Jaundice

Neonatal jaundice and Hemolytic Disease of the Newborn

Definition • Neonatal jaundice is the term used when a newborn has an excessive amount of bilirubin in the blood. • Bilirubin is a yellowish-red pigment that is formed and released into the bloodstream when red blood cells are broken down. • Jaundice comes from the French word jaune, which means yellow; thus a jaundiced baby is one whose skin color appears yellow due to bilirubin.

Description • Jaundice is the most common condition requiring medical attention in newborns • Neonatal jaundice affects 60 percent of fullterm infants and 80 percent of preterm infants in the first three days after birth.

Background • Bilirubin is formed when the body breaks down old red blood cells. The liver usually processes and removes the bilirubin from the blood. • Jaundice in babies usually occurs because their immature livers are not efficient at removing bilirubin from the bloodstream.

Neonates,however,may not appear jaundice until the serum bilirubin concentration exceeds 5.0~7.0mg/dl(119µmol/l)

Infants of East Asian and Native American descent have higher levels of bilirubin than white infants, who in turn have higher bilirubin levels than infants of African descent

Early peak

RE.system Catabolism of effete RBC

Ineffective Erythropoiesis-Bone Marrow Tissue Heme-heme protein

Heme oxygenase 75%Heme

Biliverdin

Bilirubin + serum Albumin

Enterohepatic circulation

25%Heme Biliverdin reductase

Acceptor proteins Y,Z Glucurony 1 tranferase Bilirubin glucuronide β-glucuronase Bilirubin Fecal bilirubin ,stercobilinogen

Features of metabolism of bilirubin in neonate

Chacteristic of the bilirubin metabolism in neonate Over product in bilirubin –8.8mg/kg/d,but 3.8mg in adult • •

RBC life span 80 days Shunt bilirubin-from bone marrow ,liver

Transport of bilirubin • •

Phintensively relative to the binding of albumin to bilirubin (PH>7.4) Relative lower concentration of serum album

Immaturity in metabolism in liver • •

Acceptor proteins Y,Z in lower level Lower activity of uridine diphosphoglucurony1 transferase

Enterohepatic circulation • •

Relative intestinal sterile High activity of β-glucuronase

Typing the Neonatal jaundice into Physiological and pathological states Physiological

Pathological

• Visible at 2~3 day of brith and most apparent at 4~6 day after birth • Absent after 2 and 3~4 weeks of birth for full-term and preterm infants • Total serum bilirubin <12mg/dl(205 µmol/l),<15mg/dl(257 µmol/l) • No disorders were found

• •

• • •

Clinical jaundice in first 24 h Total serum bilirubin>12~15mg/dl (205 ~257 µmol/l) or increase by 5mg/dl (85 µmol/l) a day Direct serum bilirubin >2.0mg/dl Prolonged jaundice Reocurrence of jaundice

Unconjugated hyperbilirubinemia related to patological state

Excessive production of bilirubin (hemolyis) • • • • • • • •

Blood group incompability(Rh,ABO ) RBC enzyme abnormalities Glucose-6-phosphate dehydrogenase Pyruvate kinase Sepsis RBC membrane defects Extravascular blood Polycythemia

Impaired conjugation or excretion •

Hormonal deficience(hypotyroidism)

Disorders of bilirubin metabolism • •

Criglers-najjar syndromes type1 Gribert disease

Enhanced Enterohepatic circulation • •

Intestinal obstruction Meconium plugs

Conjugated hyperbilirubinemia related to patological state Obstruction to biliary flow Hepatic cell injury • • • •

Infection Toxic Metabolic errors Chromosomal disorders

Chronic bilirubin overload • Erythroblastosis fetalis • Spherocytosis • Congenital erythropoietic porphyria

Newborn Jaundice Symptoms

Zone 1 2 3 4 5 SBR (umol/L) 100 150 200 250 >250

Risk Factors for High Bilirubin Levels • High bilirubin level prior to hospital discharge • Jaundice observed in the first 24 hours • Blood group incompatibility • Gestational age less than 37 weeks • Previous sibling received phototherapy/family history of jaundice • East Asian ethnicity • Presence of bruising or cephalhematoma • Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive (> 10% of birth weight)

Medical Treatment •Jaundice is most often treated with phototherapy. This involves placing the baby on a warmer beneath special lights.

•These lights are able to penetrate a baby’s skin and affect the bilirubin within the child. The light changes bilirubin into lumirubin, which is easily handled by the baby's body.

•Two factors help decide whether or not to start phototherapy: the age of the child and the level of bilirubin. •Younger children with higher bilirubin levels will more often require treatment. •The decision to begin phototherapy depends on the opinion of your pediatrician and on your comfort level

Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn • Hemolytic Disease of the Newborn is also called erythroblastosis fetalis. • This condition occurs when there is an incompatibility between the blood types of the mother and baby.

•hemolytic" means breaking down of red blood cells •"erythroblastosis" refers to making of immature red blood cells •"fetalis" refers to fetus

Causes • HDN most frequently occurs when an Rh negative mother has a baby with an Rh positive father. • When the baby's Rh factor is positive, like the father's, problems can develop if the baby's red blood cells cross to the Rh negative mother. • This usually happens at delivery when the placenta detaches. • However, it may also happen anytime blood cells of the two circulations mix, such as during a miscarriage or abortion, with a fall, or during an invasive prenatal testing procedure (i.e., an amniocentesis or chorionic villus sampling).

Causes • The mother's immune system sees the baby's Rh positive red blood cells as "foreign." Just as when bacteria invade the body, the immune system responds by developing antibodies to fight and destroy these foreign cells. • The mother's immune system then keeps the antibodies in case the foreign cells appear again, even in a future pregnancy. The mother is now "Rh sensitized."

Causes • In a first pregnancy, Rh sensitization is not likely. Usually it only becomes a problem in a future pregnancy with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the red blood cells, the baby can become sick. This is called erythroblastosis fetalis during pregnancy. In the newborn, the condition is called hemolytic disease of the newborn.

Causes • Although it is not as common, a similar problem of incompatibility may happen between the blood types (A, B, O, AB) of the mother and baby in the following situations: Mother's Blood Type Baby's Blood Type

O

A

B

A or B

B

A

Clinical features Babies affected by HDN are usually in a mother's second or higher pregnancy, after she has become sensitized with a first baby. Hemolysis Anemia Liver and spleen get bigger Erythroblasts Hyperbilirubinemia -Jaundice within 24or 36h after birth

During pregnancy: •mild anemia, hyperbilirubinemia, and jaundice The placenta helps rid some of the bilirubin, but not all. •severe anemia with enlargement of the liver and spleen When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected. •hydrops fetalis This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid build up in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn.

After birth: •severe hyperbilirubinemia and jaundice The baby's liver is unable to handle the large amount of bilirubin that results from red blood cell breakdown. The baby's liver is enlarged and anemia continues.

•kernicterus Kernicterus is the most severe form of hyperbilirubinemia and results from the buildup of bilirubin in the brain. This can cause seizures, brain damage, deafness, and death.

Workup CBC: •Anemia •Increased nucleated RBCs, reticulocytosis: The reticulocyte count can be as high as 40% •Neutropenia •Thrombocytopenia:

Serologic tests Indirect Coombs test and direct antibody test (DAT)

the following tests: •testing of the baby's umbilical cord blood for blood group, Rh factor, red blood cell count, and antibodies •testing of the baby's blood for bilirubin levels

•Characteristics

•Clinical aspects

•Rh

•ABO •50%

•First born •Later pregnancies

•5% •More severe

•Stillborn/hydro ps •Severe anemia

•Frequent

•Rare

•Frequent

•Rare

•Jaundice

•Moderate to severe, frequent

•Mild

•Late anemia •Frequent •Laboratory •DAT •Positive findings •Indirect •Positive Coombs test •Spherocytosis

•Rare

•No increased severity

•Rare •Weakly positive

•Usually positive •Frequent

Treatment  Specific treatment for hemolytic disease of the newborn will be determined by your baby's physician based on: • your baby's gestational age, overall health, and medical history • extent of the disease • your baby's tolerance for specific medications, procedures, or therapies • expectations for the course of the disease • your opinion or preference

Treatment During pregnancy, treatment for HDN may include: • intrauterine blood transfusion of red blood cells into the baby's circulation This is done by placing a needle through the mother's uterus and into the abdominal cavity of the fetus or directly into the vein in the umbilical cord. It may be necessary to give a sedative medication to keep the baby from moving. Intrauterine transfusions may need to be repeated. • early delivery if the fetus develops complications If the fetus has mature lungs, labor and delivery may be induced to prevent worsening of HDN.

Treatment  After birth, treatment may include: • blood transfusions (for severe anemia) • intravenous fluids (for low blood pressure) • help for respiratory distress using oxygen or a mechanical breathing machine • exchange transfusion to replace the baby's damaged blood with fresh blood

The exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery. Exchange transfusions may need to be repeated if the bilirubin levels remain high.

Phototherapy • the blue-green region (425 -490 nm) of visible light being the most effective; • Nonpolar bilirubin is converted into 2 types of water-soluble photoisomers (Lumirubin) • Decrease in bilirubin is mainly the result of excretion of these photoproducts in bile and removal via stool.

•. Indications for Phototherapy in the Term

Infant with Hemolytic Disease of the Newborn •Age •Unborn (cord blood) •<12 h •<18 h •<24 h •2-3 d

•Total Serum Bilirubin, (TSB) mg/dL •>3.5 •>10 •>12 •>14 •>15

Intravenous immunoglobulin • Intravenous immunoglobulin -- Several studies have reported success in minimizing the need for exchange transfusion in severe HDN with IVIG. It is an effective adjunct to phototherapy. • The mechanism of action appears to be related to blockage of Fc receptors in the neonatal reticuloendothelial system. • Its efficacy, however, depends on timing of administration, duration of treatment, and severity of hemolysis.

• 0.5-1 g/kg IV in first few h following birth for severe hemolysis in newborn; start infusion at rate of 0.01 mL/kg/min for 30 min, then increase q15-30min; not to exceed rate of 0.06 mL/kg/min; • if adverse reactions occur, reduce rate to a previously well-tolerated rate

Exchange transfusion • Exchange transfusion removes circulating bilirubin and antibody-coated RBCs, replacing them with RBCs compatible with maternal serum and providing albumin with new bilirubin binding sites.

• This process removes approximately 70-90% of fetal RBCs • Because most of the bilirubin is in the extravascular space, only about 25% of the total bilirubin is removed by an exchange transfusion. • Exchange transfusion is not free of risk, with the estimated morbidity rate at 5% and the mortality rate as high as 0.5% from the procedure. Apnea, bradycardia, cyanosis, vasospasm, and hypothermia with metabolic abnormalities (eg, hypoglycemia, hypocalcemia) are the most common adverse effects.

•Guidelines for Exchange Transfusion in Neonates with Hemolytic Disease •Total Serum Bilirubin (TSB), mg/dL •>20 •>18 •>17 •>15 •>13 •>9-12

•Weight, g •Healthy, >2500 •Septic, >2500 •2000-2499 •1500-1999 •1250-1499 •<1250

•The following are requirements for exchange transfusion 1.Severe anemia (Hb <10 g/dL) 2.Rate of bilirubin rises more than 0.5 mg/dL despite optimal phototherapy 3.Hyperbilirubinemia 4.Serum bilirubin/albumin ratio exceeding levels that are considered safe •Bilirubin/Albumin Ratio Above Which Exchange transfusion Should Be Considered

•Gestational Age •>38 weeks

•TSB (mg/dL) / Alb (g/dl) •7.2 •35 wk to 37 wk and 6 d •6.8

Complications  Bilirubin encephalopathy • Before the advent of exchange transfusion, kernicterus affected 15% of infants born with erythroblastosis. • Approximately 75% of these neonates died within 1 week of life, and a small remainder died during the first year of life. • Survivors had permanent neurologic sequelae and were thought to have accounted for 10% of all patients with cerebral palsy (CP).

• The mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. • low pH • A damaged blood-brain barrier

• Bilirubin has been postulated to cause neurotoxicity via 4 distinct mechanisms: • (1) interruption of normal neurotransmission (inhibits phosphorylation of enzymes critical in release of neurotransmitters), • (2) mitochondrial dysfunction, • (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and precipitates on phospholipid membranes of mitochondria), and • (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes

• The pathologic findings include characteristic staining and neuronal necrosis in basal ganglia, hippocampal cortex, brainstem nuclei (especially the auditory, vestibular, and oculomotor), and cerebellum (especially Purkinje cells). • The cerebral cortex is generally spared. About half of these neonates also have extraneuronal lesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic cells.

• Clinical signs of bilirubin encephalopathy typically evolve in 3 phases. • Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and hypertonia are observed in phase 2, and at times, the condition progresses to opisthotonus. • Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor feeding, and athetosis. The long-term sequelae include choreoathetoid CP, upward gaze palsy, sensorineural hearing loss, dental enamel hypoplasia of the deciduous teeth, and, less often, mental retardation. The abnormal or reduced auditory brainstem response (ABR) of wave I (auditory nerve) and wave II and V (auditory brainstem nuclei), depicted as decreased amplitudes, and increased interval I-III and I-V characterize phase I of early, but reversible, encephalopathy. Subtle bilirubin encephalopathy that consists of either cognitive dysfunction, isolated hearing loss, or movement disorder has been described in absence of kernicterus and better correlates with free bilirubin levels.

Complications  Late anemia of infancy • Infants with significant hemolytic disease often develop anemia in the first month of life and frequently (50%) require packed RBC transfusion. • The anemia appears to be due to suppression of fetal erythropoiesis from transfusion of adult Hb during intrauterine or exchange transfusion, resulting in low erythropoietin levels and reticulocyte count. • Administration of recombinant human erythropoietin (rhEPO) has been shown to minimize the need for transfusion in these newborns.

Prevention • Fortunately, HDN is a very preventable disease. • Because of the advances in prenatal care, nearly all women with Rh negative blood are identified in early pregnancy by blood testing. If a mother is Rh negative and has not been sensitized, she is usually given a drug called Rh immunoglobulin (RhIg), also known as RhoGAM. This is a specially developed blood product that can prevent an Rh negative mother's antibodies from being able to react to Rh positive cells. Many women are given RhoGAM around the 28th week of pregnancy. After the baby is born, a woman should receive a second dose of the drug within 72 hours.