Definition
Jaundice
Jaundice (as distinct from hyperbilirubinemia) relates to the yellow color produced in the sclera, skin, and subcutaneous tissues by deposition of bilirubin in those sites.
Not all jaundiced newborns are necessarily hyperbiliru-binemic.
Visual assessment of jaundice is an inaccurate way of determining whether a baby is actually hyperbilirubinemic, especially in a premature infant.
Hyperbilirubinemia
In term infants, hyperbilirubinemia is frequently defined as a serum total bilirubin (STB) concentration >95th percentile on the hour-specific bilirubin nomogram.
In preterm infants, in contrast, there are no clear definitions of normal or physiologic bilirubin levels and hence of hyperbilirubinemia. The reasons for this are multifold.
Almost all preterm infants develop some degree of jaundice during the first postnatal days.
There are dynamic changes in STB levels during this period.
The significance of the jaundice with regard to bilirubin neurotoxicity may increase with decreasing gestational age.
Phototherapy is used frequently in these infants, thereby moderating STB values and preventing these from reaching natural peaks.
Practical definitions
For practical purposes in the preterm infant in the intensive care setting, we suggest the following, based on the indications for phototherapy and exchange transfusion:
Moderate hyperbilirubinemia: Includes any STB level meeting accepted criteria for phototherapy
Severe hyperbilirubinemia: Regarded as any STB meeting or exceeding the indications for exchange transfusion
Incidence
Almost all premature infants develop some degree of increased STB concentration that may cause jaundice and, in some instances, hyperbilirubinemia.
In the absence of specific criteria for hyperbilirubinemia, the incidence of the condition is difficult to determine.
The majority of premature infants <1.5 kg birthweight will meet phototherapy requirements during the first postnatal week.
Pathophysiology
Physiology of bilirubin metabolism
The physiology of bilirubin is similar in the premature and term infant.
Bilirubin formation
Red blood cells are continually being broken down in the reticuloendothelial system and replaced. This process releases heme, which is catabolized by the enzyme heme oxygenase 1 to biliverdin and thence to bilirubin. This form of bilirubin is called unconjugated or indirect bilirubin. Bound to serum albumin the bilirubin is transported to the liver.
Bilirubin conjugation and elimination
After uptake into the hepatocyte, unconjugated bilirubin is glucuronated to form water soluble mono- and diglucuronides, known as conjugated or direct bilirubin. The enzyme controlling the conjugation process is UDP-glucuronosyltransferase 1A1 (UGT). Direct bilirubin is excreted via bile to the bowel from which it is excreted from the body.
Genetic control of bilirubin conjugation
The enzyme UGT1A1 is encoded by the gene UGT1A1. This gene contains a noncoding promoter region and a coding region. Polymorphisms of the promoter region, such as the (TA)n polymorphism, result in diminished expression of a normally formed enzyme and are associated with Gilbert syndrome. Coding area mutations result in an abnormally structured enzyme with no or little conjugating ability, such as is seen in Crigler-Najjar syndrome.
Enterohepatic circulation
In the newborn bowel, conjugated bilirubin may be unconjugated by the enzyme ?-glucuronidase and reabsorbed into the bloodstream, thereby adding to the bilirubin pool and straining the already deficient bilirubin conjugating and elimination capacity. Delay in enteral feeding may diminish intestinal motility, thereby decreasing elimination via the bowel and allowing for even greater reabsorption of bilirubin.
Significance of the serum total bilirubin
The hallmark of hyperbilirubinemia is, by definition, an increase in the STB. The STB at any point in time reflects a balance between bilirubin production or the enterohepatic circulation, on the one hand, and bilirubin elimination, including uptake into the hepatocyte, conjugation, and excretion, on the other. As long as there is equilibrium between these processes, the STB should not increase to dangerous levels. Imbalance between bilirubin production and elimination, with bilirubin production exceeding the liver’s ability to cope with the increased load, may upset the equilibrium, resulting in hyperbilirubinemia, which may at times become extreme. A high degree of heme catabolism, or hemolysis, is not essential for hyperbilirubinemia to develop. A combination of even moderately increased hemolysis in combination with excessively immature UGT activity due to extreme prematurity or genetic conditions affecting expression of the UGT gene, as in Gilbert syndrome, may be sufficient to tip the balance.
Bilirubin binding to serum albumin and unbound bilirubin
All important to the pathophysiology of bilirubin neurotoxicity is the ability to bind bilirubin to serum albumin. As long as bilirubin is bound, it is not expected to cross the blood-brain barrier and enter the brain. Should the albumin binding sites be saturated and the bilirubin unable to bind, unbound, or free, bilirubin will result. This fraction of unbound bilirubin is that which is thought to be able to enter the brain cells and cause neurotoxic damage. Target cells in the brain include the basal ganglia and auditory nerve tissue. The clinical features of bilirubin neurotoxicity reflect bilirubin deposition in these tissues.
Causes of unbound bilirubin formation: Unbound bilirubin may be formed if there is an excess of total unconjugated bilirubin or if the serum albumin concentration is low. Binding of bilirubin to albumin may be diminished in the presence of
Metabolic acidosis
Hypothermia
Sepsis
Drugs such as sulfa-containing antimicrobials
Premature infants are thought to have bilirubin that binds more weakly to serum albumin than in term counterparts.
Bilirubin metabolism in the premature infant
Heme catabolism
As in term infants, the turnover of the premature RBC is more rapid than in adults and the RBC lifespan is shorter. A relatively large heme load, therefore, contributes to the bilirubin pool.
Bilirubin conjugation in the preterm infant
An important contributor to hyperbilirubinemia in the preterm infant is immaturity of UGT. In term infants, activity of UGT is only about 1% that of adults; in preterm infants, it is even less active. UGT immaturity is actually the bottleneck of bilirubin catabolism and elimination in the preterm infant and the reason why almost every preterm has some degree of visible jaundice during the first days or weeks following delivery.
Risk factors
Risk factor assessment for hyperbilirubinemia
Whereas it is extremely important in the term infant, who will be discharged within a day or two of birth and whose peak in STB will occur postdischarge, to consider risk factors predictive of subsequent hyperbilirubinemia, this process is of lesser importance in the preterm infant who will remain hospitalized and the peak in STB will occur while under close medical and nursing supervision. Furthermore, and especially in very small and unstable babies, blood testing will be frequently performed and an STB measurement can easily be included in the routine blood work of these babies.
Etiology of hyperbilirubinemia
Determination of the etiology of hyperbilirubinemia in the preterm infant is important and should be attempted.
Identify hemolytic conditions, as these may exacerbate the risk of bilirubin neurotoxicity and warrant earlier institution of therapy.
Etiologic conditions causing hyperbilirubinemia in the preterm do not differ substantially from those contributing to hyperbilirubinemia in the term infant.
Major and commonly occurring causes of hyperbilirubinemia in both infant groups can be divided broadly into those increasing bilirubin production and those diminishing bilirubin elimination.
A summary of the more important or commonly occurring causes of hyperbilirubinemia can be found in Table 19-1.
Clinical presentation
Signs and symptoms
Jaundice and its potential for acute bilirubin encephalopathy are the features of hyperbilirubinemia expected during the NICU phase of the preterm infant.
The clinical hallmark of hyperbilirubinemia in any infant, term or preterm, is the appearance of a yellow color to the sclera, skin, and mucus membranes.
In term infants, jaundice progresses in a cephalocaudal direction, but it is not clear whether this progression occurs in premature infants as well.
In the NICU setting, the presence of clinical jaundice should be used as an indication to sample blood for STB determination, but visual assessment should not be used to estimate the degree of jaundice.
Acute bilirubin encephalopathy
The clinical features of acute bilirubin encephalopathy have been well described in term and late-preterm infants.
It is not clear whether this clinical picture is frequently seen in preterm infants. In the preterm infant, pathological evidence of bilirubin infiltration into the brain at postmortem may be found even in the absence of prior severe hyperbilirubinemia or clinical signs of acute bilirubin encephalopathy.
In term infants, the early (and sometimes reversible) phases present with lethargy and diminished feeding. Hyper- and hypotonia may alternate, the former resulting in arching of the back and opisthotonus, both classic features of bilirubin encephalopathy in term infants. Downward deviation of the eyes (“sunsetting”) may be followed by fever, seizures, and death.
In preterm infants, some features of acute bilirubin encephalopathy, including variations in tone and apnea, may be attributed to, or confused with, the clinical picture frequently seen in small premature infants but unrelated to hyperbilirubinemia. In addition to clinical signs seen in term infants, apnea and bradycardia may be manifestations of acute bilirubin encephalopathy in preterm infants.
Early auditory brainstem response (ABR) changes
If tested in the acute stage, ABR changes may be seen. These may range from absence of waves III and V to complete loss of ABR waves.
Early MRI findings
Brain MRI may show increased signal on T1-weighted images. On the other hand, premature infants who subsequently developed signs of athetoid cerebral palsy, the majority of whom had abnormal high intensity areas in the globi pallidi bilaterally, no infant had demonstrated clinical symptoms attributable to acute bilirubin encephalopathy during the acute stages of hyperbilirubinemia.
Condition variability
As phototherapy may be indicated at low levels of STB in the premature infant, STB testing should be performed at the appearance of visible jaundice in any preterm infant.
Diagnosis
Serum total bilirubin
The diagnosis of hyperbilirubinemia is by determination of the STB.
The clinical significance of any specific STB concentration depends on a multiplicity of factors including gestational age, age postdelivery, clinical stability or instability, and identifiable etiologic factors especially those with the potential of increasing hemolysis.
Unlike the hour-specific bilirubin nomogram, which is available for neonates >35 weeks’ gestation, similar graphs are nonexistent for small premature infants.
An alternative assessment of the clinical severity of a specific STB value is to determine its proximity to the indications for instituting phototherapy or performing exchange transfusion using the therapeutic guidelines in use in any specific NICU (see the Management section below).
Transcutaneous bilirubin (TcB) screening
The advantages of TcB testing include the rapidity with which the test can be performed, lack of pain, and need to actually sample blood.
Although not as accurate as in term and late-preterm infants, TcB readings do offer a reasonable reflection of the STB in preterms.
TcB results approaching or exceeding therapeutic indications should be confirmed with an STB determination.
As phototherapy may result in bleaching of the skin, TcB techniques cannot be used reliably once phototherapy has been started, unless an area of the skin has been covered to protect that region from the local cutaneous effects of phototherapy.
Management
Medical
The aim of therapy is to keep the STB at levels at which it is thought unlikely that unbound bilirubin will be formed. The mainstays of treatment of hyperbilirubinemia in the preterm infant include phototherapy and exchange transfusion.
Phototherapy
Indications for phototherapy in the preterm infant(Table 19-2, Figures 19-1 and 19-2).
Unlike the recommendations of the American Academy of Pediatrics for the management of hyperbilirubinemia, which have been incorporated widely in its original or modified versions, indications for treatment in the premature (<35 weeks) newborn have, until recently, been nonspecific and offered the practitioner a wide range of STB values to decide on the institution of therapy.
Many countries have published guidelines for the use of phototherapy and exchange transfusions in preterm infants. As there is no evidence based on which to support these guidelines, they are based on consensus and clinical judgment of the formulators.
Prophylactic phototherapy
A recent Cochrane report concluded that while prophylactic phototherapy helped maintain a lower serum bilirubin concentration and may have had an effect on the rate of exchange transfusion and the risk of neurodevelopmental impairment, further study is needed in order to determine the efficacy and safety of this technique on long-term outcomes including neurodevelopmental outcomes.
Increased irradiance
In order to increase the effect of phototherapy thereby avoiding the need to perform exchange transfusion, especially in small premature infants in whom the STB concentration is increasing despite phototherapy and approaching exchange transfusion indications, physicians frequently attempt to increase the irradiance, and, therefore, effectiveness, of phototherapy.
This can be done by increasing the number of phototherapy units, moving the sources of light closer to the baby, or using powerful light energy sources, such as light-emitting diodes (LED).
It is not clear, however, whether increased irradiation is necessarily beneficial.
Exchange transfusion
Exchange transfusion is the definitive measure for preventing any further increase, and for actively decreasing, the STB. Because of the widespread use of effective phototherapy, combined with the preventive measures for Rh isoimmunization in industrialized countries, exchange transfusion is nowadays performed rarely.
The technique of exchange transfusion in premature infants is no different from that in term infants, although the morbidity and mortality associated with this procedure may be substantially higher.
The procedure should be performed in an intensive care setting, smaller aliquots of blood used than in term infants, and a close watch kept on the cardiovascular status, pH and serum calcium levels.
Dangers of exchange transfusion: Events related to exchange transfusion are more frequent in exchanges done on preterm infants, with adverse events including thrombocytopenia, metabolic acidosis, hypocalcemia, seizures, and death in a critically ill extremely preterm infant.
The presence of signs of bilirubin encephalopathy should not be used as contraindications for exchange transfusion; there have been reports of reversibility of acute bilirubin encephalopathy with good outcome after exchange transfusion.
Intravenous immune globulin (IVIG)
IVIG has been used with some success in newborns with immune hemolytic disease.
A Cochrane review of ABO incompatible and Rh isoimmunized newborns indicated a decrease in the number of exchange transfusions and the number of exchanges per baby, although the authors recommended further study.
In isoimmunized premature infants, IVIG may be useful in putting off the exchange transfusion to allow for transport or stabilization of a sick infant, or for diminishing the rise in STB while waiting for blood to be prepared for exchange transfusion.
Drug therapy
Phenobarbital has the ability to enhance bilirubin conjugation by stimulating UGT1A1, and may also increase excretion of conjugated bilirubin via the bile.
It may take several days for the phenobarbital effect to manifest.
The drug may be useful in conditions associated with a prolonged increased bilirubin load, such as in Rh or other isoimmunization.
Surgical: N/A
Developmental/therapeutic interventions
Positioning
With the need for body surface area exposure to optimize the effect of phototherapy, swaddling the very preterm infant with hyperbilirubinemia is difficult.
Efforts should be made to contain the infant with external supports in order to maintain a flexed, developmentally appropriate position.
Eye protection
It is important to protect the infant from the stress of bright phototherapy lights with a mask.
Prognosis
In evaluating the long-term effects of hyperbilirubinemia in the premature infant, it is difficult to differentiate between the peak STB concentrations and therapy administered specifically for hyperbilirubinemia.
The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, in a retrospective cohort study, attempted to determine the correlation between STB and neurodevelopmental outcome in ELBW infants. At 18 to 22 months corrected age, peak STB was associated with increased risk of death or neurodevelopmental impairment, hearing impairment requiring the use of hearing aids, and psychomotor impairment, but not with cerebral palsy, mental impairment, and neurodevelopmental impairment, individually.
An older NICHD, multicenter study performed between 1974 and 1976 in premature infants primarily >1250 g birthweight controlled STB concentrations by phototherapy and exchange transfusion, the latter at fixed preset values, or by exchange transfusion alone. The latter were used to keep the STB within fixed preset levels. This study undoubtedly demonstrated the effect of phototherapy in decreasing the STB and diminishing the need for exchange transfusions. Phototherapy with exchange transfusion as a backup was now established as effective management of hyperbilirubinemia in preterm infants.
Aggressive versus conservative phototherapy and neurodevelopmental outcome
To attempt to clarify some issues relating to phototherapy, the NICHD randomly assigned ELBW premature infants to aggressive or conservative phototherapy.
For the purpose of this study, “aggressive” related primarily to the earlier timing of phototherapy, rather than increased irradiance.
Not surprisingly, aggressive phototherapy significantly reduced the mean peak STB, thereby confirming the efficacy of phototherapy in decreasing STB in ELBW infants.
There was no difference in the rate of the primary outcome (death or neurodevelopmental impairment). However, when analyzing for neurodevelopmental impairment alone, aggressive phototherapy was instrumental in reducing the rate (26% versus 30%).
Unfortunately, this apparent advantage with regard to improved neurodevelopmental outcome may have been offset by a 5% increase in mortality (39% versus 34%) in the smallest infants (501 to 750 g birthweight). Thus, aggressive phototherapy should be administered with caution in those <750 g birthweight.
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