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1 Page 1 of 21 Official reprint from UpToDate UpToDate Treatment of unconjugated hyperbilirubinemia in term and late preterm infants Authors Ronald J Wong, BA Vinod K Bhutani, MD, FAAP Section Editor Steven A Abrams, MD Deputy Editor Melanie S Kim, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May This topic last updated: Sep 04, INTRODUCTION Almost all newborn infants develop a total serum or plasma bilirubin (TB) value greater than 1 mg/dl (17.1 micromol/l), which is the upper limit of normal for adults. As TB increases, it causes neonatal jaundice, the yellowish discoloration of the skin and/or sclerae caused by bilirubin deposition in half of all newborn infants [1]. Hyperbilirubinemia in infants 35 weeks gestational age (GA) is defined as TB >95th percentile on the hour-specific Bhutani nomogram [2]. Hyperbilirubinemia with a TB >25 to 32 mg/dl (428 to 547 micromol/l) is associated with an increased risk for bilirubin-induced neurologic dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The term "acute bilirubin encephalopathy" (ABE) is used to describe the acute manifestations of BIND. The term "kernicterus" is used to describe the chronic and permanent sequelae of BIND. Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia. However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus) can sometimes develop. The treatment of neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical manifestations, evaluation, pathogenesis, and etiology of this disorder are discussed separately. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".) OVERVIEW Two advances in medical care had a significant impact on the need for treatment and the way in which hyperbilirubinemia is managed. The administration of Rh (D) immunoglobulin to Rhnegative mothers in the late 1960s decreased dramatically the incidence of neonatal Rh isoimmune hemolytic disease. At about the same time, the introduction of phototherapy in the United States reduced significantly the need for exchange transfusions and the risk of severe hyperbilirubinemia. Thus, the risk of kernicterus was significantly reduced from its peak incidence in the 1950s to the 1970s. Nevertheless, isolated cases of kernicterus, a preventable condition, continue to be reported. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Overview'.) Limited data based upon case reports suggest that kernicterus occurs in term or late preterm infants with hyperbilirubinemia, defined as total serum or plasma bilirubin (TB) >95th percentile on the hourspecific Bhutani nomogram [2]. In order to prevent future cases of kernicterus, the management of unconjugated hyperbilirubinemia focuses on two key elements: Prevention of hyperbilirubinemia by identifying at-risk infants and initiation of preventive therapeutic interventions (eg, phototherapy) as needed Reduction of TB in infants with severe hyperbilirubinemia

2 Page 2 of 21 Prevention of hyperbilirubinemia Universal screening of all term and late preterm infants identifies at-risk infants for hyperbilirubinemia. In these patients, phototherapy is initiated to prevent hyperbilirubinemia when TB exceeds a threshold level based upon a nomogram of TB levels adjusted by the infant's age-in-hours [3] and the presence or absence of additional risk factors [2,3]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and 'Phototherapy indications' below.) Treatment of severe hyperbilirubinemia Therapeutic interventions for infants with hyperbilirubinemia include: Phototherapy Exchange transfusion Improving the frequency and efficacy of breastfeeding or supplementing inadequate breastfeeding with formula PHOTOTHERAPY Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. In term and large preterm infants, phototherapy is safe based upon its extensive use in millions of infants over 30 years and only rare reports of significant toxicity [2]. (See 'Adverse effects' below.) Phototherapy reduces the risk that total bilirubin (TB) concentration will reach the level at which exchange transfusion is recommended [4,5]. It decreases or blunts the rise of TB in almost all cases of hyperbilirubinemia regardless of the patient's ethnicity or the etiology of hyperbilirubinemia. It is estimated that 5 to 10 infants with TB between 15 and 20 mg/dl (257 to 342 micromol/l) must receive phototherapy to prevent one patient from developing a TB >20 mg/dl (342 micromol/l) [2]. (See 'Efficacy' below and 'Exchange transfusion' below.) Mechanisms Phototherapy exposes the infant's skin to light of a specific wavelength, which reduces TB by the following three mechanisms: Structural isomerization to lumirubin Phototherapy converts bilirubin into lumirubin via structural isomerization that is not reversible [6]. Lumirubin, a more soluble substance than bilirubin, is excreted without conjugation into bile and urine. This is the principal mechanism by which phototherapy reduces TB concentration. Photoisomerization to a less toxic bilirubin isomer Phototherapy converts the stable 4Z,15Z bilirubin isomer to the 4Z,15E isomer, which is more polar and less toxic than the 4Z,15Z form. Like lumirubin, 4Z,15E isomer is excreted into bile without conjugation. Unlike structural isomerization to lumirubin, photoisomerization is reversible; however, clearance of the 4Z,15E isomer is very slow and the photoisomerization is reversible. Thus, some of the 4Z,15E isomer in bile is converted back to the stable 4Z,15Z isomer. As a result, this pathway may have little effect on TB values. In addition, standard laboratory measurements do not distinguish among the isomers, so these measurements do not reflect these changes. Nevertheless, photoisomerization does reduce the amount of potentially toxic bilirubin by rapidly converting 15 percent of it to a non-toxic form. Photo-oxidation to polar molecules Photo-oxidation reactions convert bilirubin to colorless, polar compounds that are excreted primarily in the urine. This is a slow process and accounts for a small proportion of bilirubin elimination. Technique The dose of phototherapy, known as irradiance (measured in microw/cm 2/nm), determines its efficacy. Irradiance depends upon the type of the light used, distance between the light and infant (except with light emitting diodes), and the exposed surface area of the infant. Irradiance usually is expressed for a certain wavelength band (spectral irradiance) [7]. In conventional

3 Page 3 of 21 phototherapy, the irradiance dosing is typically 6 to 12 microw/cm 2 of body surface area exposed per nm of wavelength (425 to 475 nm) and with intensive phototherapy it is 30 microw/cm 2/nm. For TB levels 20 mg/dl (342 micromol/l), phototherapy should be administered continuously, until the TB falls below 20 mg/dl (342 micromol/l). Once this occurs, phototherapy can be interrupted for feeding and parental visits. During phototherapy, the area covered by the diaper should be minimized. The eyes should be shielded with an opaque blindfold and care should be taken to prevent the blindfold from covering the nose. With fluorescent lights, the infant should be placed in an open crib, bassinet, or on a warmer, rather than in an incubator (the top of the incubator prevents the light from being brought sufficiently close to the infant). Lining the sides of the bassinet or warmer with aluminum foil or white material increases the exposed surface area of the infant and the efficiency of phototherapy [8,9]. The use of reflective white curtains around the phototherapy light source has also been shown to increase phototherapy efficiency [10]. Light sources and devices Bilirubin absorbs light most strongly in the blue region of the spectrum near 460 nm. Several light sources, utilizing different wavelengths of light and varying degrees of irradiance, and devices are available for phototherapy. Fluorescent blue light Fluorescent special blue light, F20 T12/BB and TL52 tubes (Philips, The Netherlands), should be used. They are the most effective light source in lowering TB because they deliver light in the blue-green spectrum, which penetrates the skin well and is absorbed maximally. Fluorescent special blue light should not be confused with regular blue light or blue light-emitting diodes (LEDs). Halogen white light Halogen white lamps are hot and can cause thermal injury. They should be placed at the distance from the patient recommended by the manufacturer. Fiberoptic blankets or pads Fiberoptic blankets or pads generate little heat and can be placed close to the infant, providing higher irradiance than do fluorescent lights [11]. However, blankets are small and rarely cover sufficient surface area to be effective when used alone in term infants. They can be used as an adjunct to overhead fluorescent or halogen lights. Fiberoptic blankets also can be used during feedings when overhead fluorescent or halogen lights are discontinued. This is particularly helpful for infants with severe hyperbilirubinemia. Blue LEDs LEDs use high-intensity blue gallium nitride and are commercially available as both overhead and underneath devices [7,12,13]. These devices, which deliver high intensity narrow band light in the absorption spectrum of bilirubin, are as effective as conventional fluorescent blue light [14,15]. The mattress LED device is preferable to the fiberoptic pad because it is large enough to cover the entire surface (in contact with the mattress) of a term infant. For effective (intensive) phototherapy, high levels of irradiance (usually 30 microw/cm 2/nm) are delivered to as much of an infant's surface area as possible [2]. The necessary irradiance can be achieved using a phototherapy light placed at a distance of 10 to 30 cm from the infant's body depending on the manufacturer s recommendation in combination with a fiberoptic pad, LED mattress, or special blue lights below the infant [16]. LEDs at the distance dictated by the device also provide an irradiance of 30 microw/cm 2/nm. Although there are no trials comparing the efficacy of phototherapy devices in term and late preterm infants, a trial in extremely low birth weight preterm infants (birth weight 1000 g) found that the absolute and relative decrease of TB during the first 24 hours of life was greatest for LEDs, followed

4 Page 4 of 21 by spotlights, bank of lights, and blankets [17]. (See "Hyperbilirubinemia in the premature infant (less than 35 weeks gestation)", section on 'Light source and devices'.) Home phototherapy As an alternative to readmission to the hospital, phototherapy can be administered to term infants at home. Home phototherapy is less disruptive to the family and can be considered for otherwise healthy term infants (>38 weeks gestational age [GA]) without hemolysis or other risk factors who have TB levels 2 to 3 mg/dl (34 to 51 micromol/l) below the recommended threshold level for initiation of hospital phototherapy, are feeding well, and can be closely followed [2]. (See 'Phototherapy indications' below.) Sunlight exposure Although exposure to sunlight provides sufficient irradiance in the 425 to 475 nm band and is known to lower the TB [18], exposure to sunlight is not recommended to prevent severe hyperbilirubinemia [2]. The difficulties of avoiding sunburn while exposing a naked infant to sunlight preclude the use of sunlight exposure as a reliable therapeutic option. Selection of light source Although there is a wide selection of commercially available phototherapy devices, there are no standardized methods of reporting and measuring phototherapy devices. (See 'Light sources and devices' above.) In order to help guide clinicians and hospitals to provide the most effective phototherapy, a technical report from the American Academy of Pediatrics (AAP) summarized the key features to consider in the selection of a device to treat neonatal hyperbilirubinemia [16]. After review of the available literature, the report concluded that the most effective devices displayed the following characteristics: Emission of light in the blue-to-green range (460 to 490 nm). Lights with broader emission also will work, but not as effectively. Irradiance of at least 30 microw/cm 2/nm (confirmed by an appropriate irradiance meter calibrated over the appropriate wavelength range). Ability to illuminate maximal body surface. Blocking the light source or reducing the exposed body surface area should be avoided. Demonstration of a decrease in TB during the first four to six hours of exposure. Phototherapy indications The following discussion on the indications for phototherapy for term and late preterm infants ( 35 weeks GA) is based upon the practice guideline developed by the AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by the United Kingdom s National Institute for Health and Clinical Excellence (NICE guideline for Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB values, birth weight (BW), and postnatal age [19]. Initiation of phototherapy is based upon hour-specific TB values [3], GA, and the presence or absence of risk factors that include isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, asphyxia, lethargy, temperature instability, sepsis, acidosis, or albumin <3 g/dl (if measured) (figure 1). These are conditions that increase the risk of brain damage because of their negative effects on albumin binding of bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Risk assessment' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Bilirubin/albumin ratio'.) The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific bilirubin value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). In general, the guidelines for phototherapy are as follows:

5 Page 5 of 21 For infants at low risk ( 38 weeks GA and without risk factors), phototherapy is started at the following TB values. 24 hours of age: >12 mg/dl (205 micromol/l) 48 hours of age: >15 mg/dl (257 micromol/l) 72 hours of age: >18 mg/dl (308 micromol/l) Infants in this category who have TB levels 2 to 3 mg/dl (34 to 51 micromol/l) below the recommended levels may be treated with fiberoptic or conventional phototherapy at home. For infants at medium risk ( 38 weeks GA with risk factors or 35 to 37 6/7 weeks gestation without risk factors), phototherapy is started at the following TB values. 24 hours of age: >10 mg/dl (171 micromol/l) 48 hours of age: >13 mg/dl (222 micromol/l) 72 hours of age: >15 mg/dl (257 micromol/l) The threshold for intervention may be lowered for infants closer to 35 weeks GA and raised for those closer to 37 6/7 weeks GA. For infants at high risk (35 to 37 6/7 weeks GA with risk factors), phototherapy is initiated at the following TB values. 24 hours of age: >8 mg/dl (137 micromol/l) 48 hours of age: >11 mg/dl (188 micromol/l) 72 hours of age: >13.5 mg/dl (231 micromol/l) Special circumstances Infants with clinical jaundice within the first 24 hours frequently have hemolysis. They require immediate evaluation and close surveillance to assess the need for phototherapy. In infants with other causes of increased bilirubin production, such as cephalohematoma or extensive bruising, or in infants suspected of having genetic disorder of bilirubin conjugation (eg, Crigler-Najjar or Gilbert's syndromes), we start phototherapy when the hour-specific TB concentration is in the high intermediate risk zone (>75th percentile) (figure 2). The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".) Efficacy of phototherapy Although there are no data showing that phototherapy improves neurodevelopmental outcome, phototherapy does reduce the likelihood that TB reaches a level associated with an increased risk of kernicterus or at which exchange transfusion is recommended [20,21]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Overview'.) Intensive phototherapy results in a decline of TB of at least 2 to 3 mg/dl (34 to 51 micromol/l) within four to six hours. A decrease in TB can be measured as soon as two hours after initiation of treatment. In infants 35 weeks GA, 24 hours of intensive phototherapy can result in a 30 to 40 percent decrease in the initial TB [22]. With conventional phototherapy, a decline of 6 to 20 percent can be expected in the first 18 to 24 hours [11,23,24]. The efficacy of phototherapy in preventing a rise in TB to the exchange transfusion threshold was demonstrated in a large retrospective cohort study of 281,898 infants born 35 weeks GA [25].

6 Page 6 of 21 Overall, 23 percent of patients received phototherapy within eight hours after reaching a TB within 3 mg/dl (51 micromol/l) of the AAP phototherapy threshold (figure 1). Only 1.6 percent (354 infants) ever exceeded the AAP exchange threshold (figure 3) and only three received exchange transfusions. Multivariate analysis demonstrated that lower GA and birth weight, younger age at the time TB level reached the phototherapy threshold, and a positive direct antiglobulin test (DAT) were associated with an increased risk in reaching the AAP exchange transfusion threshold. Based upon these results, phototherapy was found to be highly effective in preventing TB from rising to the AAP exchange transfusion threshold, especially in full-term infants who are appropriate size for GA, older than 48 hours at the time TB level reached the phototherapy threshold, and are not DAT positive. The rate of decline of TB during phototherapy is affected by a number of factors [2]. Increased irradiance increases the rate of TB decline Greater surface area exposure to phototherapy increases the rate of TB reduction The higher the initial TB, the more rapid is the rate of decline (as much as 10 mg/dl [171 micromol/l] within a few hours) Phototherapy is less effective in infants whose hyperbilirubinemia is due to cholestasis or hemolysis with a DAT than in infants with other causes Monitoring During phototherapy, the dose of phototherapy (irradiance) and the infant's temperature, hydration status, time of exposure, and TB are monitored. Phototherapy may increase both the body and environmental temperature resulting in increased insensible fluid loss. LED-based devices emit low levels of heat, and thus fluid loss is less of a concern with these devices [8]. (See 'Hydration' below.) The frequency of TB measurements depends upon the initial TB value. When infants are discharged and readmitted with TB values exceeding the 95th percentile for hour-specific TB levels [3] (figure 2), the TB measurement should be repeated two to three hours after initiation of phototherapy to assess the response. When phototherapy is started for a rising TB, TB should be measured after 4 to 6 hours and then within 8 to 12 hours, if TB continues to fall. If, despite intensive phototherapy, the TB is at or approaches the threshold for exchange transfusion, blood should be sent for immediate type and cross-match. In addition, if exchange transfusion is being considered, the serum albumin level should be measured so that the serum bilirubin/albumin (B/A) ratio can be used in conjunction with the TB level and other factors to determine the need for exchange transfusion. (See 'Exchange transfusion' below.) Hydration It is important to maintain adequate hydration and urine output during phototherapy since urinary excretion of lumirubin is the principal mechanism by which phototherapy reduces TB. Thus, during phototherapy, infants should continue oral feedings by breast or bottle. For TB levels that approach the exchange transfusion level, phototherapy should be continuous until the TB has declined to about 20 mg/dl (342 micromol/l). Thereafter phototherapy can be interrupted for feeding. (See 'Technique' above.) Intravenous hydration may be necessary to correct hypovolemia in infants with significant volume depletion whose oral intake is inadequate; otherwise, intravenous fluid is not recommended [2]. Breastfeeding Breastfed infants whose intake is inadequate, with excessive weight loss (>12 percent of BW), or who have evidence of hypovolemia, should receive supplementation with expressed breast milk or formula [2]. The temporary interruption of breastfeeding with the substitution of formula may enhance the efficacy of phototherapy by decreasing the enterohepatic circulation of bilirubin [4,26,27]. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Breastfeeding failure jaundice' and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Breastfed infants'.)

7 Page 7 of 21 If breastfeeding is interrupted, it should be resumed as soon as possible. (See "Infant benefits of breastfeeding".) Discontinuation For infants who have been readmitted for phototherapy, we discontinue the phototherapy when the TB has reached 12 to 14 mg/dl (205 to 239 micromol/l). For those who required phototherapy during the birth hospitalization, phototherapy is started at a significantly lower level and, therefore, is stopped at a lower level. For these infants, we generally discontinue phototherapy when the TB has fallen to, or below, the level at which phototherapy was initiated because, by this time, the infant is significantly older and the level for initiation of phototherapy has, consequently, increased. TB is measured 18 to 24 hours after phototherapy is terminated. This is important in infants who need phototherapy during their birth hospitalization, but might not be necessary in those who have been readmitted where the risk of rebound is much lower. The readmitted infant should not be kept in the hospital pending measurement of rebound. If necessary, this can be done as an outpatient. Although the value following discontinuation is known as the rebound bilirubin, typically it is lower than the TB value before the initiation of phototherapy. In one study of 161 infants with BW >1800 g, TB was significantly lower 17 hours after termination of phototherapy compared with TB at the time of termination (11.5 versus 12.2 mg/dl [197 versus 209 micromol/l]) [28]. However, in another study of 226 infants, which included 110 neonates with a positive DAT (Coombs test), 13 percent had rebound TB levels >15 mg/dl (257 micromol/l) [29]. Risk factors for significant rebound (TB levels >15 mg/dl [257 micromol/l]) were initial phototherapy beginning <72 hours of age (odds ratio [OR] 3.61, 95% CI ), GA <37 weeks (OR 3.21, 95% CI ), and a positive DAT test (OR 2.44, 95% CI ). Adverse effects Phototherapy is considered safe. Side effects include transient erythematous rashes, loose stools, and hyperthermia. Increased insensible water loss may lead to dehydration. Phototherapy is not associated with an increase in nevus count [30]. (See 'Hydration' above.) The "bronze baby syndrome" is an uncommon complication of phototherapy that occurs in some infants with cholestatic jaundice. It is manifested by a dark, grayish-brown discoloration of the skin, serum, and urine [31]. Although the etiology of the bronze appearance remains unknown, it is proposed that the color is a result of impaired biliary excretion of bile pigment photoproducts due to cholestasis [31,32]. The condition gradually resolves without sequelae within several weeks after discontinuation of phototherapy [33]. It remains controversial whether the bronze pigments have potential neurotoxic consequences. Although the effect of phototherapy on the eyes of infants is not known, animal studies indicate that retinal degeneration may occur after 24 hours of continuous exposure [34]. As a result, it is essential that the eyes of all neonates treated with phototherapy are sufficiently covered to eliminate any potential eye exposure. Limited data on long-term effects are conflicting, with some studies suggesting that blue light phototherapy (using broadband light emitting light in the UV region) increases the risk of melanocytic nevi in children and adolescents [35]. (See "Acquired melanocytic nevi (moles)".) EXCHANGE TRANSFUSION Exchange transfusion is used to remove bilirubin from the circulation when intensive phototherapy fails or in infants with signs of bilirubin-induced neurologic dysfunction (BIND). The term ABE, or "acute bilirubin encephalopathy," is used to describe the acute manifestations of overt BIND. The term "kernicterus" is used to describe the chronic and permanent sequelae of overt BIND and differentiate these from the subtle signs observed in the syndrome of BIND [36]. Exchange transfusion is especially useful for infants with increased bilirubin production

8 Page 8 of 21 resulting from isoimmune hemolysis because circulating antibodies and sensitized red blood cells also are removed. Although exchange transfusion is both expensive and time consuming, it is the most effective method for removing bilirubin rapidly. Exchange transfusion is indicated when intensive phototherapy cannot prevent a continued rise in the total bilirubin (TB) or in infants who already display signs indicative of BIND. Exchange transfusions should be performed only by trained personnel in a neonatal or pediatric intensive care unit equipped with full monitoring and resuscitation capabilities [2]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.) The need for exchange transfusions has decreased with the prevention of Rh isoimmune hemolytic disease and the systemic application of the 2004 American Academy of Pediatrics (AAP) Guideline for identification and treatment of infants at risk for severe hyperbilirubinemia with phototherapy [37-39]. This was best illustrated in a study from a large Northern California health maintenance organization of over 18,000 neonates with a gestational age (GA) 35 weeks born between 2005 and 2007 following the initiation of universal screening. In this cohort, only 22 patients (0.1 percent) had a TB level that exceeded the AAP recommended threshold for exchange transfusion [39]. Fourteen of these infants were <38 weeks GA. Only one exchange transfusion was performed and there were no reported sequelae. A similar incidence was reported from a single institution with an exchange transfusion rate of percent (8 of 55,128 inborn infants) between 1988 and 1997 [37]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Systematic approach' and 'Phototherapy indications' above.) Morbidity and mortality Because exchange transfusions are rarely performed, it is difficult to assess the current risks of morbidity and mortality associated with this procedure. Studies published in 1985 reported mortality rates of 0.3 percent associated with the procedure [40,41] and a significant complication rate of 1 percent [41]. Subsequent studies are limited by the number of patients due to the infrequency of the procedure. In the previously mentioned retrospective 21-year review, 5 of the 141 patients died within seven days of the exchange transfusion; however, none of the deaths appeared to be related to the procedure [38]. In this study, the most common complications were thrombocytopenia (38 percent of patients) and hypocalcemia (38 percent). In a retrospective study of 55 infants cared for at two neonatal intensive care units between 1992 and 2002, there was only one death, which was a critically ill preterm infant [42]. There was a high rate of complications including thrombocytopenia (44 percent), hypocalcemia (29 percent), and metabolic acidosis (24 percent). In another retrospective study published in 1997, which reviewed 106 patients who underwent exchange transfusion over 15 years from two neonatal intensive care units (NICUs), two patients died because of complications attributed to exchange transfusions. These two deaths occurred in patients classified as "ill," having other existing comorbidities [43]. Procedure The infant's circulating blood volume is approximately 80 to 90 ml/kg. A double-volume exchange transfusion (160 to 180 ml/kg) replaces approximately 85 percent of the infant's circulating red blood cells with appropriately cross-matched reconstituted (from packed red blood cells and fresh frozen plasma) blood. Irradiated blood products should be used to reduce the risk of graft versus host disease. In infants born to cytomegalovirus (CMV) seronegative mothers, CMV-safe blood products should be used. (See "Red cell transfusion in infants and children: Selection of blood products".)

9 Page 9 of 21 The procedure involves placement of at least a central catheter and removing and replacing blood in aliquots that are approximately 10 percent or less of the infant's blood volume. Exchange transfusion usually reduces TB by approximately 50 percent [44]. Infusion of albumin (1 g/kg) one to two hours before the procedure shifts more extravascular bilirubin into the circulation, allowing removal of more bilirubin, although this has not been shown to decrease the need for repeat exchange transfusion. Indications The following discussion on the indications for exchange transfusions for term and late preterm infants ( 35 weeks GA) is based upon the clinical practice guideline developed by the AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by the United Kingdom s National Institute for Health and Clinical Excellence (NICE guideline for Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB values, birth weight (BW), and postnatal age [19]. Exchange transfusions are indicated in the following settings [2]: or Jaundiced infants with signs of ABE, such as significant lethargy, hypotonia, poor sucking, or high-pitched cry, irrespective of the TB level. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.) Infants with a TB greater than threshold values established by the AAP (figure 3). For infants who have not yet been discharged from the birth hospital, exchange transfusion is recommended if the TB reaches the threshold level despite intensive phototherapy [2]. Infants who have been discharged from the nursery to home and have TB concentrations that are approaching or exceed threshold values for exchange transfusion are initially treated with phototherapy. If TB remains above the threshold TB after about six hours of phototherapy, then exchange transfusion is indicated. This approach reduces the number of infants requiring an invasive therapy that has significant morbidity and mortality. (See 'Phototherapy' above.) The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). The following are general age-in-hours specific TB threshold values for exchange transfusion recommended by the AAP based upon gestational age and the presence or absence of risk factors (isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase [G6PD] deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3 g/dl [if measured]) [2]: For infants at low risk ( 38 weeks GA and without risk factors), exchange transfusion is indicated for the following TB values. 24 hours of age: >19 mg/dl (325 micromol/l) 48 hours of age: >22 mg/dl (376 micromol/l) 72 hours of age: >24 mg/dl (410 micromol/l) Any age greater than 72 hours: 25 mg/dl (428 micromol/l) For infants at medium risk ( 38 weeks GA with risk factors or 35 to 37 6/7 weeks GA without risk factors), exchange transfusion is indicated for the following TB values. 24 hours of age: >16.5 mg/dl (282 micromol/l)

10 Page 10 of hours of age: >19 mg/dl (325 micromol/l) 72 hours of age: >21 mg/dl (359 micromol/l) The threshold for intervention may be lowered for infants closer to 35 weeks GA and raised for those closer to 37 6/7 weeks GA. For infants at high risk (35 to 37 6/7 weeks GA with risk factors), exchange transfusion is indicated for the following TB values. 24 hours of age: >15 mg/dl (257 micromol/l) 48 hours of age: >17 mg/dl (291 micromol/l) 72 hours of age: >18.5 mg/dl (316 micromol/l) Infants who are close or meet the criteria for exchange transfusion should be directly admitted or transferred to the neonatal or pediatric intensive care unit. Referral should not be through an emergency department, because this delays the initiation of treatment [45]. Upon admission, a type and cross-match of the infant s blood and placement of umbilical catheter are performed promptly, so that exchange transfusion can be started as quickly as possible. (See 'Technique' above.) Special circumstances In infants with isoimmune hemolytic disease and rising TB despite intensive phototherapy, administration of intravenous immunoglobulin (IVIG) is recommended since it may avoid the need for exchange transfusion. (See 'Intravenous immunoglobulin' below.) Exchange transfusion should be considered in infants receiving phototherapy who develop the "bronze baby" syndrome, if phototherapy has been ineffective in reducing TB below the threshold range for intensive phototherapy [2]. (See 'Adverse effects' above.) Bilirubin/albumin ratio The bilirubin/albumin (B/A) ratio can be used as an additional factor in determining the need for exchange transfusion; it should not be used alone, but in conjunction with TB values [2,46]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Bilirubin/albumin ratio'.) For infants 38 weeks GA, consider exchange transfusion when TB (mg/dl)/albumin (g/dl) ratio is >8 or TB (micromol/l)/albumin (micromol/l) is >0.94. For infants 35 to 37 6/7 weeks GA and well, or 38 weeks with high risk (eg, isoimmune hemolytic disease or G6PD deficiency), consider exchange transfusion when TB (mg/dl)/albumin (g/dl) ratio is >7.2 or TB (micromol/l)/albumin (micromol/l) is >0.84. For infants 35 to 37 6/7 weeks GA with high risk (eg, isoimmune hemolytic disease or G6PD deficiency), consider exchange transfusion when TB (mg/dl)/albumin (g/dl) ratio is >6.8 or TB (micromol/l)/albumin (micromol/l) is >0.8. Efficacy After a successful procedure, TB typically falls to approximately one-half of the preexchange value, then increases to approximately two-thirds of that of the pre-exchange concentration because there is re-equilibration between extravascular and vascular bilirubin. Observational studies report that exchange transfusions decreased the risk for prominent neurologic abnormalities in term infants with TB >20 mg/dl (342 micromol/l) [47] and improved abnormal brainstem auditory-evoked response (BAER) in infants with severe hyperbilirubinemia [48-51] Risks The risks of exchange transfusion result from the use of blood products and from the procedure itself. Complications include: Blood-borne infection

11 Page 11 of 21 Thrombocytopenia and coagulopathy Graft versus host disease Necrotizing enterocolitis (NEC) Portal vein thrombosis Electrolyte abnormalities (eg, hypocalcemia and hyperkalemia) Cardiac arrhythmias (See "Administration and complications of red cell transfusion in infants and children".) As previously mentioned, the current morbidity and mortality rates associated with exchange transfusions are not known because the procedure is rarely performed [37]. Studies published in 1985 reported mortality rates of 0.3 percent associated with exchange transfusions [40,41] and a significant complication rate of 1 percent [41]. In a retrospective review of 15 years experience from 1981 to 1995 at two academic medical centers, 1 of 81 healthy infants developed necrotizing enterocolitis after exchange transfusion and none died [52]. PHARMACOLOGIC AGENTS Pharmacologic agents, including intravenous immunoglobulin (IVIG), phenobarbital, ursodeoxycholic acid, and metalloporphyrins can be used to inhibit hemolysis, increase conjugation and excretion of bilirubin, increase bile flow, or inhibit the formation of bilirubin, respectively. However, currently only IVIG is used to treat unconjugated hyperbilirubinemia. Intravenous immunoglobulin IVIG can reduce the need for exchange transfusion in infants with hemolytic disease caused by Rh or ABO incompatibility [53-55]. Several systematic reviews and meta -analyses have shown that infants who received IVIG compared with the control group had lower rates of exchange transfusions [53-57]. Avoiding exchange transfusion reduces the risk of any of its potential adverse effects; as a result, the administration of IVIG should be considered based on the relative benefits and risks of the two interventions. IVIG (dose 0.5 to 1 g/kg over two hours) is recommended in infants with isoimmune hemolytic disease if the total bilirubin (TB) is rising despite intensive phototherapy or is within 2 or 3 mg/dl (34 to 51 micromol/l) of the threshold for exchange transfusion [2,56]. The dose may be repeated in 12 hours if necessary [2]. (See 'Exchange transfusion' above.) The mechanism is uncertain, but IVIG is thought to inhibit hemolysis by blocking antibody receptors on red blood cells. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy".) Phenobarbital Phenobarbital increases the conjugation and excretion of bilirubin and decreases postnatal TB levels when given to pregnant women or infants. However, prenatal administration of phenobarbital may adversely affect cognitive development and reproduction [58,59]. As a result, phenobarbital is not routinely used to treat indirect neonatal hyperbilirubinemia. Ursodeoxycholic acid Ursodeoxycholic acid increases bile flow and helps to lower TB levels. It is also useful in the treatment of cholestatic jaundice. Metalloporphyrins Synthetic metalloporphyrins, such as tin mesoporphyrin (SnMP), reduce bilirubin production by competitive inhibition of heme oxygenase [60-67]. There are limited data upon the safety of SnMP [67], and SnMP is not available for general use. In one report, term infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency given SnMP at approximately 27 hours of age had lower and earlier peak TB values than did control infants with and without G6PD deficiency [60]. No treated infant required phototherapy, compared with 31 and 15 percent in the controls with and without G6PD deficiency, respectively. In a systematic review of three randomized trials including 170 infants, short-term benefits of metalloporphyrin therapy included lower maximum TB, lower frequency of severe hyperbilirubinemia, decreased need for phototherapy, and shorter duration of hospitalization [61,62,66]. None of the

12 Page 12 of 21 enrolled infants required exchange transfusion. None of the studies reported on kernicterus, death, or long-term neurodevelopmental outcome. SnMP is not approved for use in the United States. OUTCOME When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae [68-70]. This was illustrated in a prospective cohort control study of 140 infants with total bilirubin (TB) levels 25 mg/dl (428 micromol/l) identified from a cohort of 106,627 term or late preterm infants [68]. The study group also included 10 infants with TB 30 mg/dl (513 micromol/l). Treatment of hyperbilirubinemia included phototherapy in 136 cases and exchange transfusions in five cases. The hyperbilirubinemic infants compared with the control group had a greater proportion of infants who were born <38 weeks gestational age (GA), Asian, and were exclusively breastfed during birth hospitalization. At two-year follow-up, results were as follows: There were no reports of kernicterus in either the hyperbilirubinemic or control group. Formal cognitive testing was performed in 82 children with neonatal hyperbilirubinemia and 168 control children at two and six years of age. There was no difference between patients with hyperbilirubinemia and matched controls in cognitive testing, reported behavioral problems, and frequency of parental concerns. On physical examination, patients with hyperbilirubinemia compared with control patients had a lower prevalence of abnormal neurologic findings (14 versus 29 percent). The degree and duration of hyperbilirubinemia had no effect on these outcomes. In a subset analysis, nine patients with hyperbilirubinemia and a positive direct antiglobulin test (DAT, Coombs test) had lower scores on cognitive testing than other patients with hyperbilirubinemia with a negative DAT. There was no difference between these two hyperbilirubinemic groups regarding the presence of an abnormal neurologic finding. Similar findings were noted in a follow-up study from the Collaborative Perinatal Project of children (n = 46,872) at seven and eight years of age who were born 36 weeks GA with a birth weight 2000 g between 1959 and 1966 [69]. Results showed an adverse effect on cognitive testing was only seen in children who had a TB 25 mg/dl (428 micromol/l) and a positive DAT result as neonates. TB in the absence of a positive DAT had no effect on cognitive testing. Population-based studies have also reported observing no or limited chronic neurologic effects of severe hyperbilirubinemia: In a report of all live-born births in Denmark from 2004 to 2007, results based on parental survey demonstrated no difference in development at one to five years of age between infants with at least one neonatal measurement of TB 25 mg/dl (428 micromol/l) from controls matched by gender, age, gestational age, and municipality of residency [71]. In a study from Nova Scotia of 61,238 infants born between 1994 and 2000, there were no reported cases of kernicterus after implementation of treatment guidelines for hyperbilirubinemia in term and late preterm infants [70]. There were no differences in the overall neurologic composite outcome (cerebral palsy, developmental delay, hearing and vision abnormalities, attention-deficit disorder, and autism) in infants with severe (TB 19 mg/dl [325 mmol/l]) or moderate (TB 19 mg/dl [325 mmol/l]) hyperbilirubinemia compared with those without hyperbilirubinemia. However, subset analysis for each neurologic outcome suggested that some neurologic impairment might be associated with hyperbilirubinemia. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic dysfunction'.)

13 Page 13 of 21 These results support the American Academy of Pediatrics (AAP) treatment guidelines for the management of hyperbilirubinemia in term and late preterm infants, especially the use of lower threshold values for intervention in infants with a positive DAT. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e- mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Jaundice in babies (The Basics)") Beyond the Basics topics (see "Patient information: Jaundice in newborn infants (Beyond the Basics)") A list of frequently asked questions and answers for parents is available through the American Academy of Pediatrics (AAP): Newborns.aspx SUMMARY AND RECOMMENDATIONS The management of neonatal hyperbilirubinemia is focused upon prevention of severe hyperbilirubinemia in identified high-risk infants and reduction of total serum or plasma bilirubin (TB) in infants with severe hyperbilirubinemia. The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-specific bilirubin value may be determined using the newborn hyperbilirubinemia assessment calculator (calculator 1). (See 'Overview' above and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants".) Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. It is a safe and effective method to reduce the toxicity of bilirubin and increase its elimination. (See 'Phototherapy' above.) Phototherapy has been shown to reduce the risk of TB values reaching a level associated with kernicterus and reduces the number of infants who reach a TB threshold for exchange transfusions. (See 'Efficacy of phototherapy' above.) We recommend phototherapy as the initial therapy to treat hyperbilirubinemia in term and late preterm infants (Grade 1B). In our practice, we initiate phototherapy based upon the guidelines developed by the American Academy of Pediatrics (AAP). (See 'Phototherapy' above.) In infants with hyperbilirubinemia due to isoimmune hemolytic disease, we recommend the administration of intravenous immunoglobulin (IVIG) if TB is rising in spite of intensive phototherapy (Grade 1B). IVIG administration may avoid the need of exchange transfusion in these patients. (See 'Intravenous immunoglobulin' above.) Exchange transfusion is the most effective method to lower TB. Although it is difficult to ascertain the current risk of morbidity and mortality, there are reported serious complications and deaths associated with the procedure.

14 Page 14 of 21 We recommend exchange transfusions in infants who exhibit clinical findings of bilirubininduced neurologic dysfunction (BIND) (Grade 1B). We suggest exchange transfusion for infants with TB that exceed threshold TB values based upon the guideline developed by the AAP who have failed initial intensive phototherapy (figure 3) (Grade 2C). (See 'Exchange transfusion' above.) When infants with hyperbilirubinemia are identified and treated appropriately, the outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae. (See 'Outcome' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Dennery PA, Seidman DS, Stevenson DK. Neonatal hyperbilirubinemia. N Engl J Med 2001; 344:581. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 1999; 103:6. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics 1993; 91:470. Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985; 75:393. Ennever JF, Costarino AT, Polin RA, Speck WT. Rapid clearance of a structural isomer of bilirubin during phototherapy. J Clin Invest 1987; 79:1674. Vreman HJ, Wong RJ, Stevenson DK. Phototherapy: current methods and future directions. Semin Perinatol 2004; 28:326. Eggert P, Stick C, Schröder H. On the distribution of irradiation intensity in phototherapy. Measurements of effective irradiance in an incubator. Eur J Pediatr 1984; 142:58. Maisels MJ. Why use homeopathic doses of phototherapy? Pediatrics 1996; 98:283. Djokomuljanto S, Quah BS, Surini Y, et al. Efficacy of phototherapy for neonatal jaundice is increased by the use of low-cost white reflecting curtains. Arch Dis Child Fetal Neonatal Ed 2006; 91:F439. Holtrop PC, Madison K, Maisels MJ. A clinical trial of fiberoptic phototherapy vs conventional phototherapy. Am J Dis Child 1992; 146:235. Vreman HJ, Wong RJ, Stevenson DK, et al. Light-emitting diodes: a novel light source for phototherapy. Pediatr Res 1998; 44:804. Seidman DS, Moise J, Ergaz Z, et al. A new blue light-emitting phototherapy device: a prospective randomized controlled study. J Pediatr 2000; 136:771. Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev 2011; :CD Tridente A, De Luca D. Efficacy of light-emitting diode versus other light sources for treatment of neonatal hyperbilirubinemia: a systematic review and meta-analysis. Acta Paediatr 2012; 101:458. Bhutani VK, Committee on Fetus and Newborn, American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2011; 128:e1046. Morris BH, Tyson JE, Stevenson DK, et al. Efficacy of phototherapy devices and outcomes among extremely low birth weight infants: multi-center observational study. J Perinatol 2013; 33:126.