Author
Aimee M. Barton, MD
Assistant Professor
Department of Pediatrics
Division of Neonatology
Georgetown University Medical Center
Washington, DC
Disclosure: Aimee M. Barton, MD, has disclosed no relevant financial relationships.
Editor
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Reviewer
Bruce Buehler, MD
Professor, Department of Pediatrics, Pathology and Microbiology
Executive Director, Hattie B. Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Omaha, Nebraska
Disclosure: Bruce Buehler, MD, has disclosed no relevant financial relationships.
You are working in a community hospital when you are informed that a nurse in postpartum is concerned because a baby's "color looks off" (shown). You examine the infant and note that her face appears very yellow, as does her upper body. Upon further questioning, you discover that the infant is twin B of a dizygotic-diamniotic gestation born via caesarean section at 37 weeks due to maternal preeclampsia. Image courtesy of the Centers for Disease Control and Prevention.
Which of the following pieces of additional information would be most helpful to you?
A. Maternal prenatal labs, including blood type
B. Maternal age
C. Infant's birth weight
D. Infant's intake and output status
Answer: A. Maternal prenatal labs, including blood type.
You request the maternal prenatal labs, including blood type. You find the mother is a gravida 2, para 1 mother with blood type O positive, with all other lab results normal. The nurse also informs you that the mother's first child spent 3 days in the neonatal intensive care unit. The infant is now 8 hours old.
You request that the nurse obtain all of the following labs EXCEPT:
A. Serum bilirubin level
B. Blood culture
C. Blood type
D. Direct antiglobulin test
Answer: B. Blood culture.
The nurse obtains blood for blood type and direct antiglobulin test in addition to a serum bilirubin level, and reports the above results to you 1 hour later.
According to the American Academy of Pediatrics' (AAP) Clinical Practice Guideline[1] for the management of hyperbilirubinemia, appropriate treatment of this infant may include all of the following EXCEPT:
A. Intensive phototherapy
B. Supplementation of breastfeeding
C. Frequent monitoring of the bilirubin level
D. Waiting to repeat the level at 24 hours of life
Answer: D. Waiting to repeat the level at 24 hours of life.
You place the infant in an incubator and start intensive phototherapy. You explain to the mother that her infant is jaundiced. She states that her first baby was also jaundiced and spent 3 days in the neonatal intensive care unit. She tearfully asks why this keeps happening to her babies. Image courtesy of Wikimedia Commons.
You explain this as:
A. Some babies just get jaundiced and there is no reason for it
B. It is because the baby is reacting to the breast milk she is feeding
C. The baby most likely has an enzyme deficiency that does not allow her to break down the bilirubin molecule appropriately
D. Because of the difference in the mother's and the baby's blood type, the infant has antibodies in her system that are causing her to produce bilirubin at a faster rate than normal
Answer: D. Because of the difference in the mother's and the baby's blood type, the infant has antibodies in her system that are causing her to produce bilirubin at a faster rate than normal.
Despite intensive phototherapy and supplementation of breast feeding with up to 30 mL of formula every 3 hours, 4 hours later you find that the bilirubin level has increased to 15 mg/dL (previously 12 mg/dL). The infant appears lethargic and her hematocrit is now 30%. Due to the rate of increase and the significant level of jaundice in this late preterm infant with risk factors, you decide an exchange transfusion is warranted. Photo courtesy of Jayashree Ramasethu, MD, Georgetown University Medical Center.
All of the following statements regarding exchange transfusion are correct EXCEPT:
A. Exchange transfusion is warranted in any infant with early signs of acute bilirubin encephalopathy
B. Exchange transfusion is indicated in infants with alloimmune hemolytic disease of the newborn to correct severe anemia and hyperbilirubinemia
C. Exchange transfusion may be contraindicated in an unstable patient
D. Donor blood prepared after birth should be negative for the antigen responsible for hemolytic disease and should be cross-matched against the infant's blood
E. The volume of blood needed for an exchange transfusion is 80 mL/kg birth weight
Answer: E. The volume of blood needed for an exchange transfusion is 80 mL/kg birth weight.
Jaundice occurs in nearly every newborn infant in varying degrees and is termed physiologic jaundice. This represents the normal transition of bilirubin clearance from the maternal/placental circulation to the neonatal liver. Jaundice develops because of increased production of bilirubin due to the breakdown of fetal erythrocytes in combination with decreased clearance by the liver. In physiologic jaundice, increased erythrocyte breakdown results from the shorter lifespan of fetal erythrocytes and the higher red blood cell mass in newborns, while low levels of glucuronyl transferase and ligandin decrease conjugation in the liver. Pathologic jaundice results from exploitation of either of these 2 mechanisms.
Bilirubin is the end product of red blood cell breakdown and occurs through a series of oxidative reactions. Approximately 75% is derived from hemoglobin. Bilirubin is relatively water insoluble and is transported in the plasma tightly bound to albumin. Binding increases postnatally with age and is reduced in sick infants. A small fraction of unconjugated bilirubin circulates unbound, and this free portion is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity. In the fetus, bilirubin freely crosses the placenta and is excreted by the mother. Image courtesy of Jayashree Ramasethu, MD, Georgetown University Medical Center.
When bilirubin reaches the liver, it is transported into a liver cell and binds to ligandin. The concentration of ligandin is low at birth and increases rapidly over the first few weeks of life. It is then bound to glucuronic acid in the endoplasmic reticulum by the uridine diphosphoglucuronyltransferase (UDPGT) enzyme. This conjugated molecule is water soluble and can be excreted into bile. The production of UDPGT is low at birth and rises steadily over the first 4-8 weeks of life. Once excreted into the bile, the molecule is further degraded by microbes in the colon and excreted; however, some deconjugation does occur in the small intestine, and this unconjugated molecule can be reabsorbed into the enterohepatic circulation, increasing the total plasma bilirubin. This is an important factor in neonatal jaundice due to the limited nutrient intake in the first few days of life, which prolongs intestinal transit time and allows for increased reabsorption. Image courtesy of Jayashree Ramasethu, MD, Georgetown University Medical Center.
The AAP has formalized algorithms for the management of the newborn in the nursery with jaundice. Establishment of a screening procedure for every newborn is necessary to prevent cases of severe jaundice and its complications. The AAP guideline also provides multiple indications for obtaining bilirubin value measurements, as shown in the table. In this patient with rapidly rising bilirubin, blood typing with a direct antiglobulin test is recommended to determine if blood group incompatibility exists.
Blood group incompatibility occurs when a mother is either Rh negative, or type O, and the infant is either Rh positive or type A or B. In Rh-negative women, prior sensitization to the Rh molecule (previous Rh-positive fetus, fetal procedures such as chorionic villous sampling) leads to the formation of Rh antibodies. All women with type O blood have blood type A and B antibodies. Antibodies can cross the placenta and attach themselves to the red blood cell membrane of the fetal cells, resulting in increased breakdown. Cases related to Rh incompatibility can be severe, especially if a mother has had multiple pregnancies that put her at risk for exposure to the Rh antigen. This severity can increase with each subsequent pregnancy and erythroblastosis fetalis can result. The worst manifestation is hydrops fetalis, in which excess accumulation of fluid can lead to spontaneous abortion or severe postnatal complications, including subcutaneous edema and pleural effusions (arrows).
On the basis of the measured bilirubin level and the hour of life, an infant can be placed into a specific "risk zone" for the development of severe hyperbilirubinemia using the nomogram above. This nomogram was developed by Bhutani and colleagues and is based on data from 2840 well newborns at 35 or more weeks' gestation. By plotting the infant's bilirubin measurement on the nomogram vs hour of life, one can determine the risk that an infant will have subsequent "severe hyperbilirubinemia" and make an informed decision on when to follow up these measurements.[1] In our infant, the serum bilirubin level of 12 mg/dL at 8 hours and 15 mg/dL at 12 hours is plotted on this nomogram (black circles). It is clear that this infant falls significantly into the high risk-zone for development of severe hyperbilirubinemia.
Risk factors for severe hyperbilirubinemia are listed in the table above, and they are divided into major and minor risk factors. Note that this case involves an infant with multiple risk factors, including:
• Serum bilirubin in high risk-zone;
• Jaundice in first 24 hours;
• Blood group incompatibility with positive direct antiglobulin test;
• Gestational age of 37 weeks; and
• Exclusive breastfeeding (although the infant was not old enough for significant weight loss to have occurred).
Understanding the major risk factors for severe hyperbilirubinemia is an important task for the clinician caring for newborns. Even if an infant does not warrant phototherapy at a specific point in time, the presence of multiple risk factors should prompt close follow up.
Multiple other conditions can lead to jaundice in the newborn. Breastfeeding jaundice occurs in exclusively breastfed infants when physiologic jaundice is exaggerated by decreased nutrient intake and dehydration in the first few days of life. Breast milk jaundice usually occurs in the first week of life and is due to the presence of certain factors in breast milk that increase enterohepatic circulation of bilirubin. The clinician faced with workup of a jaundiced infant should measure the direct or conjugated portion of the total bilirubin. Conjugated hyperbilirubinemia of more than 20% of the total, or greater than 2.0 mg/dL, is abnormal, and suggests more serious possibilities, such as biliary atresia, infection, cholestasis, inborn errors of metabolism, galactosemia, and hypothyroidism.
The decision to initiate phototherapy can be based on a nomogram adapted from the 2004 AAP guidelines. The infant's bilirubin level is plotted against the age in hours. The top (solid) line is the phototherapy threshold for a term (38 weeks or greater gestation), healthy infant. The middle line (long dashed) is the threshold for term infants with risk factors (hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin ≤ 3.0 g/dL), or healthy infants aged 35-37 weeks. The lowest line (short dashed) is the threshold for infants aged 35-37 weeks with risk factors. Infants born at less than 35 weeks are not included. In this infant with a gestational age of 37 weeks and blood group incompatibility, the lowest line should be used. Plotting the bilirubin level of 12 mg/dL at 8 hours of life (red dot) indicates that phototherapy should be used.
Phototherapy works based on 3 distinct reactions that occur when bilirubin is exposed to light. Phototherapy induces photo-oxidation, which bleaches bilirubin. However, this is a slow process and has minimal therapeutic effect. Phototherapy also induces configurational isomerization, which changes the bilirubin into water-soluble isomers allowing increased excretion in bile and urine. Photoisomers develop in as little as 15 minutes of phototherapy. Finally, phototherapy induces structural isomerization resulting in the formation of lumirubin, which can be readily excreted via bile.
The decision to initiate exchange transfusion can be based on an additional nomograph adapted from the 2004 AAP guidelines. The infant's bilirubin level is plotted against age of life using the same risk stratification as the phototherapy guidelines. In this infant, the bilirubin level of 15 mg/dL at 13-14 hours of life (red dot) is plotted above the lowest line, indicating that exchange transfusion should be considered. Based on the fact that the infant was less active and the bilirubin level was rapidly rising, an exchange transfusion is most likely the best treatment option for this infant.
Exchange transfusion is achieved by removing small aliquots of the infant's blood and replacing them with an equal volume of donor blood aliquots.[2] Indications for exchange transfusion include severe unconjugated hyperbilirubinemia, failure of phototherapy, and risk of acute bilirubin encephalopathy. Double volume exchange replaces twice the infant's total blood volume and is the most efficient way to remove bilirubin. This is usually reserved for infants with alloimmune hemolytic disease (such as in this infant). The donor cells will have a longer lifespan and are free of maternal antibodies in the plasma. To calculate the volume of donor blood, the infants blood volume should be doubled. The blood volume for term infants is approximately 80-85 mL/kg, and 100-120 mL/kg for preterm infants. Photo courtesy of Jayashree Ramasethu, MD, Georgetown University Medical Center.
The risks of exchange transfusion must be balanced against the risk of severe hyperbilirubinemia, namely kernicterus. For exchange transfusion, the risk for death or permanent sequelae is as high as 12% in sick infants, but less than 1% in healthy infants. Potential complications include apnea and bradycardia in preterm infants, hypocalcemia, thrombocytopenia, metabolic acidosis, and vascular spasm.[2]
An MRI of a patient with chronic bilirubin encephalopathy (kernicterus) is shown, revealing the classic symmetric high-intensity signal in the globus pallidus (arrows). What are the symptoms of acute bilirubin encephalopathy?
A. Lethargy, poor feeding, high-pitched cry
B. Opisthotonus, seizures
C. Hearing loss, intellectual impairment
D. Athetoid cerebral palsy, paralysis of upward gaze
Answer: A. Lethargy, poor feeding, high-pitched cry.
Acute bilirubin encephalopathy is characterized by early symptoms such as lethargy, a high-pitched cry, and poor feeding. Progressive symptoms include opisthotonus and seizures, followed by chronic and permanent symptoms of severe athetoid cerebral palsy, paralysis of upward gaze, hearing loss, and intellectual impairment. Another MRI example of kernicterus with high signal in the globus pallidus is shown (arrows).
The infant in this case did well after exchange transfusion and continued on intensive phototherapy for an additional 2 days, eventually being discharged into the care of her mother without any noted complications. All institutions and clinicians caring for newborns should have a screening protocol in place to identify newborns at risk for severe hyperbilirubinemia. Early treatment with phototherapy and exchange transfusion (if warranted) can significantly alter the course of disease in these infants because bilirubin encephalopathy is a preventable condition.
Author
Aimee M. Barton, MD
Assistant Professor
Department of Pediatrics
Division of Neonatology
Georgetown University Medical Center
Washington, DC
Disclosure: Aimee M. Barton, MD, has disclosed no relevant financial relationships.
Editor
Lars Grimm, MD, MHS
House Staff
Department of Internal Medicine
Duke University Medical Center
Durham, North Carolina
Disclosure: Lars Grimm, MD, MHS, has disclosed no relevant financial relationships.
Reviewer
Bruce Buehler, MD
Professor, Department of Pediatrics, Pathology and Microbiology
Executive Director, Hattie B. Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Omaha, Nebraska
Disclosure: Bruce Buehler, MD, has disclosed no relevant financial relationships.
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