, always pathological. Not neurotoxic because conjugated bilirubin can't pass the BBB. Signifies serious underlying disorders involve : cholestasis or hepatocellular injury. Investigations for conjugated hyperbilirubinemia : 1. Unconjugated bilirubin ( more than 20% of total serum bilirubin ). 2. Liver enzyme. 3. Metabolic screening test as ; congenital hypothyroidism and galactosemia. 4. Hepatic ultrasound. 5. Sweat chloride test. Treatment of unconjugated hyperbilirubinemia : Not phototherapy nor Exchange transfusion, instead treat the underlying cause Kernicterus Kernicterus, or bilirubin encephalopathy, is a neurologic syndrome resulting from the deposition of unconjugated (indirect) bilirubin in the basal ganglia and brainstem nuclei.

15 Lipid soluble, unconjugated, indirect bilirubin fraction is toxic to the developing CNS, occur when indirect bilirubin concentration are high and exceed the binding capacity of albumin. Kernicterus result when indirect bilirubin is deposited in brain cells and disturbs neuronal metabolism and function, especially in the basal ganglia. Indirect bilirubin may cross the BBB because of its lipid solubility. Usually it dose NOT develop in term infant when bilirubin level are less than mg/dl, but the incidence increases as serum bilirubin level exceed 25mg/dl. Kernicterus may be noted at bilirubin level less than 20mg/dl in the presence of sepsis, meningitis, hemolysis, asphyxia, hypoxia, hypothermia, bilirubin displacing drug, prematurity, other risk factors for kernicterus in term infant and hemolysis jaundice noted within 24 hours of birth. Kernicterus has developed in extremely immature infant weighing less than 1000g when bilirubin levels are less than 10mg/dl ; because more permeable BBB associated with prematurity. Clinical Feature Early signs of kernicterus ( noted after day 4 of life ), include : 1. Lethargy, drowsiness, irritability. 2. Poor moro reflex, Poor feeding. 3. High pitched cry and emesis may also be present. Early signs of kernicterus occasionally may be reversed by immediately instituting an exchange transfusion Later signs include : 1. Bulging fontanel. 2. Opisthotonic posturing. 3. Pulmonary Hemorrhage 4. Fever. 5. Hypertonicity. 6. Seziure. Root Causes for Kernicterus by AAP A Hospital discharge before 48 hours of life

16 No early follow up (especially for infants born at 35 to 37 weeks gestational age) Failure to check the bilirubin in Jaundiced infant in the first 24hr Failure to recognize the presence of risk factors for hyperbilirubinemia CASE : a pt. 20 day old has jaundice,, Take History : Postnatal history 1) Onset ( if in first 24 hr of life or appear after the 7 th day it suggests pathological process ), and progression 2) Loss of stool color ( obstructive jaundice ) 3) Breastfeeding, oral intake, activity (dehydration and low caloric intake increase bilirubin level, decrease activity suggest sepsis ) 4) Greater than average weight loss (>8%) 5) Maternal blood group, Gestational age 6) Infections or fever, General activity 7) Medications? (newborn or mother) e.g sulfa drugs can displace bilirubin from its binding site on albumin. 8) Symptoms or signs of metabolic disease (eg, galactosemia) (direct) 9) Symptoms or signs of hypothyroidism Family History 10) Previous sibling with neonatal jaundice. 11) Other family members with jaundice Anemia or splenectomy or known heredity for hemolytic disorders 12) Liver disease History of pregnancy & delivery 13) Maternal illness suggestive of viral or other infection 14) Maternal drug intake 15) Delayed cord clamping 16) Birth trauma with bruising 17) Results of newborn screening tests (if done ) Important physical examination you should do :

17 In most infants, yellow color is the only finding on physical examination. General : Does the child look well or unwell? Vitals: If febrile, the newborn will require a full septic work-up. In hemolytic states, there can be an increase in heart rate and respiration rate as well as poor perfusion Growth Parameters : excessive weight loss or insufficient weight gain may point to dehydration Head and neck : look for pallor and jaundice,look for cephalohematoma or bruising Cardiovascular : Severe haemolytic processes can result in heart failure. Abdomen: Check for hepatomegaly and splenomegaly. Neurologic: Level of consciousness,posture, Ant.fontanel, gross motor movements, tone, primitive reflexes, quality of the cry, cranial nerves and observe for any abnormal movements what's your DDx? Timing of Jaundice and Differential Diagnosis : - Early Jaundice ( in the 1 st two days ) : usually due to acute hemolytic condition as ABO or RH incompatibility. - Jaundice between 3 rd and 10 th day : may be due to physiological jaundice, infant of diabetic mother, cephalohematoma, infection or asphyxia. - Late onset or prolonged jaundice beyond 14 days : may be due to biliary atresia, galactosemia, hepatitis, or infection Finally, the END :D Resources : Nelson, past lec., Dr.Mahdi Al Shboul's slides, current Done by your colleagues from HOPE batch / 2010 : Doa'a Samarah Al Zou'bi & Nadeen Alshare' ) ق ل ه ل ي س ت و ي ال ذ ين ي ع ل م ون و ال ذ ين ال ي ع ل م ون (