Neonatal Hyperbilirubinemia and Kernicterus

Key Points

Early clinical jaundice or rapidly developing hyperbilirubinemia is often a sign of hemolysis, the differential diagnosis of which commonly includes immune-mediated disorders, red cell enzyme deficiencies, and red cell membrane defects.
Knowledge of the maternal blood type and antibody screen is critical in identifying non-ABO alloantibodies in the maternal serum that may pose a risk for severe hemolytic disease of the newborn.
Knowledge of the hour-specific predischarge bilirubin measurement, the infant's gestational age in weeks, and hyperbilirubinemia neurotoxicity risk factors are critical to determining appropriate timely postbirth hospitalization follow-up and evaluation.
Hyperbilirubinemia in late-preterm neonates (34 ^0/7 to 36 ^6/7 weeks' gestation) is more prevalent, more pronounced, and more protracted than in their term counterparts, and these immature neonates are more vulnerable to bilirubin-induced brain injury.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a noteworthy cause of bilirubin encephalopathy worldwide. Clinicians everywhere must have a high index of suspicion for G6PD deficiency in neonates whose genetic heritage derives from Africa, the Middle East, the Mediterranean region, and Asia.

Hyperbilirubinemia

Hyperbilirubinemia is the most common clinical condition requiring evaluation and treatment in the newborn, and a frequent reason for hospital readmission during the first week of life. Although generally a benign, postnatal, transitional phenomenon, some neonates develop marked, potentially hazardous bilirubin levels that can cause serious brain injury. Acute bilirubin encephalopathy (ABE) may ensue and evolve into kernicterus (chronic bilirubin encephalopathy), a permanent disabling neurologic condition classically characterized by (1) the movement disorders of dystonia and/or choreoathetosis, (2) hearing loss caused by auditory neuropathy spectrum disorders, and (3) oculomotor paresis.

Total serum bilirubin (TSB) is the measure of albumin-bound bilirubin, whereas the small circulating fraction not bound to albumin or other serum proteins is indexed by the unbound or “free” (Bf) bilirubin level. There is a keen interest in circulating Bf, its measurement, and its ability to predict bilirubin-induced neurologic injury. Indeed, Bf is the vehicle of bilirubin's biologic effects in the brain. However, bilirubin-induced neurotoxicity depends on a complex interaction between the level and duration of the central nervous system (CNS), Bf exposure, and the innate cellular characteristics of the developing CNS that may predispose or protect against bilirubin-induced neuronal injury. At present, the measurement of circulating Bf is not generally available in clinical laboratories. As a result, clinicians must rely on the TSB and the bilirubin/albumin (B/A) ratio, an imperfect surrogate of circulating Bf, to index the risk for ABE and drive treatment decisions.

The genesis of neonatal hyperbilirubinemia reflects the interplay of developmental red blood cell (RBC), hepatic, and gastrointestinal immaturities that result in an imbalance favoring bilirubin production over hepatic enteric bilirubin clearance ( Fig. 72.1 ). The equation below summarizes the interactions among the rates of bilirubin production ( a ), the enterohepatic circulation of bilirubin ( b ), and bilirubin elimination ( c ), in determining the TSB at any postnatal time point t , where TSB ₀ is the cord blood TSB.

{TSB}_{t} = {TSB}_{0} + \sum {[a (t) + b (t) - c (t)]}^{Δ t}

${TSB}_{t} = {TSB}_{0} + \sum {[a (t) + b (t) - c (t)]}^{Δ t}$

Fig. 72.1, Schematic of Bilirubin Production and Hepatic Bilirubin Clearance in Neonates.

A variety of clinical conditions can increase the bilirubin load or decrease bilirubin clearance and thereby contribute to neonatal hyperbilirubinemia in any given infant ( Box 72.1 ). In a small fraction of neonates, a constellation of conditions may lead to hazardous levels of hyperbilirubinemia that pose a neurotoxic risk. Accelerated RBC turnover (hemolysis) plays a pivotal role in increasing the risk for subsequent severe hyperbilirubinemia and in potentiating the risk of bilirubin neurotoxicity. Treatment interventions are therefore recommended at a lower bilirubin level whenever hemolysis is present.

Box 72.1

Causes of Indirect Hyperbilirubinemia in Neonates

A. Increased Hepatic Bilirubin Load

1.
Hemolytic disease—immune mediated (positive direct Coombs test)
- a.
  Rhesus isoimmunization
- b.
  ABO incompatibility
- c.
  Minor blood group incompatibility
2.
Hemolytic disease—red blood cell enzyme abnormalities
- a.
  Glucose-6-phosphate dehydrogenase deficiency
- b.
  Pyruvate kinase deficiency
3.
Hemolytic disease—red blood cell membrane defects
- a.
  Hereditary spherocytosis
- b.
  Elliptocytosis
- c.
  Stomatocytosis
- d.
  Pyknocytosis
4.
Hemolytic disease—hemoglobinopathies
- a.
  Alpha-thalassemia
- b.
  Gamma-thalassemia
5.
Extravascular blood (e.g., cephalohematoma)
6.
Polycythemia
7.
Enhanced enterohepatic bilirubin circulation
- a.
  Intestinal obstruction, pyloric stenosis
- b.
  Ileus, meconium plugging, cystic fibrosis
- c.
  Breast-milk feeding

B. Decreased Hepatic Bilirubin Clearance

1.
Prematurity including late-preterm gestation
2.
Hormonal deficiency
- a.
  Hypothyroidism
- b.
  Hypopituitarism
3.
Impaired hepatic bilirubin uptake
- a.
  Patent ductus venosus
- b.
  SLCO1B1 gene polymorphisms
4.
Disorders of bilirubin conjugation— UGT1A1 gene variants
- a.
  Crigler-Najjar syndrome type I
- b.
  Crigler-Najjar syndrome type II (Arias disease)
- c.
  Gilbert syndrome
5.
Enhanced enterohepatic circulation
- a.
  Intestinal obstruction, pyloric stenosis
- b.
  Ileus, meconium plugging, cystic fibrosis
- c.
  Breast-milk feeding

SLCO1B1 , Solute carrier organic anion transporter 1B1; UGT1A1 , uridine diphosphate glucuronosyltransferase 1A1.

Increased Hepatic Bilirubin Load: Hemolytic Disease

The causes of hemolysis in the neonatal period can be broadly grouped into five major categories: (1) abnormalities in red cell membrane structure, (2) red cell enzyme defects, (3) hemoglobinopathies, (4) acquired causes of hemolysis, and (5) immune-mediated mechanisms (see Box 72.1 ).

Red Cell Membrane Defects

Of the many red cell membrane defects that lead to hemolysis, only hereditary spherocytosis, elliptocytosis, stomatocytosis, and infantile pyknocytosis manifest themselves in neonates. Establishing a diagnosis of these disorders is often difficult because newborns normally exhibit a marked variation in red cell membrane size and shape. Spherocytes, however, are not often seen on RBC smears of hematologically normal newborns, and when prominent, suggest a diagnosis of hereditary spherocytosis, as does an elevated mean corpuscular hemoglobin concentration (MCHC >36.5 to 37 g/dL) or MCHC to mean corpuscular volume (MCV) ratio (MCHC/MCV >0.36). Given the likelihood of autosomal dominant inheritance, a positive family history can often be elicited. The diagnosis of hereditary spherocytosis can be confirmed using the incubated osmotic fragility test coupled with fetal red cell controls or eosin-5-maleimide flow cytometry. Symptomatic ABO hemolytic disease must be excluded by performing a direct Coombs test, as affected infants can manifest prominent microsphero-cytosis. Moreover, hereditary spherocytosis and symptomatic ABO hemolytic disease can occur in the same infant and result in anemia and severe hyperbilirubinemia.

Hereditary elliptocytosis and stomatocytosis are rare but reported causes of hemolysis in the newborn period. Infantile pyknocytosis is a transient red cell membrane abnormality manifesting itself during the first few months of life. The pyknocyte, an irregularly contracted red cell with multiple spines, can normally be observed in premature infants, whereas many as 5% of red cells may manifest this morphologic variant. In newborns affected with infantile pyknocytosis, however, up to 50% of red cells may exhibit the morphologic abnormality with anemia that may necessitate transfusion, and hyperbilirubinemia that can be severe enough to require control by exchange transfusion. Whatever the mechanism underlying infantile pyknocytosis, the disorder tends to resolve after several months of life. Pyknocytes may also occur in other conditions, including glucose-6-phosphate dehydrogenase (G6PD) deficiency and hereditary elliptocytosis, and these must be excluded before a diagnosis of infantile pyknocytosis is made.

Red Cell Enzyme Deficiencies

The two most common red cell enzyme defects that can lead to hyperbilirubinemia in the neonatal period are G6PD deficiency and pyruvate kinase deficiency. Of these, pyruvate kinase (PK) deficiency is far less frequent. PK deficiency is an autosomal recessive disorder largely confined to populations in which consanguinity is prevalent, including newborns of Amish descent and other isolated communities. Pyruvate kinase deficiency often presents with anemia, reticulocytosis, and severe hyperbilirubinemia. A full third of affected infants require exchange transfusion to control their hyperbilirubinemia, and kernicterus is a real risk. The diagnosis of pyruvate kinase deficiency is often difficult, as the enzymatic abnormality is frequently not simply a quantitative defect but may involve abnormal enzyme kinetics or an unstable enzyme that decreases in activity as the red cell ages. The diagnosis of pyruvate kinase deficiency should be considered whenever marked hyperbilirubinemia and a picture of nonspherocytic, Coombs negative hemolytic anemia is observed.

Glucose-6-Phosphate Dehydrogenase Deficiency

G6PD deficiency is an X-linked enzymopathy affecting hemizygous males, homozygous females, and a subset of heterozygous females (via X chromosome inactivation). G6PD deficiency is an important cause of hazardous hyperbilirubinemia and kernicterus worldwide, including the United States. Although most prevalent in Africa, the Middle East, East Asia, and the Mediterranean, G6PD deficiency has evolved into a global neonatal problem as a result of past and present migration patterns, the transatlantic slave trade, and intermarriage. The condition is a noteworthy contributor to endemic rates of bilirubin encephalopathy in several developing countries and accounts for a substantial and disproportionate number of neonates with kernicterus in the United States Pilot Kernicterus registry (20.8% of all reported cases). The majority of these kernicterus cases have been in African-American neonates, an at-risk population—given that the G6PD deficiency prevalence rates in the United States are 12.2% for African-American males and 4.1% for African-American females. Other subgroups at risk for G6PD deficiency include newborns of East Asian, Greek, Italian (especially Sardinia and Sicily), and Middle Eastern descent.

G6PD is remarkable for its genetic diversity (230 variants have been described), and the mutations seen in the United States include among numerous others (1) the African A variants, a group of double-site mutations, all of which share a mutation in codon 126 (376A>G) known as G6PD A (which expressed alone is a nondeficient variant) coupled most commonly with the 202G>A mutation (202G>A;376A>G, known as G6PD A− ) but on occasion with the 968T>C variant (968T>C;376A>G; also known as G6PD Betica ), or the 680G>T mutation (680G>T;A376G); (2) the Mediterranean (563C>T) mutation; (3) the Canton (1376G>T) mutation; and (4) the Kaiping (1388G>A) variant.

G6PD is critical to the redox metabolism of red blood cells. G6PD deficiency can result in acute severe neonatal hemolysis following exposure to oxidative stress, possibly even the stress accompanying perinatal transition to the extrauterine environment. Reported hemolytic triggers in G6PD deficiency are outlined in Box 72.2 . A sudden, often rapid exponential rise in TSB to potentially hazardous levels may occur and result in kernicterus that may not always be preventable. Severe jaundice rather than anemia may predominate in the clinical presentation. In some neonates, G6PD deficiency and the hepatic uridine diphosphate-glucuronosyltransferase 1A1 gene ( UGT1A1 ) polymorphisms of Gilbert syndrome (that limit hepatic bilirubin conjugation) combine to significantly increase the risk of hyperbilirubinemia. Kaplan et al. have demonstrated a dose-dependent genetic interaction between the UGT1A1*28 promoter variant and G6PD deficiency that substantially increases neonatal hyperbilirubinemia risk. Details regarding this icterogenic genetic interaction and other aspects of UGT1A1 gene variants in neonates are described later under Hepatic Bilirubin Conjugation. Coexistent nongenetic factors may also impact hyperbilirubinemia risk in G6PD-deficient neonates, as shown in those who are also late-preterm and breastfed.

Box 72.2

Agents Reported to Produce Hemolysis in Patients With Glucose-6-Phosphate Dehydrogenase Deficiency

Adapted from Oski FA, Naiman JL. Hematologic Problems in the Newborn , 2nd ed. Philadelphia, PA: WB Saunders; 1972 and updated from Valaes F. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl . 1994;394:58–76, and Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Blood . 2020;136(11):1225–40.

Antimalarials

Pamaquine
Pentaquine
Plasmoquine
Primaquine
Quinacrine
Quinine
Quinocide
- Tafenoquine

Sulfonamides

Sulfacetamide
- Sulfadiazine
Sulfamethoxazole/cotrimoxazole
Sulfanilamide
Sulfamethoxypyridazine
Sulfapyridine
- Sulfasalazine
Sulfisoxazole
Trisulfapyrimidine

Sulfones

Nitrofurans
Furaltadone
Furazolidone
Nitrofurantoin
Nitrofurazone
Thiazolesulfone

Antipyretics and Analgesics

Acetophenetidin
Acetylsalicylic acid
Aminopyrine
Antipyrone
p -Aminosalicylic acid

Others

Ascorbic acid
Chloramphenicol
Chloroquine
- Ciprofloxacin
Aniline dyes
Dimercaprol
- Dimercaptosuccinic acid
- Dapsone-containing combinations
Fava beans
- Glibenclamide (glyburide)
- Henna (cosmetic use)
Methylene blue
- Moxifloxacin
- Nalidixic acid
Naphthalene (used in mothballs)
Naphthoquinones (used in mothballs)
- Niridazole
- Norfloxacin
- Ofloxacin
Paradichlorobenzenes (moth repellent, car freshener, bathroom deodorizer)
Phenylhydrazine
- Phenazopyridine
Probenecid
Quinidine
- Rasburicase and pegloticase
- Sulfonylureas
- Tolbutamide
- Tolonium chloride (toluidine blue)
Vitamin K analogs
Menadiol sodium phosphate

Infection

Sepsis
Urosepsis
Necrotizing enterocolitis

Caretakers must have a high index of suspicion for G6PD deficiency in populations at increased risk (Mediterranean region, Africa, the Middle East, southern and southeastern Asia) who demonstrate significant hyperbilirubinemia. Although there has been discussion on the potential utility of screening for G6PD deficiency in the United States, no consensus has emerged on whether or how best to screen, and point-of-care testing during birth hospitalization is not routinely practiced. Models of point-of-care testing have demonstrated the feasibility and utility of identifying G6PD-deficient newborns. Data from other countries (e.g., Israel, Singapore, and Taiwan) show that point-of-care G6PD screening strategies are associated with reductions in the prevalence of severe hyperbilirubinemia and kernicterus.

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