8 Flashcards
Newborn bilirubin physiology (pathway)
Hgb - liver - excretion
Adult vs newborn metabolism of bike
Most (~75%) of the bilirubin produced in the healthy newborn comes from physiological breakdown of red blood cells.
Pathway
The hemoglobin released from the red cells is converted to unconjugated bilirubin that is insoluble in aqueous solutions and binds to albumin in the blood stream.
In the liver the bilirubin is extracted by the hepatocytes where it binds to cytosolic proteins and is then conjugated with glucuronide by uridine diphosphate glucuronyl transferase (UDPGT, also known as glucuronosyl transferase).
The conjugated bilirubin is water-soluble and is excreted into the bile and then into the intestine.
In adults, most of the bile is metabolized by the intestinal flora to urobilin and excreted in the stool. The newborn infant, however, lacks the gastrointestinal flora to metabolize bile, which allows the β-glucuronidase present in the meconium to hydrolyze the conjugated bilirubin back to its unconjugated form.
The unconjugated bilirubin is then reabsorbed into the blood stream where it binds to albumin.
Newborns absorb significant quantities of bilirubin through this process, known as enterohepatic circulation.
Most serious complication of unconjugated bilirubin
Sequalae 4
Surviving infants 7
Screening (Rh incompatibility)
Tx
Definition
Kernicterus is the pathological term used to describe staining of the basal ganglia and cranial nerve nuclei by bilirubin. Kernicterus also describes the clinical condition that results from the toxic effects of high levels of unconjugated bilirubin.
Sequelae
Severely affected newborn infants may:
lose the suck reflex become lethargic develop hyperirritability and seizures, and ultimately die Infants who survive may develop:
opisthotonus (abnormal posturing that involves rigidity and severe arching of the back, with the head thrown backward) rigidity oculomotor paralysis tremors hearing loss, and ataxia Screening and Treatment
In the past, kernicterus among full-term newborn infants primarily resulted from the hemolysis and subsequent unconjugated hyperbilirubinemia that was caused by Rh incompatibility (erythroblastosis fetalis). These infants typically were severely anemic, in shock and acidotic, and had total bilirubin levels well above 25 mg/dL (428 μmol/L).
Screening for Rh incompatibility and the use of anti-Rh immunoglobulin (RhoGAM®) have markedly reduced Rh-induced hemolysis and the incidence of kernicterus.
In addition, treatment of unconjugated hyperbilirubinemia with phototherapy has had an important impact on management of hyperbilirubinemia.
Greater risk of jaundice -2
Breastfed infants (B) have a greater risk of developing jaundice than do formula fed infants.
Infants born to parents with Mediterranean ancestry (e.g., Greek) (E) also have higher rates of jaundice. Both topics will be discussed later.
ABO mismatch, set up, incompatibility and hemolysis
Mismatch vs. Incompatibility vs. “Set-up”
An ABO mismatch between the mother and the infant is present in 20% of pregnancies.
ABO incompatibility occurs when the mother has blood group O, the baby has blood group A or B, and the direct Coombs test is positive.
A positive direct Coombs test occurs in about a third of pregnancies with an ABO mismatch, but only 1 in 5 of blood-type A or B infants born to blood-type O mothers develops clinically significant jaundice.
Severe jaundice in these infants is uncommon.
If the direct Coombs test is negative, the condition is often referred to as an “ABO set-up.”
Hemolysis
ABO hemolytic disease probably represents only the extreme end of the spectrum of ABO mismatched newborns. Remember that jaundice in ABO incompatibility usually appears in the first 24 hours and the direct Coombs test may be only weakly positive (or the Coombs test may be negative).
The fact that a baby is jaundiced, has ABO incompatibility, and is Coombs test positive does not always mean that the infant has ABO hemolytic disease.
One way that the red blood cells of the newborn differ from adult red cells is that newborn cells have a much lower number of reactive A or B sites.
This is why the Coombs test may be read as weakly positive in ABO hemolytic disease, and may also explain the fact that red-cell life span in infants with ABO hemolytic disease is only slightly shortened.
Knowledge that a jaundiced newborn has ABO isoimmunization and hemolysis can help management. It is probably most helpful in those infants with severe jaundice, as they would be treated more aggressively for their hyperbilirubinemia than an infant without hemolytic disease.
Etiologies of jaundice 3 and other causes
Physiologic Jaundice
This is defined as a total bilirubin level ≤ 15 mg/dL (≤ 257 μmol/L) in full-term infants who are otherwise healthy and have no other demonstrable cause for elevated bilirubin.
Almost all newborn infants have hyperbilirubinemia, but it is benign and self-limited.
Physiologic jaundice in a full-term baby is usually first noticed on the second or third day of life, with the bilirubin level reaching its peak at day three or four of life.
Numerous factors promote the increased enterohepatic circulation that results in physiologic jaundice:
Increased bilirubin production (from the breakdown of the short-lived fetal red cells) - tissue are hypoxic before infant takes first breath Relative deficiency of hepatocyte proteins and UDPGT Lack of intestinal flora to metabolize bile High levels of β-glucuronidase in meconium Minimal oral (enteral) intake in the first 2-4 days of life, resulting in slow excretion of meconium (especially common with breastfed infants).
Jaundice Associated with Breastfeeding
Some clinicians divide this into two separate entities–breastfeeding jaundice and breast-milk jaundice. There is probably overlap, where a combination of both of these problems occurs simultaneously.
- Breastfeeding jaundice
Happens early in the first week of life and occurs when the milk supply is relatively or absolutely low, resulting in limited enteral intake.
This may be referred to as a “lack-of-breast milk jaundice” or “breastfeeding-associated jaundice.”
The low intake results in decreased gastrointestinal motility that in turn promotes retention of meconium.
The β-glucuronidase in meconium deconjugates bilirubin and the unconjugated bilirubin is reabsorbed via the enterohepatic circulation, causing an elevation of serum levels.
Breast milk production typically increases greatly once “let-down” occurs.
Occasionally, persistently low volume of breast milk can cause the neonate to become dehydrated and malnourished. Breastfeeding jaundice is often difficult to distinguish from physiologic jaundice.
2. Breast-milk jaundice
Begins in the first 4 to 7 days of life but may not peak until about 10 to 14 days.
Not the result of low breast milk volume.
While the cause is not completely understood, one explanation is that β-glucuronidase present in breast milk deconjugates bilirubin in the intestinal tract; the unconjugated bilirubin is then reabsorbed via enterohepatic circulation.
Breast-milk jaundice can persist for up to 12 weeks, but total bilirubin concentration rarely, if ever, reaches concerning levels.
The time course of breast-milk jaundice is quite different from that of physiologic jaundice.
Hemolysis In pathological processes hemolysis causes breakdown of red blood cells (RBCs). The hemoglobin released is metabolized to unconjugated bilirubin, which results in jaundice.
Antibody-positive hemolysis is labeled “direct Coombs” or “direct antibody test (DAT)” positive. The most common forms of antibody-positive hemolysis include:
Rh incompatibility (mother is Rh-negative and baby is Rh-positive) ABO incompatibility (mother is type O and baby is type A or B) Incompatibilities with minor blood group antigens (much less common) Antibody-negative hemolysis occurs in infants who have red blood cell membrane defects (e.g., spherocytosis) or red blood cell enzyme defects (glucose-6-phosphate dehydrogenase or pyruvate kinase deficiency).
Other Causes
Non-hemolytic red cell breakdown causes increased bilirubin production and development of jaundice and occurs in a variety of conditions, including:
Extensive bruising from birth trauma
Large cephalohematoma or other hemorrhage (e.g., intracranial)
Polycythemia
Swallowed blood (large amounts) during delivery.
Metabolic errors
Crigler-Najjar syndrome: hyperbilirubinemia results from decreased bilirubin clearance caused by deficient or completely absent UDPGT.
Galactosemia and hypothyroidism also have jaundice as prominent clinical findings.
These congenital disorders are detected by neonatal screening.
Ethnicity
Hyperbilirubinemia is more common in Asian newborn infants than in Caucasian infants and is less common in black infants.
These additional factors can also contribute to hyperbilirubinemia:
Prematurity
Bowel obstruction
Birth at high altitude
Evaluation of cause of hyperbilirubinemia 5
The following information is all necessary in determining the cause of hyperbilirubinemia:
Age at which jaundice begins
Can help determine the risk for severe hyperbilirubinemia and can direct you to specific causes of jaundice, especially hemolysis.
Weight history
Breastfed infants may lose up to 7–10% of their birth weight during the first 4 to 5 days of life and typically regain birth weight by at least 2 weeks of age.
A more rapid weight loss in the first days after birth or delayed weight gain mandates further assessment and intervention.
Inadequate weight gain indicates a potential insufficient fluid and calorie intake making a diagnosis of breastfeeding jaundice more likely.
Feeding history
Aids in distinguishing among possible causes of jaundice.
Pregnancy history
Maternal infections may affect the fetus in utero, resulting in congenital infection and intrauterine growth restriction (IUGR).
The consequence may be a newborn who is born small for gestational age (SGA) with risk of direct hyperbilirubinemia.
Signs of illness in the newborn
It is important to inquire about fever or other signs of illness in jaundiced newborns because septic infants can have jaundice (with elevated total and direct bilirubin) as one sign of serious infection, along with other clinical manifestations, such as:
Temperature instability Respiratory distress Apnea Irritability Lethargy Poor tone Vomiting Poor feeding When jaundice is the only clinical finding, sepsis is highly unlikely as the cause of the increased bilirubin levels.
G6pd Epi Inheritance Fava beans Bilirubin
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Epidemiology
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme problem that affects red blood cell metabolism worldwide.1
Inheritance
G6PD deficiency has an X-linked recessive inheritance pattern:
Males with a mutation of the G6PD gene on the X-chromosome will have the complete enzyme deficiency.
Females must have the mutation of the G6PD gene on both X-chromosomes to be enzyme deficient, although heterozygous females will be at risk for hyperbilirubinemia.
There are more than 100 distinct enzyme variants of G6PD associated with a wide spectrum of hemolytic disease. One of these variants in Greek babies can be a cause of hyperbilirubinemia and potential kernicterus.
Fava Beans
In areas where populations are at high risk for G6PD deficiency, it is prudent to warn mothers of the dangers of eating fava beans while nursing or ingesting any drugs known to be triggers of hemolysis in G6PD deficiency.
There is also a case report of severe hemolysis (“favism”) in a newborn infant whose mother ingested fava beans before delivery.2
Decreased Bilirubin Conjugation
Infants with G6PD deficiency may also be jaundiced without anemia.
Decreased bilirubin conjugation is now thought to be the most important factor in hyperbilirubinemia with G6PD deficiency.
This is the result of a gene interaction between the G6PD deficiency and the variant promoter for the gene for the bilirubin-conjugating enzyme, UDP glucuronosyltransferase (similar to what is seen with Gilbert’s syndrome where there is a partial deficiency of this bilirubin conjugating enzyme).3
Biliary atresia symptoms
Tx
A healthy-appearing infant who develops jaundice, dark urine, and acholic (pale) stools between 3 and 6 weeks of age may have biliary atresia.
Any infant who develops jaundice after two weeks of age must be evaluated with fractionated bilirubin (i.e., total and direct bilirubin levels).
A patient suspected of having biliary atresia generally will be referred to a pediatric gastroenterologist or pediatric surgeon.
Treatment
When diagnosed early, biliary atresia can be treated surgically with the Kasai procedure (anastomosis of the intrahepatic bile ducts to a loop of intestine to allow bile to drain directly into the intestine).
If done early, the Kasai procedure will restore bile flow and prevent liver damage.
Major, minor and decsreased RF for hyperbilirubinemia
Major Risk Factors
Pre-discharge total serum bilirubin (TSB) or total conjugated bilirubin (TcB) level in the high-risk zone
Jaundice observed in the first 24 hours of life
Blood group incompatibility, with positive direct antiglobulin test
Gestational age 35-36 week
Previous sibling received phototherapy
Cephalohematoma or significant bruising
Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive
East Asian race
Minor Risk Factors
Pre-discharge TSB or TcB level in the high intermediate-risk zone Gestational age 37-38 week Jaundice observed before discharge Previous sibling with jaundice Macrosomic infant of a diabetic mother Maternal age >25 y Male gender Decreased Risk
TSB or TcB level in the low-risk zone Gestational age 41 week Exclusive bottle feeding Black race Discharge from hospital after 72 hours
Supplement exclusively breast fed babies need
400 IU of vita,in d within first 6 months of life
Physical findings that can contribute to hyperbilirubinemia 2
A cephalohematoma (see photo) is a subperiosteal hemorrhage that is localized to the cranial bone that was traumatized during delivery.
The swelling does not extend across a suture line.
As the blood is reabsorbed from the cephalohematoma it will contribute to hyperbilirubinemia.
Bruising on the head—or elsewhere on the body—from birth trauma or any other bleeding can also lead to increased bilirubin production because blood extravasated into tissues will be broken down and converted to bilirubin.
A caput succedaneum (B) is an edematous swelling over the presenting portion of the scalp of an infant.
It overlies the periosteum and the swelling crosses suture lines.
The swelling consists of serum and would not cause hyperbilirubinemia.
Diff dx for jaundice in newborn
Diagnosis Comment
Breast milk jaundice
Begins in the middle of the first week of life (usually day 4 through 7) but may not reach its peak until the second week.
Physiologic jaundice
Physiologic jaundice typically appears earlier than on day 4.
The level of hyperbilirubinemia and the time course helps to distinguish physiologic from breast milk jaundice.
Hemolysis
Possible reasons for hemolysis include:
ABO incompatibility
Rh incompatibility
G6PD deficiency
To completely investigate the possiblity of a hemolytic process you need a laboratory test (a peripheral smear).
Hypothyroidism
Typically detected by the neonatal screen.
Metabolic disease
Often children with inborn errors of metabolism—such as galactosemia or urea cycle defects—present with liver dysfunction, including jaundice, in addition to other features (like seizures, sepsis, ascites) depending on the defect.
The newborn screen can help rule out these diagnoses.
Biliary atresia
Typically presents after 2 weeks of age with progressive jaundice and acholic stools.
Causes a direct hyperbilirubinemia.
Intrinsic liver disease
Very rare cause of neonatal jaundice
Birth trauma (cephalohematoma or other bruising)
Reabsorption of blood and metabolism of red blood cells can cause jaundice.
Sepsis
While sepsis can lead to jaundice, jaundice as the only sign of sepsis is rare.
Breastfeeding offers some protection against infection, particularly early on when colostrum provides preformed antibodies, cells, and other anti-infective substances.
TORCH infection
In utero exposure to one of the TORCH infections can lead to jaundice.
Physical findings may include hepatosplenomegaly, microcephaly, and/or rash.
Gilbert syndrome
Gilbert’s syndrome (reduced activity of the enzyme glucuronyltransferase) is a relatively common cause of harmless jaundice (~5% of the population).
Final diagnosis usually does not occur until later in life, when it is found that hyperbilirubinemia persists, with no other abnormalities.
Crigler-Najjar syndrome
Due to the absence or low levels of UDP glucuronosyltransferase 1 family, polypeptide A1.
Can cause severe (type I) or mild/moderate (type II) jaundice.
Also very rare.
Evaluation of neonate with hyperbilirubinemia 10
Evaluation of Neonatal Hyperbilirubinemia
Test Indication
Maternal ABO and Rh typing and screen for unusual isoimmune antibodies
During prenatal testing, this test identifies an Rh-sensitized mother who could put the fetus at risk for Rh-isoimmune disease.
Infant (cord blood) ABO and Rh typing, and direct Coombs’ test
When mother is Rh-negative (or prenatal testing has not been done).
Saving a sample of cord blood is encouraged for future testing of blood type and Coombs’ (particularly when the mother’s blood type is Group O).
Note: A family might ask you about cord blood banking. Learn more in the AAP Policy Statement: Cord Blood Banking for Potential Future Transplantation.
G6PD screen
When the family history, the ethnic or geographic origin, or the time of the onset of jaundice suggests the possibility of G6PD deficiency (particularly if late-onset jaundice).
Similar criteria can be used to justify testing of an infant whose jaundice is caused by other specific hemolytic disorders.
Total serum bilirubin (TSB)
If jaundice is noted in the first 24 hours of life or with significant jaundice.
Direct bilirubin level and/or urine dipstick for bilirubin
Infant has dark urine or light stools.
Persistent jaundice (> 3 weeks).
Infant is ill (there will be an increased direct bilirubin with sepsis/congenital infection).
Note: Most pediatricians would order a direct bilirubin level at least once during the evaluation of an exaggerated/high level of total bilirubin.
CBC or hemoglobin level
If there is a suspicion of hemolytic disease or anemia (e.g., jaundice in the first day of life or TSB >14 mg/dL in the first 48 hours).
If anemia is found, an elevated reticulocyte count would be further evidence of hemolysis (some might obtain a reticulocyte count with the CBC).
Reticulocyte count and blood smear
Consider if infant is anemic or there is a strong clinical suspicion of hemolytic disease other than isoimmunization.
Neonatal screening
All infants need to have a neonatal screen.
There is no uniform screening program throughout the U.S.; specific disorders tested by the screen vary from state to state.
There is a movement to try to establish standards that specify the number and types of disorders that are screened.
Tests for newborn sepsis:
CBC and d ifferential cell count
C-reactive protein
Blood cultures
Lumbar puncture with chemistry and cultures
If the jaundiced infant is ill or has other clinical signs suggesting possible infection.
Jaundice as the only sign of sepsis would be rare.
Tests for congenital infections (TORCHS titres)
TORCHS titres test for congenital infections: TOxoplasmosis; Rubella; Cytomegalovirus; Herpes; and Syphilis.
Obtain if the maternal history or infant’s physical exam and clinical course suggested a congenital infection.
Signs and symptoms of untreated congenital hypothyroidism
Hypothyroidism that is not detected early in life can cause the following:
Prolonged jaundice Lethargy Large fontanelles Macroglossia (enlargement of the tongue) Umbilical hernia Constipation Abdominal distention Severe developmental delay
