Neonatal Jaundice Treatment & Management Author: Thor WR Hansen, MD, PhD, MHA, FAAP; Chief Editor: Ted Rosenkrantz, MD

Medical CarePhototherapy, intravenous immune globulin (IVIG), and exchange transfusion are the most widely used therapeutic modalities in infants with neonatal jaundice. Although medications that impact bilirubin metabolism have been used in studies, drugs are not ordinarily used in unconjugated neonatal hyperbilirubinemia.

Phototherapy

Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia. [3] This therapeutic principle was discovered rather serendipitously in England in the 1950s and is now arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in newborns.

Phototherapy is effective because 3 reactions can occur when bilirubin is exposed to light, as follows:

Initially, photooxidation was believed to be responsible for the beneficial effect of phototherapy. However, although bilirubin is bleached through the action of light, the process is slow and is now believed to contribute only minimally to the therapeutic effect of phototherapy.

Configurational isomerization is a very rapid process that changes some of the predominant 4Z,15Z bilirubin isomers to water-soluble isomers in which one or both of the intramolecular bonds are opened (E,Z; Z,E; or E,E). In human infants, the 4Z,15E isomer predominates, and, at equilibrium conditions, the isomer constitutes about 20-25% of circulating bilirubin after a few hours of phototherapy. [32] This proportion is not significantly influenced by the intensity of light, nor by the character of the light source or use of "double phototherapy." [32]  Data have shown that formation of photoisomers is significant after as little as 15 minutes of phototherapy. [32]  More recent studies suggest that the initial rate of isomerization is inversely related to the hemoglobin level. [32]

Structural isomerization consists of intramolecular cyclization, resulting in the formation of lumirubin. This process is enhanced by increasing the intensity of light. During phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin concentration.

The photoisomers of bilirubin are excreted in bile and, to some extent, in urine. The half-life of lumirubin in serum is much shorter than that in E isomers, and lumirubin is the primary pigment found in bile during phototherapy.

Bear in mind when initiating phototherapy that lowering of the total serum bilirubin concentration may be only part of the therapeutic benefit. Because photoisomers, by virtue of their water-soluble nature, should not be able to cross the blood-brain barrier, phototherapy may reduce the risk of bilirubin-induced neurotoxicity as soon as the lights are turned on. At any given total serum bilirubin concentration, the presence of 20-25% of photoisomers means that only 75-80% of the total bilirubin may be present in a form that can enter the brain. Please note that although theoretically coherent, no experimental data support this speculation.

Phototherapy can be administered in a number of ways. To understand the benefits and limitations of the various approaches, some basic principles regarding wavelength and types of light are discussed below with comments and suggestions regarding each system.

First, wavelength must be considered. Bilirubin absorbs light primarily around 450-460 nm. However, the ability of light to penetrate skin is also important; longer wavelengths penetrate better. Thus, lamps with output predominantly in the blue region of the spectrum (460-490 nm) are probably most effective. In practice, light is used in the white, blue, turquoise, and green wavelengths.

Second, previously a dose-response relationship was thought to exist between the amount of irradiation and reduction in serum bilirubin up to an irradiation level of 30-40 µW/cm2/nm. Many older phototherapy units deliver much less energy, some at or near the minimally effective level, which appears to be approximately 6 µW/cm2/nm. On the other hand, newer phototherapy units, when properly configured and with the use of reflecting blankets and curtains may deliver light energy above 40 µW/cm2/nm. Recent data do not confirm that there really is a saturation level.[33] Thus, the relationship between irradiance and the 24-hour decrement in total serum bilirubin was linear up to 55 μW/cm2, and with no evidence of a saturation point.

Third, the energy delivered to the infant's skin decreases with increasing distance between the infant and the light source. This distance should not be greater than 50 cm (20 in) and can be less (down to 10 cm) provided the infant's temperature is monitored.

Fourth, the efficiency of phototherapy depends on the amount of bilirubin that is irradiated. Irradiating a large skin surface area is more efficient than irradiating a small area, and the efficiency of phototherapy increases with serum bilirubin concentration.

Fifth, the nature and character of the light source may affect energy delivery. Irradiation levels using quartz halide spotlights are maximal at the center of the circle of light and decrease sharply towards the perimeter of the circle. Large infants and infants who can move away from the circle's center may receive less efficient phototherapy.

Although green light theoretically penetrates the skin better, it has not been shown unequivocally to be more efficient in clinical use than blue or white light. Because green light makes babies look sick and is unpleasant to work in, green light has not gained widespread acceptance.

Blue fluorescent tubes are widely used for phototherapy. Narrow-spectrum blue lamps (special blue) appear to work best, while ordinary blue fluorescent lamps are probably equivalent to standard white daylight lamps. Blue lights may cause discomfort in hospital staff members, which can be ameliorated by mixing blue and white tubes in the phototherapy unit.

White (daylight) fluorescent tubes are less efficient than special blue lamps; however, decreasing the distance between infants and lamps can compensate for the lower efficiency. Use of reflecting materials also helps. Thus, in LMICs where the cost of special blue lamps may be prohibitive, efficient phototherapy is accomplished with white lamps.

White quartz lamps are an integral part of some radiant warmers and incubators. They have a significant blue component in the light spectrum. When used as spotlights, the energy field is strongly focused towards the center, with significantly less energy delivered at the perimeter, as discussed above.

Quartz lamps are also used in single or double banks of 3-4 bulbs attached to the overhead heat source of some radiant warmers. The energy field delivered by these is much more homogeneous than that of spotlights, and the energy output is reasonably high. However, because the lamps are fixed to the overhead heater unit, the ability to increase energy delivery by moving lights closer to infants is limited.

Fiberoptic lights are also used in phototherapy units. These units deliver high energy levels, but because spectral power (ie, irradiance multiplied by the size of the irradiated area) is related to the size of the lighted field, the smaller "pads" are less efficient than larger wrap-around blankets. Drawbacks of fiberoptic phototherapy units may include noise from the fan in the light source and a decrease of delivered energy with aging and/or breakage of the optic fibers. Some new fiberoptic units now incorporate photodiodes as a light source. Advantages of fiberoptic phototherapy include the following:

Low risk of overheating the infant No need for eye shields Ability to deliver phototherapy with the infant in a bassinet next to the mother's bed Simple deployment for home phototherapy The possibility of irradiating a large surface area when combined with conventional overhead

phototherapy units (double/triple phototherapy)Light-emitting diode (LED) lights are found in most newer phototherapy units. Advantages include low power consumption, low heat production, and a much longer life span of the light-emitting units (20,000 hours) compared with older light sources. Blue LED lights have a narrow spectral band of high-intensity light that overlaps the absorption spectrum of bilirubin. Trials comparing LED phototherapy to other light sources were recently reviewed by the Cochrane Collaboration and by Tridente and DeLuca. The authors of these reviews conclude that the efficacy of LED lights in reducing total serum bilirubin levels is comparable to that of conventional light sources (fluorescent or halogen lamps).[34, 35]  Formation of bilirubin photoisomers also appears comparable between LEDs and blue fluorescent lamps.[32]

"Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy units to treat the same patient, has often been used in the treatment of infants with very high levels of serum bilirubin. The studies that appeared to show a benefit with this approach were performed with old, relatively low-yield

phototherapy units. Newer phototherapy units provide much higher levels of irradiance. Whether double or triple phototherapy also confers a benefit with the newer units, has not been tested in systematic trials. However, because recent studies appear to rule out the existence of a saturation point (see discussion above), the utility of double or triple phototherapy in extreme jaundice should not be discounted. [32]

The purpose of treating neonatal jaundice is to avoid neurotoxicity. Thus, indications for treatment have been based on clinical studies of infants who developed kernicterus. Historical data, much of which was derived from infants with hemolytic jaundice, appeared to suggest that total serum bilirubin levels greater than 350 µmol/L (20 mg/dL) were associated with increased risk of neurotoxicity, at least in full-term infants.

As treatment of premature infants became more widespread and increasingly successful during the last half of the 20th century, autopsy findings and follow-up data suggested that immature infants were at risk of bilirubin encephalopathy at lower total serum bilirubin levels than mature infants. Treatment was initiated at lower levels for these infants.

Until the 1940s, a truly effective treatment was not available. At that time, exchange transfusion was shown to be feasible and was subsequently used in the treatment of Rh-immunized infants with severe anemia, hyperbilirubinemia, or hydrops. However, exchange transfusion is not without risk for the infant, and only with the discovery of phototherapy did neonatal jaundice start to become an indication for treatment on a wider scale. Once phototherapy was shown to be an apparently innocuous treatment, lights were turned on at lower serum bilirubin values than those that had triggered exchange transfusion.

Exchange transfusion became the second-line treatment when phototherapy failed to control serum bilirubin levels. However, data have shown that treatment with IVIG in infants with Rh or ABO isoimmunization can significantly reduce the need for exchange transfusions.[36, 37] At the author's institution, a tertiary center where exchange transfusions used to be frequent, currently only 0-2 such procedures per year are performed, and IVIG has replaced exchange transfusion as the second-line treatment in infants with isoimmune jaundice. [38]  In a recent 1-year prospective national survey of NICU phototherapy practices in Norway, Mreihil and collaborators found that only 6 exchange transfusions had been performed in a birth population of 60.000 infants (Mreihil K et al, preliminary data).

Clearly, the scientific data on which current therapeutic guidelines are based have very significant shortcomings. Unfortunately, because the endpoint of bilirubin neurotoxicity is permanent brain damage, a randomized study to reassess the guidelines is ethically unthinkable.

In most neonatal wards, total serum bilirubin levels are used as the primary measure of risk for bilirubin encephalopathy. Numerous people would prefer to add a test for serum albumin at higher bilirubin levels because bilirubin entry into the brain, a sine qua non for bilirubin encephalopathy, increases when the bilirubin-albumin ratio exceeds unity. Tests for bilirubin-albumin binding or unbound bilirubin levels are used by some but have failed to gain widespread acceptance. New analytical tools for measurement of unbound bilirubin have greatly simplified the process, but the effect on clinical practice remains to be seen.

Numerous guidelines for the management of neonatal jaundice have been published, and even more appear to be in local use without submission for critical review. In a survey published in 1996, the author analyzed clinical practices in this field based on responses from 108 neonatal intensive care units (NICUs) worldwide. [39] The survey revealed a significant disparity in guidelines.

The image below shows a box-and-whisker plot of the range of serum bilirubin values that trigger phototherapy and exchange transfusion, respectively, in these NICUs. Evidently, an infant might receive an exchange transfusion in one NICU for a serum bilirubin level that would not trigger phototherapy in many other NICUs. This disparity illustrates how difficult it has been to translate clinical data into sensible treatment guidelines.

The graph represents indications for phototherapy and exchange transfusion in infants (with a birthweight of 3500 g) in 108 neonatal ICUs. The left panel shows the range of indications for phototherapy, whereas the right panel shows the indications for exchange transfusion. Numbers on the vertical axes are serum bilirubin concentrations in mg/dL (lateral) and mmol/L (middle). In the left panel, the solid line refers to the current recommendation of the American Academy of Pediatrics (AAP) for low-risk infants, the line consisting of long dashes (- - - - -) represents the level at which the AAP recommends phototherapy for infants at intermediate risk, and the line with short dashes (-----) represents the suggested intervention level for infants at high risk. In the right panel, the dotted line (......) represents the AAP suggested intervention level for exchange transfusion in infants considered at low risk, the line consisting of dash-dot-dash (-.-.-.-.) represents the suggested intervention level for exchange transfusion in infants at intermediate risk, and the line consisting of dash-dot-dot-dash (-..-..-..-) represents the suggested intervention level for infants at high risk. Intensive phototherapy is always recommended while preparations for exchange transfusion are in progress. The box-and-whisker plots show the following values: lower error bar = 10th percentile; lower box margin = 25th percentile; line transecting box = median; upper box margin = 75th percentile; upper error bar = 90th percentile; and lower and upper diamonds = 5th and 95th percentiles, respectively.

In 2004, the AAP published new guidelines for the management of hyperbilirubinemia in healthy full-term newborns.[40] These guidelines have been plotted on the image above.

The 2004 AAP guidelines represent a significant change from the 1994 guidelines. [40] Thus, the emphasis on preventive action and risk evaluation is much stronger. An algorithm aids in the assessment of risk and the decision about further management and follow-up (see the image below). The committee that wrote the guidelines has carefully assessed the strength of the scientific evidence on which the guidelines are based.

Algorithm for the management of jaundice in the newborn nursery.

Practitioners in North America are advised to follow the 2004 AAP guidelines. Although the 2004 AAP guidelines do not provide guidance for treatment of jaundice in the smaller and more premature/immature

infants, a group of US experts recently published their suggestions for management of jaundice in preterm infants younger than 35 weeks' gestation.[41]

Clinicians in different ethnic or geographic regions should consider tailoring these guidelines as pertinent to their own populations and must consider factors that are unique to their medical practice settings. Such factors may include racial characteristics, prevalence of congenital hemolytic disorders, prevalence of genetic variants, and environmental concerns. Such adaptation of guidelines should also take into consideration how healthcare delivery systems are organized, as this is likely affect both in-hospital delivery of care as well as follow-up. At present, the wisest course of action may be to apply local guidelines, assuming that these have been successful in the prevention of kernicterus..

With this background and the clear understanding that this is meant only as an example, the image below shows the chart currently in use in all pediatric departments in Norway. These guidelines are the result of a 2006 consensus in the Neonatal Subgroup of the Norwegian Pediatric Society. The similarities between the Norwegian chart and the 2004 AAP guidelines are apparent.

Guidelines for management of neonatal jaundice currently in use in all pediatric departments in Norway. The guidelines were based on previously used charts and were created through a consensus process in the Neonatal Subgroup of the Norwegian Pediatric Society. These guidelines were adopted as national at the fall meeting of the Norwegian Pediatric Society. The reverse side of the chart contains explanatory notes to help the user implement the guidelines. A separate information leaflet for parents was also created.

The Norwegian chart suggests intervention limits for premature/immature infants. For infants of less than 1000 gram birthweight, these guidelines propose starting phototherapy at 100 µmol/L (6 mg/dL) at age 24 hours, increasing gradually to 150 µmol/L (8.8 mg/dL) at age 4 days, and remaining steady thereafter at that level. This compares with a range of 85 µmol/L (5 mg/dL) to 171 µmol/L (10 mg/dL) used in a Neonatal Research Network (NRN) phototherapy trial in infants of less than 1000 gram birthweight. The intervention level depended on postnatal age and whether the infant was allocated to conservative or aggressive phototherapy. [42]

In a post hoc analysis of the NRN data, which compared infants who had not received any phototherapy with those who had received such treatment, the subgroup of infants with birthweights of 501-750 grams who had not received any phototherapy had a significantly higher rate of mental developmental index of less than 50.[43] However, it should be noted that in the original trial analysis, mortality in the aggressive phototherapy group at 501- to 750-g birthweight was 5 percentage points higher than in the conservative group, which, although not significant with the statistical approach chosen for analysis, appeared to offset the possible developmental gain

in survivors.[42] Recently these data were reanalyzed using Bayesian statistics[44] and showed that aggressive phototherapy significantly increased the risk of death in the sickest (being on mechanical ventilation at 24 h) and smallest infants (≤750 g birthweight), while at the same time reducing impairment/severe impairment.

Key points in the practical execution of phototherapy include maximizing energy delivery and the available surface area. Also consider the following:

The infant should be naked except for diapers (use these only if deemed absolutely necessary and cut them to minimum workable size), and the eyes should be covered to reduce risk of retinal damage.

Check the distance between the infant's skin and the light source. With fluorescent lamps, the distance should be no greater than 50 cm (20 in). This distance may be reduced down to 10-20 cm (4-8 in) if temperature homeostasis is monitored to reduce the risk of overheating. Note that this does not apply to quartz lamps.

Cover the inside of the bassinet with reflecting material; white linen works well. Hang a white curtain around the phototherapy unit and bassinet. These simple expedients can multiply energy delivery by several fold.

When using spotlights, ensure that the infant is placed at the center of the circle of light, since photoenergy drops off towards the circle's perimeter. Observe the infant closely to ensure that the infant doesn't move away from the high-energy area. Spotlights are probably more appropriate for small premature infants than for larger near-term infants.

Older data suggested that phototherapy was associated with increased insensible water loss; therefore, many clinicians have routinely added a certain percentage to the infant's estimated basic fluid requirements. Newer data suggest that if temperature homeostasis is maintained, fluid loss is not significantly increased by phototherapy. At the author's institution, routine fluid supplementation for infants under phototherapy has not been used for more than a decade and is not recommended in national guidelines. Rather, the infant is monitored for weight loss, urine output, and urine specific gravity. Fluid intake is adjusted accordingly. In infants who are orally fed, the preferred fluid is milk because it serves as a vehicle to transport bilirubin out of the gut.

Timing of follow-up serum bilirubin testing must be individualized. In infants admitted with extreme serum bilirubin values (>500 µmol/L or 30 mg/dL), monitoring should occur every hour or every other hour. Reductions in serum bilirubin values of 85 µmol/L/h (5 mg/dL/h) have been documented under such circumstances. In infants with more moderate elevations of serum bilirubin, monitoring every 6-12 hours is probably adequate.

Expectations regarding efficacy of phototherapy must be tailored to the circumstances. In infants in whom serum bilirubin concentrations are still rising, a significant reduction of the rate of increase may be satisfactory. In infants in whom serum bilirubin concentrations are close to their peak, phototherapy should result in measurable reductions in serum bilirubin levels within a few hours. In general, the higher the starting serum bilirubin concentration, the more dramatic the initial rate of decline.

Discontinuation of phototherapy is a matter of judgment, and individual circumstances must be taken into consideration. In practice, phototherapy is discontinued when serum bilirubin levels fall 25-50 µmol/L (1.5-3 mg/dL) below the level that triggered the initiation of phototherapy. Serum bilirubin levels may rebound after treatment has been discontinued, and follow-up tests should be obtained within 6-12 hours after discontinuation.

Indications for prophylactic phototherapy are debatable. Phototherapy probably serves no purpose in an infant who is not clinically jaundiced. In general, the lower the serum bilirubin level, the less efficient the phototherapy. It seems more rational to apply truly effective phototherapy once serum (and skin) bilirubin has reached levels at which photons may do some good.

Wherever phototherapy is offered as a therapeutic modality, a device for measuring the irradiance delivered by the equipment used should be readily at hand. This assists in configuring the phototherapy set-up to deliver optimal efficiency. Some recommend this routinely, every time phototherapy is initiated, and use this as a tool to focus staff attention on maximizing energy delivery.

Generally, phototherapy is very safe and may have no serious long-term effects in neonates; however, the following adverse effects and complications have been noted:

Insensible water loss may occur, but data suggest that this issue is not as important as previously believed. Rather than instituting blanket increases of fluid supplements to all infants receiving phototherapy, the author recommends fluid supplementation tailored to the infant's individual needs, as measured through evaluation of weight curves, urine output, urine specific gravity, and fecal water loss.

As noted above, a reanalysis of the NRN trial of ”aggressive” versus ”conservative” phototherapy in premature infants of less than 1000 g birthweight showed that mortality was increased in the subgroup of sick 501- to 750-g birthweight infants receiving aggressive' phototherapy. [44] In a recent recommendation for treatment of hyperbilirubinemia in premature infants younger than 35 weeks’ gestation, the authors propose that initial irradiance should be reduced in the most vulnerable infants. [41] However, as pointed out in an editorial to this paper, extant data seem to be more compatible with the interpretation that duration of phototherapy is more dangerous than irradiance levels. [45] Thus, it may be argued that phototherapy should be short and efficient rather than less efficient and of longer duration. This question is still open to interpretation and discussion.

Phototherapy may be associated with loose stools. Increased fecal water loss may create a need for fluid supplementation.

Retinal damage has been observed in some animal models during intense phototherapy. In an NICU environment, infants exposed to higher levels of ambient light were found to have an increased risk of retinopathy. Therefore, covering the eyes of infants undergoing phototherapy with eye patches is routine. Care must be taken lest the patches slip and leave the eyes uncovered or occlude one or both nares.

The combination of hyperbilirubinemia and phototherapy can produce DNA-strand breakage and other effects on cellular genetic material. In vitro and animal data have not demonstrated any implication for treatment of human neonates. However, because most hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding may be moot.

Skin blood flow is increased during phototherapy, but this effect is less pronounced in modern servocontrolled incubators. However, redistribution of blood flow may occur in small premature infants. An increased incidence ofpatent ductus arteriosus (PDA) has been reported in these circumstances. The appropriate treatment of PDA has been reviewed. [46]

Hypocalcemia  appears to be more common in premature infants under phototherapy lights. This has been suggested to be mediated by altered melatonin metabolism. Concentrations of certain amino acids in total parenteral nutrition solutions subjected to phototherapy may deteriorate. Shield total parenteral nutrition solutions from light as much as possible.

Regular maintenance of the equipment is required because accidents have been reported, including burns resulting from a failure to replace UV filters.

Intravenous immune globulin

In relatively recent years, IVIG has been used for numerous immunologically mediated conditions. In the presence of Rh, ABO, or other blood group incompatibilities that cause significant neonatal jaundice, IVIG has been shown to significantly reduce the need for exchange transfusions. However, it must be recognized that some studies have failed to show efficacy. The reasons for this discrepancy have not been explained, but it should be noted that in the studies that failed to show significant effects, IVIG was used more or less prophylactically for all apparently immunized infants, whereas in the studies that reported benefits IVIG was used exclusively as a rescue therapy in infants headed for exchange transfusion. Also, one can speculate whether differences in the origin and characteristics of the IVIG preparation might play a role. If one particular IVIG preparation appears not to work, it may be worthwhile to try IVIG from a different source/manufacturer.

The 2004 AAP guidelines suggest a dose range for IVIG of 500-1000 mg/kg.[40]

The author routinely uses 500 mg/kg infused intravenously over a period of 2 hours for Rh or ABO incompatibility when the total serum bilirubin levels approach or surpass the exchange transfusions limits. The author has, on occasion, repeated the dose 2-3 times. In most cases, when this is combined with intensive phototherapy, avoiding exchange transfusion is possible. In the authors' institution, with about 750 NICU admissions per year, the use of exchange transfusions has decreased to 0-2 per year following the implementation of IVIG therapy for Rh and ABO isoimmunization.[38] The author does not use IVIG in the presence ofhydrops. Anecdotally, IVIG appears less likely to be successful when the infant is anemic (Hb < 10 g/dL).

Exchange transfusion

Exchange transfusion is indicated for avoiding bilirubin neurotoxicity when other therapeutic modalities have failed or are not sufficient. In addition, the procedure may be indicated in infants with erythroblastosis who present with severe anemia, hydrops, or both, even in the absence of high serum bilirubin levels.

Exchange transfusion was once a common procedure. A significant proportion was performed in infants with Rh isoimmunization. Immunotherapy in Rh-negative women at risk for sensitization has significantly reduced the incidence of severe Rh erythroblastosis. Therefore, the number of infants requiring exchange transfusion is now much smaller, and even large NICUs may perform only a few procedures per year. As mentioned previously, the incidence of infants requiring exchange transfusion in Norway was in a prospective survey shown to be only 0.01% (Mrehil K et al, preliminary data). ABO incompatibility has become the most frequent cause of hemolytic disease in industrialized countries.

Early exchange transfusion has usually been performed because of anemia (cord hemoglobin < 11 g/dL), elevated cord bilirubin level (>70 µmol/L or 4.5 mg/dL), or both. A rapid rate of increase in the serum bilirubin level (>15-20 µmol/L /h or 1 mg/dL/h) was an indication for exchange transfusion, as was a more moderate rate of increase (>8-10 µmol/L/h or 0.5 mg/dL/h) in the presence of moderate anemia (11-13 g/dL).

The serum bilirubin level that triggered an exchange transfusion in infants with hemolytic jaundice was 350 µmol/L (20 mg/dL) or a rate of increase that predicted this level or higher. Strict adherence to the level of 20 mg/dL has been jocularly referred to as vigintiphobia (fear of 20).

Currently, most experts encourage an individualized approach, recognizing that exchange transfusion is not a risk-free procedure, that effective phototherapy converts 15-25% of bilirubin to nontoxic isomers, and that transfusion of a small volume of packed red cells may correct anemia. Administration of IVIG (500 mg/kg) has been shown to reduce red cell destruction and to limit the rate of increase of serum bilirubin levels in infants with Rh and ABO isoimmunization (see above).

Current AAP guidelines distinguish between 3 risk categories: low, intermediate, and high. [40] These correspond to 3 levels of suggested intervention, which increase from birth and plateau at age 4 days. Naturally, intervention levels associated with exchange transfusion are higher than those for phototherapy. Intensive phototherapy is strongly recommended in preparation for an exchange transfusion. In fact, intensive phototherapy should be performed on an emergency basis in any infant admitted for pronounced jaundice; do not await laboratory test results in these cases. Phototherapy has minimal side effects in this scenario, whereas the waiting period for laboratory test results and blood for exchange can take hours and could constitute the difference between intact survival and survival with kernicterus. If phototherapy does not significantly lower serum bilirubin levels, exchange transfusion should be performed.

Many believe that hemolytic jaundice represents a greater risk for neurotoxicity than nonhemolytic jaundice, although the reasons for this belief are not intuitively obvious, assuming that total serum bilirubin levels are equal. In animal studies, bilirubin entry into or clearance from the brain was not affected by the presence of hemolytic anemia.

The technique of exchange transfusion, including adverse effects and complications, is discussed extensively elsewhere. For more information, please consult Hemolytic Disease of Newborn.

Management of infants with extreme jaundice

Numerous cases have been reported in which infants have been readmitted to hospitals with extreme jaundice. In some cases, significant delays have occurred between the time the infant was first seen by medical personnel and the actual commencement of effective therapy. [47]

Any infant who returns to the hospital with significant jaundice within the first 1-2 weeks of birth should be immediately triaged with measurement of transcutaneous bilirubin. High values should result in immediate initiation of treatment. If such a measuring device is not available, or if the infant presents with any kind of neurological symptoms, the infant should be put in maximally efficient phototherapy as an emergency procedure, preferably by fast-tracking the infant to a NICU. Waiting for laboratory results is not necessary before instituting such therapy because no valid contraindications to phototherapy are possible in this scenario. Plans for an exchange transfusion do not constitute an argument for delaying or not performing phototherapy. Immediate benefit may be obtained within minutes, as soon as conversion of bilirubin into water-soluble photoisomers is measurable (see discussion above).

The need for intravenous hydration in such infants has been discussed. In the absence of clinical signs of dehydration, no evidence suggests that overhydration is helpful. If the infant is dehydrated, hydration should be given as clinically indicated. However, if the infant is able to tolerate oral feeding, oral hydration with a breast

milk substitute is likely to be superior to intravenous hydration because it reduces enterohepatic circulation of bilirubin and helps "wash" bilirubin out of the bowel.

Every hospital in which babies are delivered, or which has an emergency department in which infants may be seen, should develop a protocol and triage algorithm for rapid evaluation and management of jaundiced infants. The objective of such a protocol should be rapid recognition of risk severity and reduction in the time to initiate appropriate treatment.

Infants admitted with signs of intermediate to advanced acute bilirubin encephalopathy (ABE) are in urgent need of treatment because reversibility may be possible, even in such cases. The term "crash-cart approach" has been used as a recommendation in such cases. The author, together with other European colleagues, has published a series that included 6 patients with signs of ABE who were urgently managed and appear to have escaped neurologic sequelae.[48]

In a review of the Kernicterus Registry, full recovery was noted in 8 of 11 cases treated with a crash-cart approach, which included effective phototherapy plus exchange transfusion; full recovery was not noted in cases in which delays had occurred.[47] In the Kernicterus Registry, reversal was not observed in cases treated with only phototherapy; the authors strongly recommend that exchange transfusion be performed in such cases.[47] In the European study, reversal was also seen in 2 patients who did not receive exchange transfusion.[48] In one of these cases, IVIG was used in lieu of exchange transfusion; in the other case, intensive phototherapy and intravenous albumin were used.

Other therapies

In infants with breast milk jaundice, interruption of breastfeeding for 24-48 hours and feeding with breast milk substitutes often helps to reduce the bilirubin level. Evidence suggests that the simple expedient of supplementing feeds of breast milk with 5 mL of a breast milk substitute reduces the level and duration of jaundice in breast milk–fed infants. Because this latter intervention causes less interference with the establishment of the breastfeeding dyad, the author prefers to use this approach rather than complete interruption of breast feeding in most cases.

Oral bilirubin oxidase can reduce serum bilirubin levels, presumably by reducing enterohepatic circulation; however, its use has not gained wide popularity. The same may be said for agar or charcoal feeds, which act by binding bilirubin in the gut. Bilirubin oxidase is not available as a drug, and for this reason, its use outside an approved research protocol probably is proscribed in many countries.

Prophylactic treatment of Rh-negative women with Rh immunoglobulin has significantly decreased the incidence and severity of Rh-hemolytic disease.